Conditions: Cough
Keywords: GSK2798745, efficacy, safety, chronic cough, crossover study
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 17
Healthy volunteers: no

Brief summary:
GSK2798745 is a potent and selective transient receptor potential vanilloid 4 (TRPV4) channel blocker being investigated for the treatment of chronic cough. This is a multi-center, randomized, placebo-controlled, double-blind, two-period crossover study with a purpose to evaluate efficacy and safety of GSK2798745. Each subject will have 2 treatment periods, and will be randomized to one of the following treatments in each period: A) Placebo matching to GSK2798745 once daily for 7 days. B) 4.8 milligrams (mg) GSK2798745 on Day 1, followed by 2.4 mg GSK2798745 once daily for 6 days. There will be a washout period of 14 to 21 days between the treatment periods. A maximum of 48 subjects will be enrolled in the study and the total duration of participation in the study will be maximum of 10 and a half weeks including follow-up visit.

Detailed description:

Arms:
arm 1: Subjects will receive GSK2798745 matching placebo tablets (two tablets on Day 1 followed by one tablet once daily for 6 days), via oral route (treatment period of total 7 days). After a washout period of 14 to 21 days, subjects will then receive 4.8 mg (two tablets of 2.4 mg) GSK2798745 on Day 1, followed by 2.4 mg GSK2798745 tablets once daily for 6 days via oral route (treatment period of total 7 days). arm 2: Subjects will receive 4.8 mg (two tablets of 2.4 mg) GSK2798745 on Day 1, followed by 2.4 mg GSK2798745 tablets once daily for 6 days via oral route (treatment period of total 7 days). After a washout period of 14 to 21 days, subjects will then receive GSK2798745 matching placebo tablets (two tablets on Day 1 followed by one tablet once daily for 6 days), via oral route (treatment period of total 7 days).

Interventions: intervention 1: GSK2798745 intervention 2: Placebo
Intervention descriptions: intervention 1: GSK2798745 tablets will be available as white to almost white, round, film-coated tablets (micronized active pharmaceutical ingredient \[API\]) to be taken with a glass of water (approximately 240 mL). intervention 2: Placebo tablets will be available as white to almost white, round, film-coated tablets to be taken with a glass of water (approximately 240 mL).

Protocol document:
Prot_000.pdf: 
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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.
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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.

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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.

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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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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 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.
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 8.1.2 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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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 /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 
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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.
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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
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 8.1.2 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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SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
207702
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Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for a placebo-controlled, 
double-blind (sponsor open), randomised, crossover study to 
assess the efficacy, safety, and tolerability of GSK2798745 in
participants with chronic cough
Compound Number 
:
GSK2798745
Effective Date 
:
07-SEP-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 207702

This RAP is intended to describe the efficacy, safety and pharmacokinetic analyses 
required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Interim Analysis (IA) and Statistical Analysis Complete (SAC) deliverables.
RAP Author(s):
Approver
Date
Approval Method
Not Applicable
Not Applicable
Principal Statistician
(Respiratory, Clinical Statistics)
29-AUG-2018
Pharma TMF
Senior Director 
(Respiratory, Clinical Pharmacology)
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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RAP Team Approvals:
Approver
Date
Approval Method
03-SEP-2018
Pharma TMF
Clinical Development Manager
(CPSSO)
29-AUG-2018
Pharma TMF
Clinical Development Director
(Respiratory TAU)
02-SEP-2018
Pharma TMF
Project Physician (Respiratory TAU)
29-AUG-2018
Pharma TMF
Data Manager (CPSSO)
Programming Manager (Respiratory, 
Clinical Programming)
29-AUG-2018
Pharma TMF
SERM Director (GCSP)
07-SEP-2018
Pharma TMF
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
05-SEP-2018
Pharma TMF
Director 
(Respiratory, Clinical Statistics)
30-AUG-2018
Pharma TMF
Programming Manager
(Respiratory, Clinical Programming)
 
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................6
2.3.
Study Design ................................................................................................7
2.4.
Statistical Analyses.......................................................................................7
3.
PLANNED ANALYSES ............................................................................................9
3.1.
Interim Analyses ...........................................................................................9
3.1.1.
Review of the Interim Analysis Results ........................................10
3.1.2.
Conditional Probabilities to Support Sample Size Re-
estimations ..................................................................................12
3.2.
Final Analyses ............................................................................................13
4.
ANALYSIS POPULATIONS ...................................................................................14
4.1.
Protocol Deviations.....................................................................................14
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................15
5.1.
Study Treatment & Sub-group Display Descriptors.....................................15
5.2.
Baseline Definitions ....................................................................................15
5.3.
Multicentre Studies .....................................................................................16
5.4.
Examination of Covariates, Other Strata and Subgroups............................16
5.5.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................17
6.
STUDY POPULATION ANALYSES .......................................................................18
6.1.
Overview of Planned Study Population Analyses........................................18
7.
EFFICACY ANALYSES..........................................................................................19
7.1.
Primary Efficacy Analyses ..........................................................................19
7.1.1.
Endpoint / Variables.....................................................................19
7.1.2.
Missing Data Imputation (0-10h)..................................................19
7.1.3.
Summary Measure ......................................................................20
7.1.4.
Population of Interest...................................................................20
7.1.5.
Statistical Analyses / Methods .....................................................20
7.1.5.1.
Statistical Methodology Specification..........................21
7.2.
Exploratory Efficacy Analyses.....................................................................23
7.2.1.
Endpoint / Variables.....................................................................23
7.2.1.1.
Total Cough Counts over 24 Hours ............................23
7.2.1.2.
Cough Severity and Urge (VAS).................................23
7.2.1.3.
Leicester Cough Questionnaire (LCQ)........................23
7.2.2.
Missing Data Imputation ..............................................................24
7.2.3.
Summary Measure ......................................................................25
7.2.4.
Population of Interest...................................................................25
7.2.5.
Statistical Analyses / Methods .....................................................26
7.2.5.1.
Statistical Methodology Specification..........................26
 
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8.
SAFETY ANALYSES .............................................................................................30
8.1.
Adverse Events Analyses ...........................................................................30
8.2.
Clinical Laboratory Analyses.......................................................................30
8.3.
Other Safety Analyses ................................................................................30
9.
PHARMACOKINETIC ANALYSES.........................................................................31
9.1.
Primary Pharmacokinetic Analyses.............................................................31
9.1.1.
Endpoint / Variables.....................................................................31
9.1.1.1.
Drug Concentration Measures....................................31
9.1.1.2.
Derived Pharmacokinetic Parameters.........................31
9.1.2.
Population of Interest...................................................................31
9.1.3.
Statistical Analyses / Methods .....................................................31
9.2.
Secondary Pharmacokinetic Analyses........................................................31
9.2.1.
Endpoint / Variables.....................................................................31
9.2.1.1.
Drug Concentration Measures....................................31
9.2.1.2.
Derived Pharmacokinetic Parameters.........................32
9.2.2.
Population of Interest...................................................................32
9.2.3.
Statistical Analyses / Methods .....................................................32
10. POPULATION PHARMACOKINETIC (POPPK) AND 
PHARMACODYNAMIC ANALYSES.......................................................................33
10.1.
Statistical Analyses / Methods ....................................................................33
11. REFERENCES.......................................................................................................34
12. APPENDICES........................................................................................................35
12.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................35
12.2.
Appendix 2: Schedule of Activities ..............................................................36
12.2.1.
Protocol Defined Schedule of Events...........................................36
12.3.
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................40
12.3.1.
Study Phases and Treatment Emergent Rules for AEs................40
12.3.1.1.
Study Phases for Concomitant Medication .................40
12.4.
Appendix 4: Data Display Standards & Handling Conventions....................41
12.4.1.
Reporting Process .......................................................................41
12.4.2.
Reporting Standards....................................................................41
12.4.3.
Reporting Standards for Pharmacokinetic Data ...........................42
12.5.
Appendix 5: Derived and Transformed Data ...............................................43
12.5.1.
General........................................................................................43
12.5.2.
Study Population..........................................................................43
12.5.3.
Efficacy........................................................................................44
12.5.3.1.
Cough Count SI and A&R Dataset 
Specifications .............................................................44
12.5.3.2.
Cough Count Missing Data Period Algorithms............51
12.5.3.3.
Cough Count Imputation Derivations ..........................54
12.5.4.
Pharmacokinetic ..........................................................................54
12.5.5.
Population Pharmacokinetic (PopPK) ..........................................54
12.5.6.
Operating Characteristics of Decision Criteria Based on 
Conditional Probabilities ..............................................................54
12.6.
Appendix 6: Reporting Standards for Missing Data.....................................58
12.6.1.
Premature Withdrawals................................................................58
 
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12.6.2.
Handling of Missing Data.............................................................58
12.6.2.1.
Handling of Missing and Partial Dates ........................58
12.7.
Appendix 7: Values of Potential Clinical Importance ...................................59
12.7.1.
Laboratory Values........................................................................59
12.7.2.
ECG.............................................................................................60
12.7.3.
Vital Signs....................................................................................60
12.8.
Appendix 8: Population Pharmacokinetic (PopPK) Analyses ......................61
12.8.1.
Population Pharmacokinetic (PopPK) Methodology.....................61
12.8.1.1.
Software.....................................................................61
12.8.1.2.
Outline........................................................................61
12.8.2.
Population Pharmacokinetic (PopPK) Dataset 
Specification ................................................................................61
12.8.2.1.
Data Specification ......................................................61
12.8.2.2.
Dataset Variable Conventions ....................................61
12.9.
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses ......................65
12.9.1.
Pharmacokinetic / Pharmacodynamic Methodology.....................65
12.9.1.1.
Exposure-Response Relationship...............................65
12.9.2.
Pharmacokinetic / Pharmacodynamic Dataset 
Specification ................................................................................65
12.9.2.1.
Data Specification ......................................................65
12.9.2.2.
Dataset Variable Conventions ....................................65
12.10. Appendix 10: Abbreviations & Trade Marks ................................................69
12.10.1. Abbreviations...............................................................................69
12.10.2. Trademarks .................................................................................70
12.11. Appendix 11: List of Data Displays..............................................................71
12.11.1. Data Display Numbering..............................................................71
12.11.2. Mock Example Shell Referencing ................................................71
12.11.3. Deliverables.................................................................................71
12.11.4. Study Population Tables..............................................................72
12.11.5. Efficacy Tables ............................................................................74
12.11.6. Efficacy Figures ...........................................................................76
12.11.7. Safety Tables...............................................................................81
12.11.8. Pharmacokinetic Tables...............................................................83
12.11.9. Pharmacokinetic Figures .............................................................85
12.11.10.ICH Listings .................................................................................88
12.11.11.Non-ICH Listings..........................................................................91
12.12. Appendix 12: Example Mock Shells for Data Displays ................................93
 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 207702:
Revision Chronology:
2017N319286_00
31-MAY-2017
Original
2017N319286_01
09-OCT-2017
Removal of Simplified Nutritional Appetite Questionnaire (SNAQ).
2017N319286_02
22-NOV-2017
Addition of CSSRS at follow-up and updates to emergency 
unblinding text on request of MHRA.
2017N319286_03
25-JUN-2018
Increasing the upper BMI limit and removing the upper limit for 
FEV1
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol (Dated: 31/MAY/2017), amendment 01 (Dated: 09/OCT/2017), 
amendment 02 (Dated: 22/NOV/2017) and amendment 03 (Dated: 25/JUN/2018)
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

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 Objectives
Secondary Endpoints

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 Objectives
Exploratory Endpoints

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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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

Multi-centre

Randomised

Double-blind (sponsor open)

Placebo-controlled

Two-period crossover, each period 7 days with 14-21 day washout between 
periods

Study duration maximum of 10.5 weeks

Coughs recorded using 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
Dosing

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
Time & 
Events

Appendix 2: Schedule of Activities
Treatment 
Assignment

Treatment A: Placebo tablets for 7 days

Treatment B: GSK2798745 tablets for 7 days

Participants will be randomised to one of two treatment sequences AB or BA
Interim 
Analysis

Planned after at least 12 participants have completed both dosing periods.  
Following the results of the interim analysis, the study may be stopped for 
futility, or a re-estimation of the sample size will take place
2.4.
Statistical Analyses
The study is designed to estimate the effect of GSK2798745 relative to placebo on day-
time cough counts following seven days of dosing.  Day-time cough count totals will be 
 
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derived from the total number of coughs during the first 10 hours following dosing, 
during which 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 a reduction 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), with corresponding 90% credible interval. 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 is less than 0.7 will be obtained and will be 
referred to as PP (ratio<0.7).
 
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3.
PLANNED ANALYSES
3.1.
Interim Analyses
An interim analysis is planned after at least 12 participants have completed both dosing 
periods and will be based on day-time 10h total cough count data, as well as supporting 
PK data, if required.  PK data will remain blinded if assessed as part of any interim 
analyses.
An ongoing review will take place to ensure that compliance to study drug and validity of 
cough data are acceptable for the interim analysis.  For cough data to be valid, at least 
60% of the recording time during the first 10 hours must be available, See Section 7.1.2.  
If compliance or cough data are deemed to be invalid for the first 12 participants who 
have completed both dosing periods, then consideration will be given to waiting for 
additional participants to meet the minimum of 12 participants with valid data for 
analysis.
The primary objectives of the interim analysis are to:
i)
Stop the study on the grounds of futility
ii) Re-estimate the sample size based on the treatment effect and variability observed 
at the time of the interim.  
As the study is double blind (sponsor-open), the results will be made available to a core 
subset of the GSK study team, who will review the data (treatment level only), before 
making a decision on whether to stop the study for futility or adjust the sample size.  
Decisions from the interim analyses and details of members of the GSK study team who 
reviewed the results, will be documented in the interim results meeting minutes. Any 
adjustment to the sample size will be communicated to the sites.
The sample size re-estimation will be supplemented by deriving conditional probabilities. 
As a result of this supportive information, 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.
The interim analysis will be performed by GSK Clinical Statistics and only the 
responsible statistician(s) (including QC statistician(s)) and programmers will have
access to the study reporting area where the individual participant data which will be 
unblinded for the interim analyses.  Unblinded treatment sequences will only be made 
available for participants who will be included in the interim analysis.  A list of 
randomisation numbers of those who have completed the relevant treatment periods for 
the interim analysis will need to be provided by the study manager or designee, to release 
the treatment sequence codes.  
The interim analysis will use clean efficacy data (cough count data provided by 
Vitalograph and subject to QC and cleaning processes) and will be supplemented by the 
following in stream data from the eCRF for use in standard HARP programs; cough dates 
and times, exposure and compliance information, demography data and stratification 
responses.  SI datasets for the specified eCRF data will be provided by Data Management 
 
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to a level as clean as possible at the time of the interim, with data as complete as possible 
(up to Period 2 Day 8) for the randomised participants who will be included in the interim 
analysis.  Statistics and programming will cut the data (subset) based on the list of 
randomised participants available for the interim analysis.
It is expected that outputs from the Interim Analysis will not be required for the Clinical 
Pharmacology Study Report (CPSR) as only final data will be formally reported.  The 
CPSR will provide brief details that an interim analysis was performed and sample size 
subsequently increased or decreased.  
Details for the statistical analysis of total 10h day-time cough counts are provided in 
Section 7.1.5.  The proposed outputs to be provided for the interim analysis are as
follows, refer to Section 12.11 for further details and examples:

Summary of statistical analysis (including treatment ratio and 90% credible 
intervals along with posterior probabilities of interest, see example EF_T1).  A 
preliminary assessment of carry-over and/or period by treatment interaction will 
be investigated as part of this analysis.  The analysis will be based on imputed 10h 
totals (see Section 7.1.2).

Figure of treatment group geometric means and 95% CIs for both baseline and
Day 7 10h day-time cough counts (see example EF_F1)

Figure as above split by treatment period to assist with assessment of carryover 
and/or period by treatment interaction

Figure of overall hourly profiles (0-10h), geometric (or arithmetic dependent on
data) means 95% CIs for GSK2798745 vs Placebo at each hourly timepoint (see 
example EF_F2).
3.1.1.
Review of the Interim Analysis Results
Once the interim results are available, the following steps will be taken to support 
decision making moving forward.
1.
Assessment of results
The results from the interim analysis (as well as final analysis) will be compared with 
pre-defined criteria for a positive and negative study as follows:
The pre-defined criterion for a positive study is a posterior probability of more than 70% 
that the true treatment ratio (GSK2798745 / placebo) is less than 0.7, i.e. 
PP(ratio<0.7)>70%. 
The pre-defined criterion for a negative study is a posterior probability of less than 30% 
that the true treatment ratio (GSK2798745 / placebo) is less than 0.7, i.e. 
PP(ratio<0.7)<30%.
There is a grey area in which neither criterion is satisfied.
 
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2. Sample Size Re-estimation
A graphic will be produced displaying the conditional probability of achieving various 
sample sizes (see Section 3.1.2) under positive and negative scenarios.  From these 
estimates, an initial re-estimated sample size will be identified.
3. Supportive Information
Further information to be considered, which may influence what the final sample size 
will be:

The change in conditional probability achieved vs. the change in the number of 
participants required to achieve it, e.g. increasing the sample size by 10 
participants to achieve an extra 2% of conditional probability might not be 
deemed worthwhile 

The results of the Bayesian mixed model analysis of the interim data, i.e. the 
treatment ratio and variability observed in the interim data, and the probabilities 
that the true treatment ratio is less than 0.5, 0.7 and 1 based on the interim data

Information on the profile of coughing over time as provided by the figure of 
geometric means and 95% CI for cough counts at each hourly interval

Results of any further exploratory analyses of the cough count data dependent on 
the interim analysis results
4. Final Sample Size Decision
The estimate of sample size in the protocol is 24. The maximum revised sample size can 
be up to 40 evaluable participants (maximum 48 randomised).  Factors as described in #1, 
#2 and #3 above will be reviewed to support a decision on increasing or decreasing the 
sample size from the planned 24 participants.
Based on the results of the interim analyses, if there is strong evidence of a positive
outcome based on conditional probabilities then this may, once other factors as described 
above have been considered, lead to a reduction in sample size equal to the total number 
of participants who have completed the study together with those who are currently 
in the study.
If there is strong evidence of a negative outcome based on conditional probabilities and 
there are no further factors which suggest that more information is needed, then the 
sample size may be reduced, again to equal the total number of participants who have 
completed the study together with those who are currently in the study.
In both cases, the total sample size will be estimated closer to the interim based on 
recruitment at the time and all ongoing participants will complete the study.  Strong 
evidence would include results from the interim that meet our pre-defined criteria and the 
supporting conditional probabilities indicating a reduction in sample size to close to the 
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The full rationale for the decision on the final sample size, incorporating any 
considerations beyond the primary conditional probabilities, will be documented in the 
interim analysis meeting minutes.
3.1.2.
Conditional Probabilities to Support Sample Size Re-estimations
Sample size re-estimation will be supported by conditional probabilities of meeting the 
pre-defined positive and negative criteria for the study.  This method utilises the data we 
have from the interim, but makes assumptions on the future data based on different 
scenarios.  When calculating conditional probabilities, scenarios as detailed below will be 
considered.
The sample size giving a 90% conditional probability of meeting the positive criterion at 
the end of the study, based on the variability observed in the interim sample and based on 
the variability assumed for the protocol, conditioning on:
o
a treatment ratio of 0.5 for the post-interim data
o
the treatment ratio observed in the interim sample for the post-interim data
The sample size giving approximately 90% conditional probability of meeting the 
negative criterion at the end of the study, based on the variability observed in the interim 
sample and based on the variability assumed for the protocol, conditioning using:
o
a treatment ratio of 0.95 for the post-interim data
o
the treatment ratio observed in the interim sample for the post-interim data
All scenarios will be evaluated as part of the interim results review, however, the positive 
and negative study scenarios that utilise the interim observed variability and condition on 
the treatment ratio observed in the interim sample would be the key focus for decision 
making (yellow and brown dotted lines in the example graphic below). 
Example of Graphic to illustrate Conditional Probabilities at the Interim
The graphic below shows an example of a ‘conditional probabilities’ graphic.  In this 
example, it is based on overwhelming success at the interim, a ratio of 0.45 observed.  If 
we assume that effect continues in the study (i.e., yellow line, conditioning on the interim 
ratio of 0.45) then there is no impact on the probability of meeting the success rule as the 
sample size increases, this is maintained at ~100% as we have already reached our 
success criteria.  In this instance, we may continue the study until the currently 
randomised participants could complete the study, without randomising further
participants.
Similarly, there is no impact on the probability of meeting the negative rule, brown dotted 
line, conditioning on the interim ratio of 0.45.  This stays at ~0% (again as we have 
already met the success criteria).  
The green line shows the impact of observing a very good drug effect at the interim but 
the probability of declaring a negative study if we still believe our true effect may be 
‘no/little effect’, i.e. conditioning on a ratio of 0.95.  In this case, we would have ~25% 
 
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probability of declaring a negative study with N=24 patients if we continued this study, 
when the true effect was in fact ‘no effect’.  
For the current study, if at the interim we have observed a good effect (ratio close to 
0.70) then this graphic will help determine the sample size to continue with based on the 
variability observed at the interim.  If the interim variability is lower than originally
predicted, as defined in the protocol, then we may meet our success criteria at that point 
with a ratio of 0.7 or less.  If the variability is as expected or higher, we may need to
continue the study to reach our success probability and this graphic will guide us to the 
sample size most likely to achieve success.
Example operating characteristics for the above scenarios are presented in Section 12.5.6.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol (and subject to 
decisions made based on the interim analyses).
2.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management.
3.
All criteria for unblinding the randomisation codes have been met.  Note that the 
study is being run as sponsor open, however for the interim analyses, only a partial 
randomisation schedule will be made available to GSK Clinical Statistics, applicable 
 
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to those participants who completed two dosing periods and for whom cough data 
will be transferred. 
4.
Randomisation codes have been distributed according to RandAll NG procedures.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened 

All participants screened and for whom a record 
exists on the study database

Disposition 
(including reasons 
for screening 
failures)
All Subjects

All randomized participants who take at least 1 
dose of study treatment. Participants will be 
analysed according to the treatment they actually 
received

Study Population

Efficacy

Safety
Pharmacokinetic 
(PK)

All randomized participants who take at least 1 
dose of study treatment and for whom a 
pharmacokinetic samplea was obtained and 
analysed

PK
Refer to Appendix 11: List of Data Displays which details the population used for each display.
a refers to sample taken for the analysis of GSK2798745 and metabolite OR sample taken for analysis of Atorvastatin.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the current version of the Protocol Deviation Management Plan.
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations are captured and categorised on the protocol deviations 
dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This
summary will be based on data as recorded on the eligibility page of the eCRF.
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
Note that all displays (Tables, Figures & Listings) will use the term 'Subjects'.
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
A
Placebo
Placebo
1
B
GSK2798745
GSK2798745
2
Treatment comparisons will be displayed as follows using the descriptors as specified:
GSK2798745 vs Placebo
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline.  Baseline definitions are applicable to each period.
Parameter
Study Assessments Considered as Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Efficacy
Total day-time cough 
count
X
Day -1
Total 24 hour cough 
count
X
Day -1
Cough Severity (VAS)
X
X
Day -1
Urge to Cough (VAS)
X
Day -1
Leicester Cough 
Questionnaire (LCQ)
X
Day -1
Columbia Suicidality 
Severity Rating Scale 
(CSSRS)
X
X
Day -1
Safety
Labs
X
Xa
Day 1 (Pre-Dose)
ECGs
Xb
X
Day 1 (Pre-Dose)
Vital Signs
Xb
X
Day 1 (Pre-Dose)
Audiometry
X
Day -1
a Can be completed on Day 1 (pre-dose) or Day -1
 
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b Performed in triplicate
Unless otherwise stated, if baseline data is missing no derivation (e.g., change from 
baseline) will be performed and baseline will be set to missing.
For statistical analyses (for example, Bayesian mixed model) in a crossover design the 
following baseline derivations may apply:

Baseline is defined as the 10h daytime cough count total observed pre-dose (Day -1) 
of each treatment period.  This can also be referred to as ‘period-specific baseline’.

Subject-level baseline is defined as the mean of the two period-specific baseline 
readings (the Day -1 10h cough count total from each of the two treatment periods) 
for each participant.  

Period-level baseline (or ‘adjusted period-specific baseline’) is defined as the 
difference between the baseline (‘period-specific baseline’) and ‘subject-level 
baseline’ for each period and each participant (i.e., the ‘period-specific baseline’
minus ‘subject-level baseline’ in each period).  
The statistical modelling may include terms for ‘subject-level baseline’ and ‘adjusted 
period-specific baseline’.
5.3.
Multicentre Studies
In this multicentre study (UK), enrolment will be presented by investigative site in 
listings.  Data will be summarised for all sites combined.  A treatment-by-centre 
interaction may be investigated in the statistical analysis if sufficient data is available.
5.4.
Examination of Covariates, Other Strata and Subgroups
The list of covariates, strata and subgroups may be used in descriptive summaries and 
statistical analyses. Additional covariates and other strata of clinical interest may also be 
considered.
Category
Details
Strata
Prior cough study stratification:  Participants who did/did not take part in previous cough 
studies in the last 12 months.  This is a stratification factor within the randomisation and 
will also be included in the database.  The effect of this will be investigated as part of the 
statistical analysis.
Covariates
Centre If sufficient data is available, the effect of centre on the primary endpoint will be 
investigated.  For data displays, data from centres will be combined unless otherwise 
specified in the list of outputs.
Subgroups
No subgroups are pre-specified, will be considered on an adhoc basis if required.
 
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5.5.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
12.3
Appendix 3: Study Phases and Treatment Emergent Adverse Events
12.4
Appendix 4: Data Display Standards & Handling Conventions
12.4
Appendix 5: Derived and Transformed Data
12.6
Appendix 6: Reporting Standards for Missing Data
12.7
Appendix 7: Values of Potential Clinical Importance
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the All Subjects population, unless 
otherwise specified.
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 11: List of Data Displays.
 
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7.
EFFICACY ANALYSES
7.1.
Primary Efficacy Analyses
7.1.1.
Endpoint / Variables
The primary efficacy endpoint is the total day-time cough count (10 hours).
This will be calculated from the time of the monitor being attached i.e., immediately after 
dosing on Day 7 to 10h past the start time of monitoring.  The participant is expected to 
be awake during this period.
In addition, hourly total cough counts will be calculated for descriptive purposes.  These 
will be measured in 60 minute intervals post the start time of the device monitoring.  
A dataset of cough events (one row per cough) will be provided by Vitalograph.  Four 
24 hour sessions of data are expected for each participant (Period 1 Day -1, Period 1 
Day 7, Period 2 Day -1 and Period 2 Day 7).  This data will be made available to S&P via 
Data Management.  Vitalograph will also provide an additional file (SAS format) 
containing information related to each session with regards to removal and re-attachment 
of the cough monitor as well as clearly defined sleep periods within each session.  Further 
details on the cough count data to be transferred is provided in a Cough Analysis Plan 
written by Vitalograph.
Further details of the file structure for the cough count totals and additional session 
information are provided in Section 12.5.3.
7.1.2.
Missing Data Imputation (0-10h)
In the unlikely event that a participant removes the cough monitor, turns off the device, 
has a period of data that cannot be analysed (flagged area) or other reasons for potential 
missing cough monitoring during the 10h from the start of the monitoring period, then the 
participant’s cough profiles will be assessed to determine whether it is best to pro-rata the 
results based on the full 10h period, or to calculate the day-time 10h cough count total as 
missing. Should any data be pro-rated the resulting number of coughs will be rounded to 
the nearest integer value.  As a rule of thumb, allowance for pro-rated data can be made if 
at least 60% of the first 10 hours of monitoring includes valid cough monitoring data
(e.g., the monitor is attached and working for at least 6 out of the first 10 hours).  
For example, if a participant recorded 200 coughs between 0 and 8 hours but the monitor 
was removed for the next 2 hours, we could estimate the 2 hour cough count as 50, with a 
resulting imputed 10h total of 250 coughs. 
Pro-rated missing data rules as above will also be applied separately to hourly cough
count totals, where at least 60% of the hourly interval has valid cough monitoring 
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Note that the rules applied to hourly intervals vs the 10h total, could result in the sum of 
the imputed hourly interval cough totals not being equal to the 10h total.  For example, if 
a participant had an error with the device during the first hour resulting in no cough data 
then this hourly interval could not be imputed (as > 60% missing).  However, if further 
monitoring was complete then the 10h total could use data from the remaining 9 hours to 
impute a cough count for the first hour.  Hence in this example, the 10h total would be 
slightly higher than the sum of individual hourly totals.
Information regarding removal and re-attachment, late attachment, early 
termination/stoppage, sleep periods and flagged periods during the cough monitoring will 
be provided by Vitalograph in a separate information file (see Section 7.1.1).  Dates and 
times of the events within this file will be merged with the databased cough data to assess 
the extent of missing time periods.  Sleep periods will also be identified and will be 
classed as missing data, if the sleep period is within the first 10 hours of monitoring.
Further details of the file structure for the cough count totals and additional session
information, plus further examples of missing data imputation and associated algorithms 
are provided in Section 12.5.3.
Details of any imputation will be fully documented and highlighted in participant listings.
7.1.3.
Summary Measure
The summary measure for the primary analysis is the adjusted median posterior 
difference and 90% credible interval for GSK2798745 vs Placebo at Day 7 for total day-
time cough counts (10 hours).  A log-transformation of the cough count data is expected 
prior to analysis, in which case, the treatment effect will be evaluated in terms of a ratio 
of total day-time cough counts (GSK2798745/Placebo).
The primary analysis will be performed on pro-rated/imputed 10h cough count totals.
A sensitivity analysis will be conducted for the final analysis based on raw unimputed 
data.
7.1.4.
Population of Interest 
The primary efficacy analyses will be based on the All Subjects population, unless 
otherwise specified.
7.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and
listed.
 
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7.1.5.1.
Statistical Methodology Specification
Endpoint / Variables

Total day-time cough counts (10 hours)
Model Specification

The description below describes the current thinking of how to analyse these endpoints.  The 
proposed model will be assessed, and if not appropriate alternative models could be used.

The data will be inspected prior to analysis to determine whether a data transformation is 
required.  A log-transformation is expected for the total cough count data.  Any data 
transformations will be applied to observed individual daytime 10h total cough counts prior to 
any modeling or derivations (e.g. prior to deriving subject baseline or period-adjusted baseline)

A Bayesian mixed effects model (fitted using SAS PROC MCMC), will be used to model the 
total day-time cough counts (10 hours) after 7 days of dosing. 

Covariates for period, treatment, centre and previous cough study participation (stratification 
factor in the randomisation) will be included as fixed effects.  Adjusted period-specific baseline
and subject-level baseline will be included as continuous parameters.  Subject will be included 
as a random effect.  A treatment by period interaction will be included to investigate preliminary
carry-over effects and/or a period by treatment interaction and if deemed appropriate an 
analysis by period may be performed.  The assessment of the interaction will be performed 
using the equivalent PROC MIXED model and graphical representation.

An unstructured variance-covariance matrix will be fitted.  A non-informative prior distribution 
will be assumed for posterior probabilities.

Examination of additional covariates (for example Age group) may take place, if data permit.  
In this case, the equivalent model may be fitted in PROC MIXED and the covariate assessed 
at a 10% alpha level.  The final Bayesian model would then be fitted based upon the final 
model (after covariate examination) obtained using PROC MIXED. 

Appropriate combinations of the model parameters will be used to obtain the posterior 
distribution for the GSK2798745 vs placebo on Day 7.  Total 10h day-time cough counts will be 
represented via adjusted posterior medians for GSK2798745 and placebo, as well as 
associated 95% equi-tailed credible intervals.  These results will be presented within tabular 
and graphical form after data has been back transformed.

The difference in total day-time cough counts between GSK2798745 and placebo, will be 
represented via an adjusted median, as well as associated 90% equi-tailed credible interval.  
These results will be presented within tabular form after data has been back transformed, 
hence representing the ratio of GSK2798745/placebo.  

The posterior distributions will also be used to produce several posterior probability 
statements, presented in tabular format; the most important being the probability that the true 
ratio (GSK2798745/placebo) is less than 0.7, representing a 30% reduction in total day-time 
cough counts on GSK2798745.  Probabilities that the true ratio is less than 1 (any effect) and 
less than 0.5 (excellent effect) will also be constructed.
Model Checking & Diagnostics

Fixed effects will be assigned a non-informative prior of N(0, Var=1E6) and may be entered as 
separate univariate priors or as part of a multivariate distribution (variance covariance structure 
with zeros for off diagonals) in model hyperpriors.

The non-informative UN priors should be an inverse Wishart distribution.  If the equivalent of 
 
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an unstructured variance covariance matrix does not fit then an AR(1) w/Random Effect 
structure may be considered, with non-informative priors ~U[-1,1] for the off diagonal 
elements and 2 ~ invGamma(0.0001, scale=0.0001).  Example, for N=2:


Centring of any continuous covariates will take place at the input dataset stage: (valuei –
average) for each subject i.

Examination of trace plots to assess convergence. Autocorrelation plots and lag summary 
table to assess the degree of autocorrelation. Monte Carlo standard errors compared to 
posterior standard deviations (target would be MCSE/SD<0.01). 

Number of burn ins, thinning, starting points, number of posterior draws to take (10,000 may be 
a suitable starting default) will be customised to each model and may not be possible to specify 
in advance but will be modified to ensure satisfactory diagnostics are produced.

For robustness, where non-informative priors are used the equivalent PROC MIXED model 
may be fitted (no output from this would be reported) and LS Means and estimates of 
treatment differences/ratios compared to the results obtained from the PROC MCMC analysis.  

Model assumptions will be applied, but appropriate adjustments may be made based on the 
data.  A log-transformation is expected to total day-time 10h cough counts.
Model Results Presentation

Summary table for total 10h day-time cough counts

Listing of total hourly cough counts and 10h day-time cough counts by timepoint (baseline and 
Day 7) and treatment

Individual hourly subject profiles (4 subjects per page) of day-time cough counts by treatment 
group and timepoint (0-10h)

Boxplots of cough counts by treatment group and hourly timepoint (0-10h)

(A) (*) Figure of geometric means 95% CIs of cough counts by treatment group and hourly 
timepoint (0-10h) (data permitting, arithmetic means may be presented)

(B) (*) Figure of geometric means 

95% CIs by treatment for Day -1 vs Day 7 10h day-time cough count totals

Figure of subject by total 10h day-time cough counts and treatment

Figure of individual changes from baseline for 10h cough counts (Day -1) to Day 7 by 
treatment group

(*) Summary table of statistical analysis of total 10h day-time cough counts including: adjusted 
posterior medians and 95% credible intervals by treatment, estimated posterior median 
treatment effect (ratio GSK2798745/placebo) and 90% credible interval, posterior probabilities 
of interest (ratio<1, ratio<0.7 and ratio<0.5) – based on imputed data

Summary table of statistical analysis of total 10h day-time cough counts including: adjusted 
posterior medians and 95% credible intervals by treatment, estimated posterior median 
treatment effect (ratio GSK2798745/placebo) and 90% credible interval, posterior probabilities 
of interest (ratio<1, ratio<0.7 and ratio<0.5) – sensitivity analysis not accounting for missing 
 
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data

Figure of statistical analysis adjusted medians and 95% credible intervals by treatment group

Figures (A) and (B) above may also be reproduced split by stratification factor (prior study 
participation) 
(*) To be produced for the interim analysis
Sensitivity and Supportive Analyses

Period 1 analysis:  Should the interim analysis or final analysis provide evidence of a possible 
carryover effect from the treatment of GSK2798745 from period 1 into period 2 and/or period 
by treatment interaction, then an analysis of period 1 data only may take place.  

In this case, a Bayesian model will be fitted including terms for treatment, stratification factor, 
centre and period 1 baseline.  An equivalent PROC MIXED model will be fitted for robustness
or as an alternative method.  Adjusted posterior medians will be provided as described 
previously.  
7.2.
Exploratory Efficacy Analyses
7.2.1.
Endpoint / Variables
7.2.1.1.
Total Cough Counts over 24 Hours
The endpoint is total cough counts over 24 hours.  This will be calculated from the time 
of the monitor being attached i.e., immediately after dosing on Day 7 to 24h past the start 
time of monitoring.  
In addition, hourly total cough counts will be calculated for descriptive purposes.  These 
will be measured in 60 minute intervals post the start time of the device monitoring.
7.2.1.2.
Cough Severity and Urge (VAS)
The endpoints are:

Change from baseline in cough severity

Change from baseline in urge to cough
Both will be measured on a 0-100mm visual analogue scale, where 0 represents a good
response (no severity or urge to cough) and 100 represents a poor response (extremely 
severe cough or severe urge to cough).
7.2.1.3.
Leicester Cough Questionnaire (LCQ)
The endpoint is change from baseline in Leicester Cough Questionnaire total and domain 
scores (LCQ).
The Leicester Cough Questionnaire consists of 19 questions, each with a 7 point Likert 
response scale., where 1 represents a poor response (affecting quality of life) and 7 
represents a good response. The 19 questions fall into 3 domains as follows:
 
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Physical:
1, 2, 3, 9, 10, 11, 14, 15
Psychological:4, 5, 6, 12, 13, 16, 17
Social:
7, 8, 18, 19
For each of the above domains, the domain score will be calculated as the sum of the 
scores for the questions in that domain, divided by the number of items in the domain. 
The LCQ Total Score is then calculated as the sum of the three domain scores, and ranges 
from 3 to 21. A higher score indicates a better health status.
7.2.2.
Missing Data Imputation
Total cough counts 24h
Please refer to Section 7.1.2 detailing that at least 60% of cough monitoring data must be 
available.  The 60% cut-off will apply to data over 24 hours, but will apply to intervals 
within the 24 hours as detailed below.  The totals from these intervals will be summed to 
provide a 24 hour total.  
Two methods of determining intervals within the 24h will be used:
1. Where only one sleep period is recorded (will be for the majority of participants), 
then the 24h data will be split into ‘awake’ and ‘asleep’ intervals as determined by the 
sleep start/stop times provided by Vitalograph.  Within each ‘awake’ and ‘asleep’ 
interval if at least 60% of the monitoring data is available, then missing data will be 
imputed from the remaining data within that interval.
2. If there is more than one sleep period, or where there is no information on sleep
times, then the 24 hour data will be split into three distinct intervals:  0-12h (12h) 
representing an awake period, 12-20h (8h) representing most likely sleep interval and 
20-24h (4h) representing the last 4 hours of monitoring on the second day of wearing 
the device (morning).  Missing data, based on the 60% rule, will then be imputed 
within each of these intervals.
Each interval as described above will be assessed against the 60% criteria.  However, in 
the event that one or more intervals cannot be imputed (as less than 60% of data is 
available), the following will apply:

If the overall amount of data available over the 24h period is still at least 
60%, then an individual interval can be imputed (regardless of 60% rule 
within that interval), provided the monitor was switched on and recording 
for some part of the interval of interest.

If an interval is completely missing, but the full 24h period still has at least 
60% of data, then the imputed 24h total will be calculated based on the 
full 24h period of data available, ignoring sleep/awake intervals. 
 
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If there is no missing data, then the imputed variable will be set to the raw cough total.  If 
there is less than 60% of data available over the 24h period then the imputed variable will 
be set to missing.
Pro-rated missing data rules as above will also be applied separately to hourly cough
count totals over the 24h period, where at least 60% of the hourly interval has valid 
cough monitoring recorded.  For hourly intervals, awake and asleep times will not be 
evaluated.
On review of the data and potential for scenarios outside of those described above, the 
most appropriate method of imputation will be used.  Any changes to the above methods 
will be described in the CSR.
Details of any imputation will be fully documented and highlighted in participant listings.
Please refer to Section 12.5.3 with regards to further details on variable naming and the 
proposed structure of an A&R dataset for cough counts.
Severity and Urge to Cough (VAS)
Data will not be imputed.
Leicester Cough Questionnaire (LCQ)
Data for the individual responses that contribute to the domain and total scores will not 
be imputed.  Missing data is unlikely as the questionnaires are completed at clinic visits.  
In the event of a missing individual question, the domain scores will still be calculated, 
with the number of questions answered modified in the calculation, see Section 7.2.1.3.
7.2.3.
Summary Measure
The summary measure for total 24h cough counts is the adjusted median posterior 
difference and 90% credible interval for GSK2798745 vs Placebo at Day 7.  
The analysis will be performed on pro-rated/imputed 24h cough count totals and a 
sensitivity analysis will be conducted for the final analysis based on raw unimputed data.
The summary measure for change from baseline in cough severity and urge to cough 
(VAS) is the adjusted median posterior difference and 90% credible interval for
GSK2798745 vs Placebo at Day 7 (pre-dose).
The summary measure for change from baseline in total and domain LCQ scores is the 
adjusted median posterior difference and 90% credible interval for GSK2798745 vs
Placebo at Day 7 (pre-dose).
7.2.4.
Population of Interest 
The exploratory efficacy analyses will be based on the All Subjects population, unless 
otherwise specified.
 
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7.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
7.2.5.1.
Statistical Methodology Specification
Endpoint / Variables

Total cough counts over 24 hours
Model Specification

Data for this endpoint will be analysed in the same way as for the primary endpoint, see 
Section 7.1.5.1
Model Checking & Diagnostics

Refer to Section 7.1.5.1
Model Results Presentation

Summary table for total 24h day-time cough counts

Listing of total hourly cough counts and 24h day-time cough counts by timepoint (baseline 
and Day 7) and treatment

Individual hourly subject profiles (4 subjects per page) of day-time cough counts by 
treatment group and timepoint (0-24h)

Boxplots of cough counts by treatment group and hourly timepoint (0-24h)

(A) Figure of geometric means 95% CIs of cough counts by treatment group and hourly 
timepoint (0-24h) (data permitting, arithmetic means may be presented)

(B) Figure of geometric means 95% CIs by treatment for Day -1 vs Day 7 24h cough 
count totals

Figure of subject by total 24h cough counts and treatment

Figure of individual changes from baseline for 24h cough counts (Day -1) to Day 7 by 
subject and treatment group

Summary table of statistical analysis of 24h day-time cough counts including: adjusted 
posterior medians and 95% credible intervals by treatment, estimated posterior median 
treatment effect (ratio GSK2798745/placebo) and 90% credible interval, posterior 
probabilities of interest (ratio<1, ratio<0.7 and ratio<0.5) – based on imputed data

Summary table of statistical analysis of 24h day-time cough counts including: adjusted 
posterior medians and 95% credible intervals by treatment, estimated posterior median 
treatment effect (ratio GSK2798745/placebo) and 90% credible interval, posterior
probabilities of interest (ratio<1, ratio<0.7 and ratio<0.5) – sensitivity analysis not 
accounting for missing data

Figure of statistical analysis adjusted medians and 95% credible intervals by treatment 
group

Figure (A) and Figure (B) above may also be reproduced split by stratification factor (prior 
study participation) 
 
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Subgroup Analyses

Refer to Section 7.1.5.1
Sensitivity and Supportive Analyses

Refer to Section 7.1.5.1
Endpoint / Variables

Change from baseline to Day 7 (pre-dose) in cough severity and urge to cough (VAS)
Model Specification

VAS is measured on a 0 to 100mm scale.

The description below describes the current thinking of how to analyse these endpoints.  The 
proposed model will be assessed, and if not appropriate alternative models could be used.

The data will be inspected prior to analysis to determine whether a data transformation is 
required.  

A Bayesian mixed effects model (fitted using SAS PROC MCMC), will be used to model the 
change from baseline to Day 7 (pre-dose) VAS endpoints as detailed above. 

Covariates for period, treatment, centre and previous cough study participation (stratification 
factor in the randomisation) will be included as fixed effects.  Adjusted period-specific baseline
and subject-level baseline will be included as continuous parameters.  Subject will be included 
as a random effect.  A treatment by period interaction will be included to investigate preliminary 
carry-over effects and/or a period by treatment interaction and if deemed appropriate an 
analysis by period may be performed.

An unstructured variance-covariance matrix will be fitted.  A non-informative prior distribution 
will be assumed for posterior probabilities.

Examination of additional covariates (for example Age group) may take place, if data permit.  
In this case, the equivalent model may be fitted in PROC MIXED and the covariate assessed 
at a 10% alpha level.  The final Bayesian model would then be fitted based upon the final 
model (after covariate examination) obtained using PROC MIXED. 

Appropriate combinations of the model parameters will be used to obtain the posterior 
distribution for the GSK2798745 vs placebo.  

Change from baseline to Day 7 (pre-dose) VAS endpoints will be represented via adjusted 
posterior medians for GSK2798745 and placebo, as well as associated 95% equi-tailed 
credible intervals.  These results will be presented within tabular and graphical form after data 
has been back transformed (if necessary).

The difference in change from baseline to Day (pre-dose) VAS endpoints between 
GSK2798745 and placebo, will be represented via an adjusted median, as well as associated 
90% equi-tailed credible interval.  These results will be presented within tabular form after data 
has been back transformed to represent a ratio (if necessary).  

The posterior distributions will also be used to produce posterior probability statements, 
presented in tabular format; for example, the probability that the true difference (GSK2798745-
placebo) in change from baseline in VAS is less than 0, less than -17mm or less than -30 mm, 
i.e. any treatment difference in favour of GSK2798745, a difference of 17 mm in favour of 
GSK2798745 or a difference of 30 mm in favour of GSK2798745.  
 
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Model Checking & Diagnostics

Refer to Section 7.1.5.1
Model Results Presentation

Summary table by visit and treatment group (separate outputs for severity and urge)

Summary table of change from baseline by treatment group (separate outputs for severity and 
urge)

Listing of severity and urge to cough VAS by timepoint (baseline and Day 7) and period
(endpoints in one listing)

Figure of absolute mean VAS 95% CI by timepoint and treatment group (separate graphic for 
severity and urge)

Summary table of statistical analysis of change from baseline to Day 7 (pre-dose): adjusted 
posterior medians and 95% credible intervals by treatment, estimated posterior median 
treatment effect and 90% credible interval, posterior probabilities of interest (difference <0, 
difference <-17 mm and difference <-30 mm on VAS scale) (separate outputs for severity and 
urge)

Figure of statistical analysis adjusted medians and 95% credible intervals by treatment group
(separate outputs for severity and urge)
Subgroup Analyses

Refer to Section 7.1.5.1
Sensitivity and Supportive Analyses

Refer to Section 7.1.5.1
Endpoint / Variables

Change from baseline to Day 7 (pre-dose) in LCQ domain mean scores and total score
Model Specification

LCQ is on a 1 to 7-point scale

The description below describes the current thinking of how to analyse these endpoints.  The 
proposed model will be assessed, and if not appropriate alternative models could be used.

The data will be inspected prior to analysis to determine whether a data transformation is 
required.  

A Bayesian mixed effects model (fitted using SAS PROC MCMC), will be used to model the 
change from baseline to Day 7 (pre-dose) LCQ endpoints as detailed above. 

Covariates for period, treatment, centre and previous cough study participation (stratification 
factor in the randomisation) will be included as fixed effects.  Adjusted period-specific baseline
and subject-level baseline will be included as continuous parameters.  Subject will be included 
as a random effect.  A treatment by period interaction will be included to investigate preliminary 
carry-over effects and/or a period by treatment interaction and if deemed appropriate an 
analysis by period may be performed.

An unstructured variance-covariance matrix will be fitted.  A non-informative prior distribution 
will be assumed for posterior probabilities.

Examination of additional covariates (for example Age group) may take place, if data permit.  
In this case, the equivalent model may be fitted in PROC MIXED and the covariate assessed 
at a 10% alpha level.  The final Bayesian model would then be fitted based upon the final 
 
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model (after covariate examination) obtained using PROC MIXED. 

Appropriate combinations of the model parameters will be used to obtain the posterior 
distribution for the GSK2798745 vs placebo.  

Change from baseline to Day 7 (pre-dose) LCQ endpoints will be represented via adjusted 
posterior medians for GSK2798745 and placebo, as well as associated 95% equi-tailed 
credible intervals.  These results will be presented within tabular and graphical form after data 
has been back transformed (if necessary).

The difference in change from baseline to Day 7 (pre-dose) LCQ endpoints between 
GSK2798745 and placebo, will be represented via an adjusted median, as well as associated 
90% equi-tailed credible interval.  These results will be presented within tabular form after data 
has been back transformed to represent a ratio (if necessary).  

The posterior distributions will also be used to produce several posterior probability statements, 
presented in tabular format; the most important being the probability that the true difference 
(GSK2798745-placebo) is > 0, > 1 and > 1.3, i.e., any treatment difference or a difference of 1 
or 1.3 points on the LCQ domain/total score in favour of GSK2798745.
Model Checking & Diagnostics

Refer to Section 7.1.5.1
Model Results Presentation

Summary table by visit and treatment group (domain scores and total in one output)

Summary table of change from baseline by treatment group (domain scores and total in one 
output)

Listing of LCQ scores by timepoint (baseline and Day 7) and period

Plot of absolute mean LCQ - 95% CI by timepoint and treatment group (4 graphics one for 
each domain and total score, page by endpoint)

Summary table of statistical analysis of change from baseline to Day 7 (pre-dose): adjusted 
posterior medians and 95% credible intervals by treatment, estimated posterior median 
treatment effect and 90% credible interval, posterior probabilities of interest (difference >0, >1
and >1.3 points on LCQ scale) (page by LCQ endpoint).  A difference of 1.3 points is 
considered to be a minimally important difference.

Figure of statistical analysis adjusted medians and 95% credible intervals by treatment group 
(page by LCQ endpoint)
Subgroup Analyses

Refer to Section 7.1.5.1
Sensitivity and Supportive Analyses

Refer to Section 7.1.5.1
 
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8.
SAFETY ANALYSES
The safety analyses will be based on the All Subjects population, unless otherwise 
specified.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 11: List of Data Displays.
8.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 11: List of Data Displays.
8.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 11: List of Data Displays.
The CSSRS questionnaire will be summarised by the use of a listing, to present data by 
participant, treatment group and timepoint.  
Weight measured during the study will be summarised with standard vitals signs data.
A listing of audiometry changes from baseline will be produced.
 
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9.
PHARMACOKINETIC ANALYSES
9.1.
Primary Pharmacokinetic Analyses
9.1.1.
Endpoint / Variables
9.1.1.1.
Drug Concentration Measures
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 12.4.3
Reporting Standards for Pharmacokinetic Data).
9.1.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin. All calculations of non-compartmental parameters will be based on actual 
sampling times. Pharmacokinetic parameters listed will be determined from the plasma
concentration-time data, as data permits.
Parameter
Parameter Description
Cmax
GSK2798745 for Day 1 and Day 7
Tmax
GSK2798745 for Day 1 and Day 7
AUC(0-3.5) 
GSK2798745 for Day 1 and Day 7
C24
GSK2798745 for Day 8
NOTES:  Additional parameters may be included as required.
9.1.2.
Population of Interest 
The primary pharmacokinetic analyses will be based on the Pharmacokinetic population, 
unless otherwise specified.
9.1.3.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 9.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
9.2.
Secondary Pharmacokinetic Analyses
9.2.1.
Endpoint / Variables
9.2.1.1.
Drug Concentration Measures 
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 12.4.3
Reporting Standards for Pharmacokinetic Data).
 
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For atorvastatin, it is expected that patients are on a stable daily dose.  Dosing date and 
time of atorvastatin for Day -1, Day 1, Day 6 and Day 7 will be recorded separately for 
applicable participants.  Therefore, the PKCNC dataset created for atorvastatin will 
require some non-standard programming to ensure the last dose prior to PK sampling on 
Day 1 and Day 7 is selected to derive actual sampling times.  Time from last dose will 
therefore vary across participants dependent on when their last dose of atorvastatin was 
taken.
9.2.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin. All calculations of non-compartmental parameters will be based on actual 
sampling times. Pharmacokinetic parameters listed will be determined from the plasma
concentration-time data, as data permits.
Parameter
Parameter Description
Cmax
M1 metabolite for GSK2798745 Day 1 and Day 7
Atorvastatin and metabolite in available participants Day 1 and Day 7
Tmax
M1 metabolite for GSK2798745 Day 1 and Day 7
Atorvastatin and metabolite in available participants Day 1 and Day 7
AUC(0-3.5)
M1 metabolite for GSK2798745 Day 1 and Day 7
Atorvastatin and metabolite in available participants Day 1 and Day 7
C24
M1 metabolite for Day 8
Atorvastatin and metabolite in available participants for Day 8
NOTES:  Additional parameters may be included as required.
9.2.2.
Population of Interest 
The secondary pharmacokinetic analyses will be based on the Pharmacokinetic
population, unless otherwise specified.
9.2.3.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 9.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
 
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10.
POPULATION PHARMACOKINETIC (POPPK) AND 
PHARMACODYNAMIC ANALYSES
Given the sparse plasma sampling scheme for GSK2798745, a non-linear mixed effects 
methodology will be applied to characterise the population PK of GSK2798745 allowing 
for the relatively few number of participants. This poppk model will be adapted from a 
previous model characterised for GSK2798745 in healthy participants [report in progress]
to derive some key PK parameter estimates including Cmax, AUC and average 
concentration of drug over dosing interval (Cav). The influence of participant
demographics, baseline characteristics, including baseline disease activity (cough 
counts), and co-medication on the pharmacokinetics of GSK2798745 in this population 
will be investigated. The individual participant PK parameters will be estimated and 
documented for the purposes of any subsequent exposure-response (PK/PD) analyses.
A population systemic exposure-efficacy model will be developed if data permit. 
Individual PK metrics such as trough concentration observed on Day 8 as well as the 
estimated average concentration over the dosing interval (Cav) will be used to derive a 
parametric model quantifying relationship between drug levels and the primary efficacy 
endpoint (total day-time cough count (10 hours)). 
10.1.
Statistical Analyses / Methods
A summary of the planned population pharmacokinetic analyses are outlined below:
o
Drug plasma concentration-time data will be subjected to nonlinear mixed effects 
modelling using the program NONMEM to develop a population PK model or apply 
a previous pop pk model developed in healthy participants receiving GSK2798745.  
o
Individual post-hoc estimated PK parameters will be summarised descriptively.
o
To support this analysis PopPK and population PK-PD datasets will be generated.
The timeline for these analyses will be independent of statistical analysis complete 
(SAC).  Further details will be documented in a separate CPMS RAP.
The details for the dataset specifications are provided in Appendix 8: Population 
Pharmacokinetic (PopPK) Analyses.
Detailed Population PK-PD methodology and dataset specifications are presented in
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses.
 
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11.
REFERENCES
GlaxoSmithKline Document Number. : 2017N31986_00, A study to assess the 
effectiveness and side effects of GSK2798745 in participants with chronic cough; 31-
MAY-2017.
GlaxoSmithKline Document Number. : 2017N31986_01, A study to assess the 
effectiveness and side effects of GSK2798745 in participants with chronic cough; 09-
OCT-2017.
GlaxoSmithKline Document Number. : 2017N31986_02, A study to assess the 
effectiveness and side effects of GSK2798745 in participants with chronic cough; 22-
NOV-2017.
GlaxoSmithKline Document Number. : 2017N31986_03, A study to assess the 
effectiveness and side effects of GSK2798745 in participants with chronic cough; 25-
JUN-2018.
 
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12.
APPENDICES
12.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
A Per Protocol Population is not defined for the study.  Important protocol deviations will 
be summarised and listed.
 
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12.2.
Appendix 2: Schedule of Activities
12.2.1.
Protocol Defined Schedule of Events
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 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 [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 & Urgency)
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.
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).
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).
 
 
 
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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
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 cough 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
Leicester Cough Questionnaire (LCQ)
X
X (pre-dose)
To be completed before other assessments 
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
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.
 
 
 
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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
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.

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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12.3.
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events
12.3.1.
Study Phases and Treatment Emergent Rules for AEs
This study is a multiple dose two period crossover study.  As such, AEs will be attributed to the 
treatment received within the relevant study period based on the dates of the AEs in relation to 
dosing date.  This is as per IDSL dataset standards. This is detailed in the table below.
Study Phase
Definition
Pre-Treatment 
AE Start Date < Study Treatment Start Date (Period 1)
On-Treatment
(Period 1)
If AE Start Date is on or after Study Treatment Start Date (Period 1) & before Study 
Treatment Start Date (Period 2).
Study Treatment Start Date (Period 1)  ≤ AE Start Date < Study Treatment Start 
Date (Period 2)
On-Treatment 
(Period 2)
If AE Start Date is on or after Study Treatment Start Date (Period 2) & before Follow-
Up.
Study Treatment Start Date (Period 2)  ≤ AE Start Date ≤ Follow-Up Date
Post-Treatment
If AE Start Date is on or after Follow-Up.
AE Start Date > Follow-Up Date
NOTES: 

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.
12.3.1.1.
Study Phases for Concomitant Medication
This study is a multiple dose two period crossover study.  As such, Concomitant Medications will 
be attributed to the treatment received within the relevant study period based on the dates of the 
AEs in relation to dosing date.  This is as per IDSL dataset standards. This is detailed in the table 
below.
Study Phase
Definition
Pre-Treatment 
CM Start Date < Study Treatment Start Date (Period 1)
On-Treatment 
(Period 1)
If CM Start Date is on or after Study Treatment Start Date (Period 1) & before Study 
Treatment Start Date (Period 2).
Study Treatment Start Date (Period 1)  ≤ CM Start Date < Study Treatment Start 
Date (Period 2)
On-Treatment 
(Period 2)
If CM Start Date is on or after Study Treatment Start Date (Period 2) & before Follow-
Up.
Study Treatment Start Date (Period 2)  ≤ CM Start Date ≤ Follow-Up Date
 
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12.4.
Appendix 4: Data Display Standards & Handling 
Conventions
12.4.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: UK1SALX00175.corpnet2.com
HARP Compound
: \ARPROD\GSK2798745\207702\Internal_01 
: \ARPROD\ GSK2798745\207702\Final_01
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset standards (Integrated Data 
Standards Library).
Generation of RTF Files

RTF files will be generated for the Final reporting effort.
12.4.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject level 
listings should be located in the modular appendices as ICH or non-ICH listings
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.
 
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
All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principles 7.01 to 7.13.
12.4.3.
Reporting Standards for Pharmacokinetic Data
Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
PC WNL file (CSV format) for the non-compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
GUI_51487. 
Note: Concentration values will be imputed as per GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
NONMEM/Pop PK 
File
Pop-PK file (CSV format) for the POP-PK analysis by CPMS will be created by S&P 
according to the data specification detailed in Section 12.8.2 Population 
Pharmacokinetic (PopPK) Dataset Specification.
NONMEM/PK/PD 
File
PK/PD file (CSV format) for the PK/PD analysis by CPMS will be created by S&P 
according to the data specification detailed in Section 12.9.2
Pharmacokinetic/Pharmacodynamic Dataset Specification.
Pharmacokinetic Parameter Derivation
PK Parameters to be 
Derived
The following PK parameters will be derived by CPMS:
Non Compartmental (to be forwarded to Statistics and Programming) : Cmax, Tmax 
and AUC(0-3.5), C24 on Day 8
PopPK parameters include CL/F, AUC(0-24), Cav and Cmax
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
Yes, refer to Standards for Handling NQ Impacted PK Parameters, December 
2009.
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
 
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12.5.
Appendix 5: Derived and Transformed Data
12.5.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

If there are two values within a time window the value closest to the target day for that window will be 
used. If values are the same distance from the target, then the mean will be taken.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
12.5.2.
Study Population
Treatment Compliance

In this study, participants take 2 tablets on Day 1 (2 x 2.4 mg) and 1 tablet (1 x 2.4 mg) on Days 2 
through to 7, therefore treatment compliance will be calculated based on the formula:  
Treatment Compliance = Number of Actual Doses / Planned Number of Doses,
which will be calculated as,
[No. of tablets taken / (No. of days in period + 1)] * 100,
where No. of days in period = (Date of last dose- Date of first Dose) +1 in each period.  
The denominator has 1 added to it to account for the fact that 2 tablets are taken on Day 1 and 
1 tablet is taken on all other days.

Treatment compliance could be greater than 100% if there are events of overdose as recorded for 
‘tablets taken’.

Reasons for treatment not being returned will be recorded (tick box on eCRF).

Compliance during each study period will be calculated.

For each study period, a bottle containing 15 tablets is dispensed.  At the end of each period, 7 tablets 
should remain if a participant has taken all medication correctly and returned unused tablets correctly.
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days on 4.2 mg x Total Daily Dose (for 4.2 mg)) + Sum of 
(Number of Days on 2.4 mg x Total Daily Dose (for 2.4 mg))
 
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Treatment Compliance

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.
12.5.3.
Efficacy
Total Cough Counts at 10h and 24h

Variance stabilising transformations (e.g. taking natural logarithms of the observed responses) may be 
implemented, if deemed necessary by the study statistician. If transformations are used the results will 
be reported on the back-transformed response scales.

Other efficacy endpoints to be statistically analysed will also be assessed for data transformation
12.5.3.1.
Cough Count SI and A&R Dataset Specifications
SI Dataset COUGH
Provided by Data Management, this is based on data provided by Vitalograph in file 
207702_cough_YYYYMMDD.csv
Column 
Name
Data 
Type/Format
Label (additional detail from transfer agreement)
STUDYID
Char 10
Unique identifier for the study
SUBJID
Num 10.
Subject ID
VISIT
Char 40
Visit description
VISITNUM
Num 7.2
Visit sequence number
PTM
Char 40
Planned timepoint description
PTMNUM
Num 7.2
Planned timepoint sequence number
CENTREID
$45
Centre ID
ACTDT
Date9.
Actual date of assessment 
(Start date of cough monitoring)
ACTSTTM
Time8.
Actual start time of assessment 
(Start time of the Cough Monitoring in 24 hour format)
ENTM
Time5.
Stop time 
(Stop time of the Cough Monitoring in 24 hour format)
COVEID
$80
Cough vendor ID 
COVEIDC
$8
Cough vendor ID code
EVNTDT
Date9.
Event date 
(Event date in DDMMMYYYY format)
EVNTTM
Time5.
Event time 
(Event time in 24 hour format displayed as HH:MM. This 
is the time with the seconds and milliseconds removed)
PRREFID
Char 20
Procedures reference ID (Sample ID (unique ID) – The 
serial number from CF Card)
ELTIMES
Num 8.3
Elapsed time, in seconds 
(The seconds and milliseconds portion of the event time 
displayed as SS.MMM. This combined with EVTDT and 
EVNTTM will provide the full date and time of the cough 
event)
 
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External Dataset g207702_session_YYYYMMDD.sas7bdat
Provided by Vitalograph directly to Statistics and Programming.  To be merged with SI 
COUGH dataset to derive missing data periods.
Column 
Name
Data Type / 
Format
Description / Notes
STUDYID
CHAR 6
Study Protocol ID – 207702
SUBJID
CHAR 6
The 6 digit Subject ID.
VISIT
CHAR 23
The name of the visit.
VISITNUM
CHAR 7
Visit sequence number. 
CENTREID
CHAR 6
The 6 digit Site ID.
ACTDT
CHAR 9
Start date of the Cough Monitoring in the format 
DDMMMYYYY.
ACTSTTM
CHAR 5
Start time of the Cough Monitoring in 24 hour format 
displayed as HH:MM.
ENTM
CHAR 5
Stop time of the Cough Monitoring in 24 hour format 
displayed as HH:MM.
COVEID
CHAR 80
To be populated with ‘Vitalograph Business Park, Maids 
Moreton, BUCKINGHAM, MK18 1SW’ 
COVEIDCD
CHAR 8
To be populated with 0001
PRREFID
CHAR 6
The Card Serial Number
FIELD_NAME
CHAR 100
“Session Status” for the status of the session row, each 
session will display this row e.g. Accepted.
The following event rows will only appear for sessions 
that have these events recorded. The label associated 
to the non-cough event will be displayed using: 
“Sleep” –  Sleep start event type
“Wake” – Wake event type, will be set to the end of the 
recording if the subject did not wake during the session
“Removal” – Removed device event type
“Restore” – Restored device event type, will be set to 
the end of the recording if the device is never restored
“Early termination” – The session is terminated early, 
possibly due to a CF card or battery failure.
“Early Stoppage” – The session is stopped when the 
clinic or subject stops the device manually.
“Late Attachment” – The device is attached late.
“Flagged Area Start” – Flagged area start event type
“Flagged Area End” – Flagged area end event type
See cough analysis plan (Vitalograph) for further details.
NCEVNTDT
CHAR 30
Date of the non-cough event.  For sessions that have 
been rejected, ‘Rejected’ will be displayed. For sessions 
that have been accepted with no events, ‘Accepted with 
no events’ will be displayed. For sessions that have 
been accepted with events, the full date and time of the 
event will be displayed including milliseconds, e.g. 
10JUL2017 01:17:00:410.
 
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A&R dataset COUGHALL
This derived dataset will include the original SI COUGH data merged together with the 
session data (transposed event dates/times) to provide all event dates/times in a format 
suitable for calculation of time periods.  This dataset will not need to be formally QCd, 
but will be available as an intermediate dataset.  QC of the dataset COUGHTOT will 
provide a QC that the non cough-events have merged and been used correctly.
Column 
Name
Data Type / 
Format
Label (additional detail from data transfer agreement)
STUDYID
Char 10
Unique identifier for the study
SUBJID
Num 10.
Subject ID
VISIT
Char 40
Visit description
VISITNUM
Num 7.2
Visit sequence number
PTM
Char 40
Planned timepoint description
PTMNUM
Num 7.2
Planned timepoint sequence number
CENTREID
$45
Centre ID
ACTDT
Date9.
Actual date of assessment 
(Start date of cough monitoring)
ACTSTTM
Time8.
Actual start time of assessment 
(Start time of the Cough Monitoring in 24 hour format)
ENTM
Time5.
Stop time 
(Stop time of the Cough Monitoring in 24 hour format)
COVEID
$80
Cough vendor ID 
COVEIDCD
$8
Cough vendor ID code
EVNTDT
Date9.
Event date 
(Event date in DDMMMYYYY format)
EVNTTM
Time5.
Event time 
(Event time in 24 hour format displayed as HH:MM. This 
is the time with the seconds and milliseconds removed)
PRREFID
Char 20
Procedures reference ID 
(Sample ID (unique ID) – The serial number from CF 
Card)
ELTIMES
Num 8.3
Elapsed time, in seconds 
(The seconds and milliseconds portion of the event time 
displayed as SS.MMM. This combined with EVTDT and 
EVNTTM will provide the full date and time of the cough 
event)
STOPDT
Date9.
Event stop date
(DERIVED VARIABLE – merge on last cough event and 
select date of event, should be the next calendar day if 
24 hour monitoring achieved)
EVNDTTM
Datetime20.
Cough event date and time
(DERIVED VARIABLE – merge together each cough 
date, time and seconds and apply format)
STADTTM
Datetime20.
Cough monitoring start date and time
(DERIVED VARIABLE – merge together start date, time 
and seconds and apply format)
STODTTM
Datetime20.
Cough monitoring stop date and time
(DERIVED VARIABLE – merge together stop date, time 
and seconds and apply format)
 
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Column 
Name
Data Type / 
Format
Label (additional detail from data transfer agreement)
FAREAS
Datetime20.
Flagged area start date and time
(DERIVED VARIABLE – convert character date variable 
provided to numeric date format)
FAREAE
Datetime20.
Flagged area stop date and time
(DERIVED VARIABLE – convert character date variable 
provided to numeric date format)
ASLEEP
Datetime20.
Sleep period start date and time
(DERIVED VARIABLE – convert character date variable 
provided to numeric date format)
AWAKE
Datetime20.
Sleep period stop date and time
(DERIVED VARIABLE – convert character date variable 
provided to numeric date format)
EARLYTRM
Datetime20.
Early termination date and time
(DERIVED VARIABLE – convert character date variable 
provided to numeric date format)
REMOVE
Datetime20.
Removal date and time
(DERIVED VARIABLE – convert character date variable 
provided to numeric date format)
RESTOR
Datetime20.
Restore date and time
(DERIVED VARIABLE – convert character date variable 
provided to numeric date format)
EARLYSTO
Datetime20.
Early stoppage date and time
(DERIVED VARIABLE – convert character date variable 
provided to numeric date format)
LATEATT
Datetime20.
Late attachment date and time
(DERIVED VARIABLE – convert character date variable 
provided to numeric date format)
STATUS
Char 120.
Status of cough recording
TRTCD
Num 8
Randomised Treatment Code (Seq)
TRTGRP
Char 120.
Randomised Treatment Group (Seq)
ATRTCD
Num 8
Actual Treatment Code (Seq)
ATRTGRP
Char 120.
Actual Treatment Group (Seq)
PTRTCD
Num 8
Period Treatment Code
PTRTGRP
Char 120.
Period Treatment Group
PATRTCD
Num 8
Period Actual Treatment Code
PATRTGRP
Char 120.
Period Actual Treatment Group
Note: If there is more than one sleep period, then name subsequent sleep and awake 
events as ASLEEP1, ASLEEP2, AWAKE1, AWAKE2 etc.  The same logic would apply 
to more than one removal/restore or flagged area.
A&R dataset COUGHTOT
This dataset will use A&R dataset COUGHALL and create hourly, 10h and 24h counts 
with missing data periods imputed where appropriate.  Log transformed variables to be 
included for use in the analysis.
Column 
Name
Data Type / 
Format
Label (additional detail from data transfer 
agreement)
STUDYID
Char 10
Unique identifier for the study
 
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Column 
Name
Data Type / 
Format
Label (additional detail from data transfer 
agreement)
SUBJID
Num 10.
Subject ID
VISIT
Char 40
Visit description
VISITNUM
Num 7.2
Visit sequence number
PTM
Char 40
Planned timepoint description
PTMNUM
Num 7.2
Planned timepoint sequence number
CENTREID
$45
Centre ID
Hourly, 10h and 24h timepoint variables
FLAGHR
Datetime20.
Timepoint Flag
(DERIVED VARIABLE – one row per hourly interval, 
10h, overall 24 period, plus one row for each of the 3 
intervals within the 24h period)
Values are:
1
2
…
23
24
100 /*for 10h*/
240 /*for 24h*/
499 /*for awake period 1*/
500 /*for sleep period*/
501 /*for awake period 2*/)
1120 /*for first 12h*/
1080 /*for next 8h*/
1040 /*for next 4h*/
FLAGHRC
Char 10
Timepoint Flag Description
(DERIVED VARIABLE – as above, one row per hourly 
interval, 10h, overall 24 period, plus one row for each of 
the 3 intervals within the 24h period)
Character values are:
0-1h
1-2h
…
22-23h
23-24h
10h
24h
24h Awake1
24h Sleep1
24h Awake2
24h 0-12h
24h 12-20h
24h 20-24h
Imputation derivation variables
FLAGIMP
Char 2
Flag Imputed
(DERIVED VARIABLE)
Values are:
Y /*Yes imputed value*/
YR /*Yes imputed but based on full 24h as an individual 
interval does not meet 60% criteria, but full 24h does */
 
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Column 
Name
Data Type / 
Format
Label (additional detail from data transfer 
agreement)
NA /*Not applicable – cannot be imputed due to 60% 
rule */
‘ ‘ data complete and not imputed
Stratification variables
PRIOR
Char 1
Prior cough study participation
(Renamed SCHORSCD variable in SC dataset)
Y=Yes, N=No for answer to stratification question
PRIORCD
Num 8
Numeric code for prior study participation 
(Derived, if PRIOR=Y then PRIORCD=1 else if 
PRIOR=N then PRIORCD=2)
Date/time event variables from COUGHALL
STADTTM
Datetime20.
Cough monitoring start date and time
(from COUGHALL)
STODTTM
Datetime20.
Cough monitoring stop date and time
(from COUGHALL)
FAREAS
Datetime20.
Flagged area start date and time
(from COUGHALL)
FAREAE
Datetime20.
Flagged area stop date and time
(from COUGHALL)
ASLEEP
Datetime20.
Sleep period start date and time
(from COUGHALL)
AWAKE
Datetime20.
Sleep period stop date and time
(from COUGHALL)
EARLYTRM
Datetime20.
Early termination date and time
(from COUGHALL)
REMOVE
Datetime20.
Removal date and time
(from COUGHALL)
RESTOR
Datetime20.
Restore date and time
(from COUGHALL)
EARLYSTO
Datetime20.
Early stoppage date and time
(from COUGHALL)
LATEATT
Datetime20.
Late attachment date and time
(from COUGHALL)
Cough count total variables
COUGHTOT
Num 8
Cough Count Total Raw
(DERIVED VARIABLE – create for each hourly interval 
and for 10h and 24h period)
COUGHIMP
Num 8
Cough Count Total Imputed
(DERIVED VARIABLE – create for each hourly interval 
and for 10h and 24h period, imputation based on rules 
as per RAP)
Log transformed cough count total variables
LOGCTOT
Num 8
Log transformed cough total 
LOGCIMP
Num 8
Log transformed imputed cough total
Subject baseline derivation variables
CTOTBS
Num 8
Subject baseline
CIMPBS
Num 8
Imputed subject baseline
CTOTBP1
Num 8
Baseline period 1
CTOTBP2
Num 8
Baseline period 2
 
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Column 
Name
Data Type / 
Format
Label (additional detail from data transfer 
agreement)
CIMPBP1
Num 8
Imputed baseline period 1
CIMPBP2
Num 8
Imputed baseline period 2
Period adjusted baseline derivation variables
CTOTPA
Num 8
Period adjusted baseline
CIMPPA
Num 8
Period adjusted imputed baseline
Log transformed subject baseline derivation variables
LCTOTBS
Num 8
Log transformed subject baseline
LCIMPBS
Num 8
Log transformed imputed subject baseline
Log transformed period adjusted baseline derivation variables
LCTOTPA
Num 8
Log transformed period adjusted baseline
LCIMPPA
Num 8
Log transformed period adjusted imputed baseline
Standard treatment group variables
TRTCD
Num 8
Randomised Treatment Code (Seq)
TRTGRP
Char 120.
Randomised Treatment Group (Seq)
ATRTCD
Num 8
Actual Treatment Code (Seq)
ATRTGRP
Char 120.
Actual Treatment Group (Seq)
PTRTCD
Num 8
Period Treatment Code
PTRTGRP
Char 120.
Period Treatment Group
PATRTCD
Num 8
Period Actual Treatment Code
PATRTGRP
Char 120.
Period Actual Treatment Group
 
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12.5.3.2.
Cough Count Missing Data Period Algorithms
Codes:
L
=
Low hour, H=High hour, M=missing time period
X
= 
Start of missing period (e.g. removal), 
Y
= 
End of missing period (e.g. restore)
LA
= 
Late attachment
ET
= 
Early Termination
ES
= 
Early Stoppage
S
= 
Beginning of sleep period
A
= 
End of sleep period (awakening)
All measured in seconds e.g. 1h = 3600 seconds
X, Y, S, A, LA, ET and ES represent time from start of cough monitoring in seconds
Shaded areas represent potential missing data time intervals
A1 = first awake interval, S1 = sleep interval, A2 = second awake interval
1. HOURLY COUGH COUNT TOTALS
a. Missing periods with a start and end (removal/restore, flagged start/flagged 
stop)
0h
1h 
2h
3h
4h
Etc
                        (L)
           (H)
X
Y
X
Y
X
         Y
X
Y
If X < L then do;
If Y <= H then M = Y – L
Else if Y > H then M = H – L (should be 3600 secs)
If L <= X < H then do;
If Y <= H then M = Y - X
Else if Y > H then M = H – X
b. Late attachment, early termination or early stoppage
0h
         1h
          2h……….         
   23h                24h
                      (L)                  (H)                                                            (L)                   (H)
LA
ET/ES
LA
ET/ES
 
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If L <= LA <= H then M = (H – L) – (H – LA), 
Else if LA > H then M=H-L
If L <= ET <= H then M = H – ET (same for ES), 
Else if ET < L then M=H-L 
2. 10H DAYTIME COUGH COUNT TOTALS
a. Missing periods with a start and end (removal/restore, flagged start/flagged stop, 
sleep/awake)
0h
10h
     0h
10h
X
Y
LA
X
Y
ET/ES
If X < 36000 then do; If Y <= 36000 then M = Y – X
Else if Y > H then M = 36000 - X
If LA < 36000 then M = LA
If ET < 36000 then M = 36000 – ET (same for ES)
3. 24H COUGH COUNT TOTALS
a. Awake Period 1 (A1) {or first 12h (0-12h) if applicable}
0h
A1      S
S1
A
A2
24h
XY 
X
Y
If X < S then do;
If Y <= S then M = Y – X
Else if Y > S then M = S – X
0h
A1
S
S1
A
A2
24h
LA 
ET
If LA < S then M = LA
If ET/ES < S then M = S – ET/ES
 
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b. Sleep Period (S1) {or next 8h (12-20h) if applicable}
0h
A1
S
S1
A
A2
24h
X
Y
X
Y
X
      Y
X
Y
If X < S then do; 
If S <= Y <= A then M = Y – S
Else if Y > A then M = A – S (sleep period)
If S <= X < A then do; 
If Y <= A then M = Y – X
Else if Y > A then M = A – X
0h
A1
S
S1
A
A2
24h
LA
ET
If S <= LA < A then M = LA - S
If S <= ET/ES < A then M = A – ET/ES
c. Awake Period 2 (A2) {or last 4h (20-24h) if applicable}
0h
A1
S
S1
A
A2
24h
X
Y
X Y
If X < A and Y > A then M = Y – A
Else if X >= A then M = Y – X
0h
A1
S
S1
A
A2       24h
LA
ET
If A <= LA < 24h then M = LA – A
If A <= ET/ES < 24h then M = 86460 – ET/ES
Note:  Value in seconds for 24 hours has 60 seconds added to allow for discrepancies 
between date/time variables that do/do not include seconds.
 
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12.5.3.3.
Cough Count Imputation Derivations
Imputation of cough counts will be applied when at least 60% of the cough monitoring 
time is present.  If less than 60% of data is available then the missing time period will not 
be imputed (with the exception of the overall 24h scenario described in Section 7.2.2).  
Imputed cough counts within each time period of interest (hourly, 10h, 24h) will be 
calculated as follows:
For example during the 10h period, if we have 3 hours of missing cough monitoring and 
the databased cough count for the remaining 7 hours is 500 then the imputed cough count 
would be:
12.5.4.
Pharmacokinetic
Pharamacokinetic Parameters

Observed Cmax

Observed AUC(0-3.5)

Observed C24 Day 8

Observed Tmax
12.5.5.
Population Pharmacokinetic (PopPK)
Estimated PK Parameters from PopPK Analyses

Model-based Cav (Average conc over 24h)

Model-based AUC(0-24)

Model-based Cmax

Model-based CL/F
Note: produced as part of the PopPK analyses and independent of SAC
12.5.6.
Operating Characteristics of Decision Criteria Based on 
Conditional Probabilities
Operating characteristics for the decision criteria were produced based on 10000 
simulations to show the long-run properties of the decision rules for a variety of 
assumptions.  For the positive criterion the operating characteristics answer the question 
“if we ran the study 10000 times, what percentage of those studies would declare a 
 
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positive result for the specified set of assumptions?”.  For the negative criterion the 
operating characteristics answer the question “if we ran the study 10000 times, what 
percentage of those studies would declare a negative result for the specified set of 
assumptions?”.
Positive Criterion
The figure below shows operating characteristics for a range of true treatment ratios and 
final sample sizes, using the variability assumed for the protocol (0.280).  This figure 
shows the percentage of studies giving a 90% conditional probability of a positive study 
at the final analysis, conditioning on a treatment ratio of 0.5 (very good effect) for the 
post-interim data.
The blue/circle line shows the operating charateristics if the true treatment ratio was 0.5.  
If the assumptions are true, a final sample size of 24 would give 86.04% of studies 
having at least 90% conditional probability of declaring a positive result when the 
variability from the protocol is assumed.  If the true treatment ratio is 1 (purple/diamond
line) only 1.78% of studies would have at-least 90% conditional probability of declaring 
a postive result.  
Similar plots were produced based on variability 80% and 120% of that assumed for the 
protocol and showed changes to these results as expected (data not shown). For example, 
assuming a smaller variance of 0.179 and larger variance of 0.403 and a true treatment 
ratio of 0.5, a final sample size of 24 would give 97.05% and 71.45% of studies, 
 
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respectively, having at least 90% conditional probability of declaring a positive result.    
Assuming a smaller variance of 0.179 and larger variance of 0.403 and a true treatment 
ratio of 1, a final sample size of 24 would give 1.63% and 1.82% of studies, 
respectively, having at least 90% conditional probability of declaring a positive result.
Negative Criterion
The figure below shows operating characteristics for a range of true treatment ratios and 
final sample sizes, using the variability assumed for the protocol (0.280).  This figure 
shows the percentage of studies giving a 90% conditional probability of a negative study 
at the final analysis, conditioning on a treatment ratio of 0.90 (minimal effect) for the 
post-interim data.
The purple/diamond line shows the operating charateristics if the true treatment ratio 
was 1.0.  If the assumptions are true, a final sample size of 24 would give 78.68% of 
studies having at least 90% conditional probability of declaring a negative result when 
the variability from the protocol is assumed.  However, if the true treatment ratio is 0.5 
(blue/circle line) only 0.57% of studies would have at-least 90% conditional probability 
of declaring a negative result.  
Similar plots were produced based on variability 80% and 120% of that assumed for the 
protocol and showed changes to these results as expected (data not shown). For example, 
assuming a smaller variance of 0.179 and larger variance of 0.403 and a true treatment 
ratio of 1.0, a final sample size of 24 would give 93.44% and 62.44% of studies, 
 
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respectively, having at least 90% conditional probability of declaring a negative result.    
Assuming a smaller variance of 0.179 and larger variance of 0.403 and a true treatment 
ratio of 0.5, a final sample size of 24 would give 0.45% and 0.75% of studies, 
respectively, having at least 90% conditional probability of declaring a negative result.
 
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12.6.
Appendix 6: Reporting Standards for Missing Data
12.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Participant study completion (i.e. as specified in the protocol) was defined as a
participant who has completed all phases of the study, including the follow-up 
visit.

Withdrawn participants will not be replaced in the study 

All available data from participants who were withdrawn from the study will be 
listed and all available planned data will be included in summary tables and 
figures, unless otherwise specified.
12.6.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument:

These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table. 

Answers such as “Not applicable” and “Not evaluable” are not considered 
to be missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
Total cough counts 
(10h, 24h, hourly)

Consideration will be given to instances where the monitor is turned off 
unexpectedly, or where a participant has a sleep period recorded during the 
primary day-time hours 10h period.

Vitalograph will provide a session acceptance file that will details removal and 
restore dates/times of the monitor for each session (e.g. period 1 day -1)

See Section 7.1.1 for further details on pro-rated data imputation.
Severity and Urge to 
Cough (VAS)

Missing data will not be replaced
LCQ

Missing data will not be replaced
12.6.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse Events

Start and End dates for adverse events must be complete in the eCRF.
Concomitant 
Medications/
Medical History

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month
o If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

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12.7.
Appendix 7: Values of Potential Clinical Importance
12.7.1.
Laboratory Values
Hematology
Analyte
Effect
Relative – Low
(Multipliers of LLN)
Relative – High
(Multipliers of ULN)
White Blood Cell Count (x109/ L)
0.67
1.82
Neutrophil Count (x109/ L)
0.83
Hemoglobin (g/L)
Male
1.03
Female
1.13
Hematocrit (ratio of 1)
Male
1.02
Female
1.17
Platelet Count (x109/ L)
0.67
1.57
Lymphocytes (x109/ L)
0.81
Monocytes (x109/ L)
0.5
1.8
Red Blood Cell Count (x109/ L)
0.7
1.7
Reticulocytes (%)
0
1.5
Chemistry
Analyte
Effect
Relative – Low
(Multipliers of LLN)
Relative – High
(Multipliers of ULN)
Calcium (mmol/L)
0.91
1.06
Glucose (mmol/L)
0.71
1.41
Potassium (mmol/L)
0.86
1.10
Sodium (mmol/L)
0.96
1.03
Blood Urea Nitrogen (mmol/L)
0.7
1.5
Total Protein (mg/dL)
0.6
1.7
Creatinine phosphokinase (IU/L)
0
1.8
Direct Bilirubin (umol/L)
0
1.6
Analyte
Effect
Relative – Low
(Absolute Value)
Relative – High
(Absolute Value)
Creatinine (umol/L) 
Chg from Baseline
> 44 umol/L
Cardiac Troponin I (ug/L)
0.09 ug/L
FOBT
Positive
Positive
Urinalysis: During the study, a dipstick result (positive or negative) will be recorded for 
each participant at each relevant timepoint.  If the dipstick result is positive, a microscopy 
will be performed.  The urinalysis dipstick result at Day 8 will be compared with Day 1 
 
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(Pre Dose) and data of PCI will be flagged where a result changes from negative to 
positive and/or a microscopy is performed.
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
≥ 2x ULN
AST/SGOT 
U/L
High
≥ 2x ULN
AlkPhos 
U/L
High
≥ 2x ULN
T Bilirubin 
µmol/L
High
≥ 1.5x ULN
T. Bilirubin + ALT
µmol/L, 
U/L
High
≥ 1.5x ULN T.Billirubin
+
≥ 2x ULN ALT
12.7.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
>500
Absolute PR Interval
msec
<110
>220
Absolute QRS Interval
msec
<75
>110
Change from Baseline
Increase from Baseline QTc
msec
>60
12.7.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
<85
>160
Diastolic Blood Pressure
mmHg
<45
>100
Heart Rate
bpm
<40
>110
Vital Sign Parameter
(Change from Baseline)
Units
Clinical Concern Range
Decrease
Increase
Lower
Upper
Lower
Upper
Systolic Blood Pressure
mmHg
≥ 20
≥ 40
≥ 20
≥ 40
Diastolic Blood Pressure
mmHg
≥ 10
≥ 20
≥ 10
≥ 20
Heart Rate
bpm
≥ 15
≥ 30
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12.8.
Appendix 8: Population Pharmacokinetic (PopPK) Analyses
12.8.1.
Population Pharmacokinetic (PopPK) Methodology
12.8.1.1.
Software
All analysis will be performed in the validated Modelling and Analysis Platform (MAP). 
MAP consists of a Linux desktop containing various modelling applications, including 
NONMEM, PsN, Pirana, R and RStudio. All software versions used will be documented.
12.8.1.2.
Outline 
The population PK analysis will be performed in the following sequence of steps:
1. Exploratory data analysis/data check out.
2. Base structural model development.
3. Covariate analysis.
4. Model refinement.
5. Model evaluation.
6. Model application using simulation
The above analysis and reporting steps follow EMEA 
(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500003067.pdf) and FDA population PK guidances 
(https://www.fda.gov/downloads/drugs/guidances/UCM072137.pdf ) 
Key components of these regulatory guidelines on population PK are also included in the 
Global CPMS guidance for pop pk RAP 
https://connect.gsk.com/sites/cpms/TandD/Guidances
The analyses described above will be the responsibility of CPMS and will be independent 
of SAC.  Further details will be provided in a separate RAP.
12.8.2.
Population Pharmacokinetic (PopPK) Dataset Specification
12.8.2.1.
Data Specification
12.8.2.2.
Dataset Variable Conventions
Column headings in NONMEM-ready datasets and specifications should be consistent to 
minimise the programming process, and facilitate a smooth transfer of projects between 
users as needed. IDSL standards will be followed where possible.
A list of most common standardised variable names for NONMEM datasets can be found
in Table below.
File to be produced for Analyte=GSK2798745 only.
 
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List of Variable Names for NONMEM-Ready Datasets for PopPK Analysis
Variable
Label (Variable description)
C
NONMEM line exclusion identifier
ID
NONMEM subject identifier
STUD
Study ID
SUBJID
Subject identifier for study
SITEID
Unique identifier for a study site
AMT
NONMEM Amount of drug administered then EVID =1- dose event record
UAMT
Unit of AMT (mg)
ADDL
NONMEM Additional dose
CONC
Drug Concentration 
UCONC
Unit of CONC (ng/mL)
LNCONC
Natural log of CONC column 
ANALYTE
Drug label e.g 745
LLQ
Lower Limit of quantification
LNLLQ
Natural log of LLQ column
DAY
Study day number of record or of dosing
TIME
Plasma sample time after last dose (actual time)
UTIME
Unit of TIME (h)
DOSE
Dose amount
EVID
NONMEM Event ID If row has dose then EVID=1 else EVID =0  
If EVID=1 then this is a dose event record
If EVID = 0 then this is an observation record 
II
NONMEM Inter-dose interval II=24 – dose every day
MDV
NONMEM Missing data value then MDV=1 else MDV=0
AGE
Subject Age (yrs)
SEX
Subject gender 0 = Male 1 =Female
SEXTEXT
Subject gender text Male or Female
BMI
Baseline Body Mass Index
WT
Baseline Subject weight
CONMED1*
Identifier for inhibitor CYP3A4 1 =Yes, 0 = No
CONMED1TXT*
Inhibitor Name
CONMED2*
Identifier for inducer CYP3A4 1 =Yes, 0 = No
CONMED2TXT*
Inducer Name
CONMED3*
Identifier for co-admin of ANY statin 1 =Yes, 0 = No
CONMED3TXT*
Statin name
CONMED4*
Identifier for co-admin of Atorvastatin 1 =Yes, 0 = No
CONMED4TXT*
ATORVASTATIN
If observation record e.g CONC  has “NA” or “NS” then assign CONC cell as  “.”
If observation record e.g CONC  has “NQ” or “BQL” then assign CONC cell as  “.” and 
MDV = 1 -this means value can be estimated by model
Missing covariate data should be imputed as “-99.
 
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Statistics & Programming in discussion with CPMS to provide dataset as specified in 
Table below based on column variables described above.   Fields marked with a ‘*’ 
above will need discussion between S&P and CPMS prior to generating the dataset, to 
identify concomitant medication data applicable to each column. 
 
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Population Pharmacokinetic (PopPK) Dataset Specification      Excel .csv file
Notes:  TIME will be actual time from dose.  File to be produced just for GSK2798745.  In example, CONMED3 represents 1 for a subject taking ANY statin and 
CONMED4 is applicable to just atorvastatin.
 
 
 
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12.9.
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses
12.9.1.
Pharmacokinetic / Pharmacodynamic Methodology
12.9.1.1.
Exposure-Response Relationship
Graphical exploration of individual predicted steady state PK exposure metric versus 
cough response (10-hour daily awake cough) on day 7 will be undertaken using both 
placebo and treatment groups. PK exposure metric for placebo group will be assigned a 
value of 0.  If there is evidence of any trend, various PK-PD models will be explored 
including linear, Emax, sigmoidal Emax relationships.
PK exposure metrics include: Day 7 Cmax (predicted), Cav (predicted) and C24
(observed) on day 8
Clinical endpoint: Baseline: Day -1 & Day 7 total day-time cough count (10 hours)
Using Monte-Carlo simulations, the optimal PK-PD model for cough count will be 
applied to provide estimate of systemic exposure range associated with significant 
clinical response (10h awake cough count) from which optimal dose of GSK2798745 can 
be estimated for future studies, taking into account estimate of PK variability of parent 
drug. 
The analyses described above will be the responsibility of CPMS and will be independent 
of SAC.  Further details will be provided in a separate RAP.
12.9.2.
Pharmacokinetic / Pharmacodynamic Dataset Specification
12.9.2.1.
Data Specification
12.9.2.2.
Dataset Variable Conventions
Column headings in NONMEM-ready datasets and specifications should be consistent to 
minimise the programming process, and facilitate a smooth transfer of projects between
users as needed. IDSL standards will be followed where possible.
A list of most common standardised variable names for NONMEM datasets can be found
in Table below.
File to be produced for Analyte=GSK2798745 only.
List of Variable Names for NONMEM-Ready Datasets for Pop PK-PD Analysis
Variable
Label (Variable description)
Source (other sources may 
be used)
C
NONMEM line exclusion identifier
Derived as ‘.’ – see example, 
required for software
ID
NONMEM subject identifier
Derived – set to 
 etc & 
linked to SUBJID – see 
example
STUD
Study ID
ARDATA.POP (STUDYID)
 
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Variable
Label (Variable description)
Source (other sources may 
be used)
SUBJID
Subject identifier for study
ARDATA.POP (SUBJID)
SITEID
Unique identifier for a study site
ARDATA.POP 
(CENTREID)
DAY
Study day Day -1 10h cough count before dosing. 
Day 7 10h cough count after day 7 dose
PKCNC (derive from VISIT)
PK1
Predicted Cmax on day 7 – Provided by POPPK 
analysis*
Create variable but leave 
blank
PK2
Predicted Cav on day 7 - Provided by POPPK 
analysis*
Create variable but leave 
blank
PK3
Predicted  C24 on day 8 - Provided by POPPK 
analysis*
Create variable but leave 
blank
Analyte
GSK2798745
ARDATA.PKCNC
R10BASE1
Raw baseline 10h cough count before period 1
ARDATA.COUGHTOT (see 
notes)
R10BASE2
Raw baseline 10h cough count before period 2
As above
RPD10
Raw 10h awake cough count [primary endpoint] 
As above
R24BASE1
Raw baseline 24h cough count before period 1
As above
R24BASE2
Raw baseline 24h cough count before period 2
As above
RPD24
Raw 24h cough count total
As above
I10BASE1
Imputed baseline 10h cough count before period 1
As above
I10BASE2
Imputed baseline 10h cough count before period 2
As above
IPD10
Imputed 10h awake cough count [primary endpoint] As above
I24BASE1
Imputed baseline 24h cough count before period 1
As above
I24BASE2
Imputed baseline 24h cough count before period 2
As above
IPD24
Imputed 24h cough count total
As above
F10BASE1
Flag for imputed baseline 10h cough count before 
period 1
As above
F10BASE2
Flag for imputed baseline 10h cough count before 
period 2
As above
FPD10
Flag for imputed 10h awake cough count [primary 
endpoint] 
As above
F24BASE1
Flag for imputed baseline 24h cough count before 
period 1
As above
F24BASE2
Flag for imputed baseline 24h cough count before 
period 2
As above
FPD24
Flag for imputed 24h cough count total
As above
AGE
Subject Age (yrs)
ARDATA.DEMO
SEX
Subject gender 0 = Male 1 =Female
ARDATA.DEMO
SEXTEXT
Subject gender text Male or Female
ARDATA.DEMO
BMI
Baseline Body Mass Index
ARDATA.DEMO
WT
Baseline Subject weight
ARDATA.DEMO
TMT
1 = Placebo ; 2 = Drug
ARDATA.TRT
TMTTEXT
Treatment text Placebo or GSK2798745
ARDATA.TRT
 
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Variable
Label (Variable description)
Source (other sources may 
be used)
PERIOD
1 = Period 1 ; 2 = Period 2
ARDATA.TRT
Statistics & Programming in discussion with CPMS to provide dataset as specified in 
Table below based on column variables described above.   
*The  predicted POPPK parameters detailed above will be generated by CPMS.  The Pop 
PK-PD dataset above will be generated by programming with these variables included as 
blank, for CPMS to populate at a later date.
Note to programmers for cough data: 
Variables, R*, I* and F* can be obtained from A&R dataset COUGHTOT.  
Cough totals are COUGHTOT (raw totals) and COUGHIMP (imputed totals)
Select where FLAGHR=100 and FLAGHR=240 to get 10h and 24h totals.
Select where VISITNUM in (20, 60) to get Day -1 totals for Period 1 and 2.
Select where VISITNUM in (40, 80) to get Day 7 totals for Period 1 and 2.
FLAGIMP will indicate if imputation occurred at timepoint of interest.  
 
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Population Pharmacokinetic-Pharmacodynamic (Pop PK-PD) Dataset Specification      Excel .csv file
 
 
 
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12.10.
Appendix 10: Abbreviations & Trade Marks
12.10.1.
Abbreviations
Abbreviation
Description
AE
Adverse Event
ALT
Alanine aminotranferase
A&R
Analysis and Reporting 
AST
Aspartate aminotransferase
AUC
Area under the concentration time curve
BMI
Body mass index
BUN
Blood urea nitrogen
Cav
Average concentration of drug over the dosing interval
CI
Confidence Interval
Cmax
Maximum observed plasma concentration
CPK
Creatinine phosphokinase
CPMS
Clinical Pharmacology Modelling & Simulation
CPSR
Clinical Pharmacology Study Report
CSSRS
Columbia Suicidality Severity Rating Scale
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DP
Decimal Places
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
FOBT
Faecal Occult Blood Test
GSK
GlaxoSmithKline
h
Hours
IA
Interim Analysis
ICH
International Conference on Harmonization
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
LCQ
Leicester Cough Questionnaire
LDH
Lactate dehydrogenase
LLN
Lower limit of normal
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular volume
mg
Milligrams
MHRA
Medicine and Healthcare Products Regulatory Agency
mm
Millimetres
MMRM
Mixed Model Repeated Measures
N
Number
 
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Abbreviation
Description
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Fridericia’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
RBC
Red blood cells
S&P
Statistics and Programming
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event(s)
SI
System Independent
SOP
Standard Operation Procedure
TFL
Tables, Figures & Listings 
Tmax
Time to maximum observed concentration
UK
United Kingdom
ULN
Upper limit of normal
VAS
Visual Analogue Scale
WBC
White blood cells
12.10.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
HARP
WinNonlin
RANDALL NG
SAS
NONMEM
 
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12.11.
Appendix 11: List of Data Displays
12.11.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
1.1 to 1.n
Efficacy
2.1 to 2.n
2.1 to 2.n
Safety
3.1 to 3.n
3.1 to 3.n
Pharmacokinetic
4.1 to 4.n
4.1 to 4.n
Population Pharmacokinetic (PopPK)
5.1 to 5.n
5.1 to 5.n
Pharmacodynamic and / or Biomarker
6.1 to 6.n
6.1 to 6.n
Pharmacokinetic / Pharmacodynamic
7.1 to 7.n
7.1 to 7.n
Section
Listings
ICH Listings
1 to x
Other Listings
y to z
Note that all displays (Tables, Figures & Listings) will use the term 'Subjects'.
12.11.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 12: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Population Pharmacokinetic (PopPK)
POPPK_Fn
POPPK_Tn
POPPK_Ln
Pharmacodynamic and / or Biomarker
PD_Fn
PD_Tn
PD_Ln
Pharmacokinetic / Pharmacodynamic
PKPD_Fn
PKPD_Tn
PK/PD_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
12.11.3.
Deliverables
Delivery [Priority] [1]
Description
IA GSK [X]
Interim Analysis Statistical Analysis Complete – Outputs to be generated by GSK
SAC [X]
Final Statistical Analysis Complete – Outputs to be generated by FSP
SAC GSK [X]
Final Statistical Analysis Complete – Outputs to be generated by GSK
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort
 
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12.11.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
All Subjects
ES1A
Summary of Participant Disposition for the Participant
Conclusion Record
ICH E3, FDAAA, EudraCT
SAC [2]
1.2.
All Subjects
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
ICH E3
SAC [2]
1.3.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
SAC [2]
Protocol Deviation
1.4.
All Subjects
DV1
Summary of Important Protocol Deviations
ICH E3
SAC [2]
Population Analysed
1.5.
All Subjects
SP1A
Summary of Study Populations 
IDSL
SAC [2]
Demographic and Baseline Characteristics
1.6.
All Subjects
DM3
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
SAC [2]
1.7.
All Subjects
DM11
Summary of Age Ranges
EudraCT
SAC [2]
1.8.
All Subjects
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
SAC [2]
Prior and Concomitant Medications
1.9.
All Subjects
MH1
Summary of Past Medical Conditions
ICH E3
SAC [2]
1.10.
All Subjects
MH1
Summary of Current Medical Conditions
ICH E3 
SAC [2]
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.11.
All Subjects
CM1
Summary of Concomitant Medications
ICH E3 See IDSL for options 
related to ATC groupings and 
multi-ingredient medications. 
SAC [2]
Exposure and Treatment Compliance
1.12.
All Subjects
EX1
Summary of Exposure to Study Treatment
ICH E3 Dose and/or time on 
treatment, as applicable. Many 
possible considerations; defer to 
therapy area standards where 
available. 
SAC [2]
1.13.
All Subjects
POP_L1
Listing of Compliance
SAC [2]
 
 
 
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12.11.5.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
10H Total Cough Count
2.1.
All Subjects
EF_T2
Summary of Day-Time 10h Total Cough Counts
Include raw cough counts and imputed 
cough counts as per mock-up, 
geometric means for log-transformed 
data on second page
SAC GSK [1]
2.2.
All Subjects
EF_T1
Summary of Statistical Analysis of Day-Time 10h Total Cough 
Counts at Day 7
Statistical analysis to be based on 
imputed cough counts
IA GSK, SAC
GSK [1]
2.3.
All Subjects
EF_T1
Summary of Statistical Analysis of Day-Time 10h Total Cough 
Counts at Day 7 (Sensitivity)
Statistical analysis to be based on non-
imputed cough counts
SAC GSK [1]
24H Total Cough Count
2.4.
All Subjects
EF_T2
Summary of 24h Total Cough Counts
Include raw cough counts and imputed 
cough counts as per mock-up, 
geometric means for log-transformed 
data on second page
SAC GSK [1]
2.5.
All Subjects
EF_T1
Summary of Statistical Analysis of 24h Total Cough Counts at
Day 7
Statistical analysis to be based on 
imputed cough counts
SAC GSK [1]
2.6.
All Subjects
EF_T1
Summary of Statistical Analysis of 24h Total Cough Counts 
atDay 7 (Sensitivity)
Statistical analysis to be based on non-
imputed cough counts
SAC GSK [1]
Severity of Cough (VAS)
2.7.
All Subjects
EF_T3
Summary of Severity of Cough (VAS)
Collected at Screening, D1(Pre-Dose), 
D7(Pre-Dose) and FU
SAC [2]
2.8.
All Subjects
EF_T4
Summary of Change From Baseline in Severity of Cough (VAS)
Include change from baseline to 
D7(Pre-Dose) only
SAC [2]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.9.
All Subjects
EF_T5
Summary of Statistical Analysis of Change From Baseline in 
Severity of Cough (VAS) at Day 7
Analysis of change from baseline 
D1(Pre-Dose) to D7(Pre-Dose)
SAC [2]
Urge to Cough (VAS)
2.10.
All Subjects
EF_T3
Summary of Urge to Cough (VAS)
Collected at D1(Pre-Dose), D7(Pre-
Dose) and FU
SAC [2]
2.11.
All Subjects
EF_T4
Summary of Change From Baseline in Urge to Cough (VAS)
Include change from baseline to 
D7(Pre-Dose) only
SAC [2]
2.12.
All Subjects
EF_T5
Summary of Statistical Analysis of Change From Baseline in 
Urge to Cough (VAS) at Day 7
Analysis of change from baseline 
D1(Pre-Dose) to D7(Pre-Dose)
SAC [2]
Leicester Cough Questionnaire (LCQ)
2.13.
All Subjects
EF_T6
Summary of the Leicester Cough Questionnaire (LCQ)
Summarise each of the 3 domains and 
an overall total score.
Collected at D1(Pre-Dose) and D7(Pre-
Dose)
SAC [2]
2.14.
All Subjects
EF_T7
Summary of Change From Baseline in the Leicester Cough 
Questionnaire (LCQ)
Include change from baseline to 
D7(Pre-Dose) for domain scores and 
total
SAC [2]
2.15.
All Subjects
EF_T8
Statistical Analysis of Change From Baseline in the Leicester 
Cough Questionnaire (LCQ) at Day 7
4 x analyses, one for each domain and 
overall score
SAC [2]
 
 
 
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12.11.6.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
10H Total Cough Count and 24 Total Cough Count
2.1.
All Subjects
EF_F1
Summary of Geometric Means and 95% CI for Baseline and Day 
7 10h Day-time Cough Counts, by Treatment Group
Footnote to include ‘Note: Imputed data 
is presented, where cough counts are 
pro-rated based on a minimum of 60% 
of data being available’
IA GSK, SAC 
GSK [1]
2.2.
All Subjects
EF_F1
Summary of Geometric Means and 95% CI for Baseline and Day 
7 24h Day-time Cough Counts, by Treatment Group
Follow example EF_F1 but use 24 hour 
totals (imputed). Footnote as above.
SAC GSK [1]
2.3.
All Subjects
EF_F2
Summary of Geometric Means and 95% CI by Hourly Intervals 
(0-10h) for Day 7 Cough Counts
If zero counts are present and log-
transformation of hourly totals not 
possible, then this figure will present 
arithmetic means and 95% CI instead.
Footnote as above. 
IA GSK, SAC 
GSK [1]
2.4.
All Subjects
EF_F2
Summary of Geometric Means and 95% CI by Hourly Intervals 
(0-24h) for Day 7 Cough Counts
If zero counts are present and log-
transformation of hourly totals not 
possible, then this figure will present 
arithmetic means and 95% CI instead.
Footnote as above.
SAC GSK [1]
2.5.
All Subjects
EF_F3
Individual Subject Profiles of Cough Count Totals by 1 Hour 
Intervals (0-10h) Day 7
4 subjects per page, hourly timepoint 
e.g 0-1h, 1-2h etc on the x-axis, cough 
total on the y-axis, treatment group in a 
legend.
Display imputed hourly data (pro-rated) 
for this plot.  
Footnote as above.
SAC GSK [1]
 
 
 
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Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.6.
All Subjects
EF_F3
Individual Subject Profiles of Cough Count Totals by 1 Hour 
Intervals (0-24h) Day 7
4 subjects per page, hourly timepoint 
e.g 0-1h, 1-2h etc on the x-axis, cough 
total on the y-axis, treatment group in a 
legend.  Extend to 24h.
Display imputed hourly data (pro-rated) 
for this plot. 
Footnote as above. 
SAC GSK [1]
2.7.
All Subjects
EF_F4
Boxplots of Cough Count Totals by 1 Hour Intervals (0-10h) Day 
7
Hourly timepoint e.g 0-1h, 1-2h etc on 
the x-axis.  Cough count total on the y-
axis.  Treatment group in a legend. 
Display imputed hourly data (pro-rated) 
for this plot.  
Footnote as above.
SAC GSK [1]
2.8.
All Subjects
EF_F4
Boxplots of Cough Count Totals by 1 Hour Intervals (0-24h) Day 
7
Hourly timepoint e.g 0-1h, 1-2h etc on 
the x-axis.  Cough count total on the y-
axis.  Treatment group in a legend. 
Display imputed hourly data (pro-rated) 
for this plot.   Extend to 24h.
Footnote as above.
SAC GSK [1]
2.9.
All Subjects
EF_F5
Individual 10h Cough Counts Day 7
Subject on the x-axis and 10h totals by 
treatment on the y-axis, with a legend 
for treatment group.  Display imputed 
10h data (pro-rated).
Footnote as above.
SAC GSK [1]
 
 
 
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Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.10.
All Subjects
EF_F5
Individual 24h Cough Counts Day 7
Subject on the x-axis and 24h totals by 
treatment on the y-axis, with a legend 
for treatment group.  Display imputed 
24h data (pro-rated).
Follow example EF_F5 but extend to 
24h.
Footnote as above.
SAC GSK [1]
2.11.
All Subjects
EF_F6
Individual Changes From Baseline in 10h Day-time Cough 
Counts
Individual subjects changes from 
baseline (Day -1) to Day 7 by 
treatment. 10h totals.
Footnote as above.
SAC GSK [1]
2.12.
All Subjects
EF_F6
Individual Changes From Baseline in 24h Day-time Cough 
Counts
Individual subjects changes from 
baseline (Day -1) to Day 7 by 
treatment. 24h totals.
Footnote as above.
SAC GSK [1]
2.13.
All Subjects
EF_F7
Adjusted Median Responses and 95% Cr. Intervals for 10h Total 
Cough Counts on Day 7
X-axis can say ‘Day 7’.  Y-axis will be 
median cough counts with 95% CrIs 
(back-transformed estimates).  
Treatment group in a legend.
Footnote as per mock example.
SAC GSK [1]
2.14.
All Subjects
EF_F7
Adjusted Median Responses and 95% Cr. Intervals for 24h Total 
Cough Counts on Day 7
X-axis can say ‘Day 7’.  Y-axis will be 
median cough counts and 95% CrIs 
(back-transformed estimates).  
Treatment group in a legend.
Footnote as per mock example.
SAC GSK [1]
2.15.
All Subjects
EF_F1
Summary of Geometric Means and 95% CI for Baseline and Day 
7 10h Day-time Cough Counts, by Treatment Group by Prior 
Cough Study Participation
Footnote to include ‘Note: Imputed data 
is presented, where cough counts are 
pro-rated based on a minimum of 60% 
of data being available’
SAC GSK [2]
 
 
 
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Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.16.
All Subjects
EF_F1
Summary of Geometric Means and 95% CI for Baseline and Day 
7 24h Day-time Cough Counts, by Treatment Group by Prior 
Cough Study Participation
Follow example EF_F1 but use 24 hour 
totals (imputed). Footnote as above.
SAC GSK [2]
2.17.
All Subjects
EF_F2
Summary of Geometric Means and 95% CI by Hourly Intervals 
(0-10h) for Day 7 Cough Counts by Prior Cough Study 
Participation
If zero counts are present and log-
transformation of hourly totals not 
possible, then this figure will present 
arithmetic means and 95% CI instead.
Footnote as above. 
SAC GSK [2]
2.18.
All Subjects
EF_F2
Summary of Geometric Means and 95% CI by Hourly Intervals 
(0-24h) for Day 7Cough Counts by Prior Cough Study 
Participation
If zero counts are present and log-
transformation of hourly totals not 
possible, then this figure will present 
arithmetic means and 95% CI instead.
Footnote as above.
SAC GSK [2]
2.19.
All Subjects
EF_F6
Individual Changes From Baseline in 10h Day-time Cough 
Counts by Period
Individual subjects changes from 
baseline (Day -1) to Day 7 by treatment 
and period. 10h totals.
Footnote as above.
SAC GSK [1]
2.20.
All Subjects
EF_F6
Individual Changes From Baseline in 24h Day-time Cough 
Counts by Period
Individual subjects changes from 
baseline (Day -1) to Day 7 by treatment 
and period. 24h totals.
Footnote as above.
SAC GSK [1]
2.21.
All Subjects
EF_F1
Summary of Geometric Means and 95% CI for Baseline and Day 
7 10h Day-time Cough Counts, by Treatment Group and Period
Footnote as above.
IA GSK, SAC 
GSK [1]
2.22.
All Subjects
EF_F1
Summary of Geometric Means and 95% CI for Baseline and Day 
7 24h Day-time Cough Counts, by Treatment Group and Period
Footnote as above.
SAC GSK [1]
 
 
 
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Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Severity of Cough (VAS)
2.23.
All Subjects
EF_F1
Summary of Severity of Cough (VAS) (Means 95% CI) by Visit
X-axis will be Day -1 and Day 7.  Y-axis 
will be mean cough severity 95% CI.  
Similar to example EF_F1 but with 
arithmetic means.
SAC [2]
2.24.
All Subjects
EF_F7
Adjusted Median Responses and 95% Cr. Intervals for Change 
From Baseline in Severity of Cough (VAS)
X-axis can say ‘Day 7 (PD)’.  Y-axis will 
be median CFB cough severity and 
95% CrIs.  Treatment group in a legend 
or on x-axis.
SAC [2]
Urge to Cough (VAS)
2.25.
All Subjects
EF_F1
Summary of Urge to Cough (VAS) (Means 95% CI) by Visit
X-axis will be Day -1 and Day 7.  Y-axis 
will be mean urge to cough 95% CI.  
Similar to example EF_F1 but with 
arithmetic means.
SAC [2]
2.26.
All Subjects
EF_F7
Adjusted Median Responses and 95% Cr. Intervals for Change 
From Baseline in Urge to Cough (VAS)
X-axis can say ‘Day 7 (PD)’.  Y-axis will 
be median CFB urge to cough and 95% 
CrIs.  Treatment group in a legend or 
on x-axis.
SAC [2]
Leicester Cough Questionnaire (LCQ)
2.27.
All Subjects
EF_F1
Summary of Leicester Cough Questionnaire (LCQ) (Means 
95% CI) by Visit
X-axis will be Day -1 and Day 7.  Y-axis 
will be mean score 95% CI.  
4 pages one for each of the 3 domains 
and one for total score.
Similar to example EF_F1 but with 
arithmetic means.
SAC [2]
 
 
 
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Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.28.
All Subjects
EF_F7
Adjusted Median Responses and 95% Cr. Intervals for Change 
From Baseline in Leicester Cough Questionniare (LCQ)
X-axis can say ‘Day 7 (PD)’.  Y-axis will 
be median CFB LCQ score and 95% 
CrIs.  Treatment group in a legend or 
on x-axis.
4 pages one for each of the 3 domains 
and one for total score
SAC [2]
12.11.7.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
All Subjects
AE1CP
Summary of All Adverse Events by System Organ Class and 
Preferred Term
ICH E3
SAC [2]
3.2.
All Subjects
AE1CP
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term/by Overall Frequency
ICH E3
.
SAC [2]
Serious and Other Significant Adverse Events
3.3.
All Subjects
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences)
FDAAA, EudraCT
SAC [2]
Laboratory: Chemistry 
3.4.
All Subjects
LB1
Summary of Chemistry Changes from Baseline 
ICH E3
SAC [2]
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Hematology
3.5.
All Subjects
LB1
Summary of Hematology Changes from Baseline
ICH E3
SAC [2]
ECG
3.6.
All Subjects
EG1
Summary of ECG Findings 
IDSL
SAC [2]
3.7.
All Subjects
EG2
Summary of Change from Baseline in ECG Values by Visit
IDSL
SAC [2]
Vital Signs
3.8.
All Subjects
VS1
Summary of Change from Baseline in Vital Signs
ICH E3
Include Weight as well as Blood 
Pressure, HR and Temperature
SAC [2]
CSSRS
3.9.
All Subjects
CSSRS4
Listing of C-SSRS Suicidal Ideation and Behaviour Data
Refer to IDSL guidance and example 
CSSRS4.  For studies with very few 
suicical events expected, this listing can 
substitute the summary table.
SAC [2]
Audiometry
3.10.
All Subjects
SAF_L1
Listing of Audiometry
Add footnote:  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).
SAC [2]
 
 
 
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12.11.8.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentration
4.1.
PK
PKCT1 (PK01)
Summary of GSK2798745 Pharmacokinetic Concentration-Time 
Data (ng/mL)
SAC [2]
4.2.
PK
PKCT1 (PK01)
Summary of GSK2798745 M1 Metabolite Pharmacokinetic 
Concentration-Time Data (ng/mL)
SAC [2]
4.3.
PK
PKCT1 (PK01)
Summary of Atorvastatin Pharmacokinetic Concentration-Time 
Data (ng/mL)
Add footnote ‘Planned Relative Time is 
based on last dose of GSK2798745 but 
the timing of the last dose of 
Atorvastatin may vary.’
SAC [2]
4.4.
PK
PKCT1 (PK01)
Summary of Atorvastatin Metabolite Pharmacokinetic 
Concentration-Time Data (ng/mL)
Add footnote ‘Planned Relative Time is 
based on last dose of GSK2798745 but 
the timing of the last dose of 
Atorvastatin may vary.’
SAC [2]
 
 
 
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Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Parameter
4.5.
PK
PKPT1 (PK03)
Summary Statistics of Derived Plasma GSK2798745
Pharmacokinetic Parameters
SAC [2]
4.6.
PK
PKPT1 (PK03)
Summary Statistics of Derived Plasma GSK2798745 M1 
Metabolite Pharmacokinetic Parameters
SAC [2]
4.7.
PK
PKPT1 (PK03)
Summary Statistics of Derived Plasma Atorvastatin
Pharmacokinetic Parameters
SAC [2]
4.8.
PK
PKPT1 (PK03)
Summary Statistics of Derived Plasma Atorvastatin Metabolite
Pharmacokinetic Parameters
SAC [2]
4.9.
PK
PKPT3 (PK05)
Summary Statistics of Log-Transformed Derived Plasma 
GSK2798745 Pharmacokinetic Parameters
SAC [2]
4.10.
PK
PKPT3 (PK05)
Summary Statistics of Log-Transformed Derived Plasma 
GSK2798745 M1 Metabolite Pharmacokinetic Parameters
SAC [2]
4.11.
PK
PKPT3 (PK05)
Summary Statistics of Log-Transformed Derived Plasma 
Atorvastatin Pharmacokinetic Parameters
SAC [2]
4.12.
PK
PKPT3 (PK05)
Summary Statistics of Log-Transformed Derived Plasma 
Atorvastatin Metabolite Pharmacokinetic Parameters
SAC [2]
 
 
 
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12.11.9.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentration
4.1.
PK
PKCF1X 
(PK16b)
Individual GSK2798745 Plasma Concentration–Time Plots 
(Linear and Semi-log)
By Subject plots – by visit (Day 1 
pre-dose to 3.5h profile and Day 7 
pre-dose to 24h profile)
SAC [2]
4.2.
PK
PKCF6 (PK24)
Individual GSK2798745 Plasma Concentration–Time Plot
(Linear and Semi-log)
Limit to 12 subjects per graphic split 
over pages (e.g. 2 pages for N=24, 
3 pages for N=36)
SAC [2]
4.3.
PK
PKCF2 (PK17)
Mean Plasma GSK2798745 Concentration-Time Plot (Linear 
and Semi-Log)
SAC [2]
4.4.
PK
PKCF3 (PK18)
Median Plasma GSK2798745 Concentration-Time Plot (Linear 
and Semi-Log)
SAC [2]
4.5.
PK
PKCF1X 
(PK16b)
Individual GSK2798745 Metabolite M1 Plasma Concentration–
Time Plots (Linear and Semi-log)
By Subject plots – by visit (Day 1 
pre-dose to 3.5h profile and Day 7 
pre-dose to 24h profile)
SAC [2]
4.6.
PK
PKCF6 (PK24)
Individual GSK2798745 Metabolite M1 Plasma Concentration–
Time Plot
(Linear and Semi-log)
Limit to 12 subjects per graphic split 
over pages (e.g. 2 pages for N=24, 
3 pages for N=36)
SAC [2]
 
 
 
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Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.7.
PK
PKCF2 (PK17)
Mean Plasma GSK2798745 Metabolite M1 Concentration-Time 
Plot (Linear and Semi-Log)
SAC [2]
4.8.
PK
PKCF3 (PK18)
Median Plasma GSK2798745 Metabolite M1 Concentration-
Time Plot (Linear and Semi-Log)
SAC [2]
4.9.
PK
PKCF1X 
(PK16b)
Individual Atorvastatin Plasma Concentration–Time Plots 
(Linear and Semi-log)
By Subject plots – by visit (Day 1 
pre-dose to 3.5h profile and Day 7 
pre-dose to 24h profile)
Add footnote ‘Planned Relative Time is 
based on last dose of GSK2798745 but 
the timing of the last dose of 
Atorvastatin may vary.’
SAC [2]
4.10.
PK
PKCF6 (PK24)
Individual Atorvastatin Plasma Concentration–Time Plot
(Linear and Semi-log)
Limit to 12 subjects per graphic split 
over pages (e.g. 2 pages for N=24, 
3 pages for N=36)
Add footnote ‘Planned Relative Time is 
based on last dose of GSK2798745 but 
the timing of the last dose of 
Atorvastatin may vary.’
SAC [2]
4.11.
PK
PKCF2 (PK17)
Mean Plasma Atorvastatin Concentration-Time Plot (Linear and 
Semi-Log)
Add footnote ‘Planned Relative Time is 
based on last dose of GSK2798745 but 
the timing of the last dose of 
Atorvastatin may vary.’
SAC [2]
4.12.
PK
PKCF3 (PK18)
Median Plasma Atorvastatin Concentration-Time Plot (Linear 
and Semi-Log)
Add footnote ‘Planned Relative Time is 
based on last dose of GSK2798745 but 
the timing of the last dose of 
Atorvastatin may vary.’
SAC [2]
 
 
 
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Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.13.
PK
PKCF1X 
(PK16b)
Individual Atorvastatin Metabolite Plasma Concentration–Time 
Plots (Linear and Semi-log)
By Subject plots – by visit (Day 1 
pre-dose to 3.5h profile and Day 7 
pre-dose to 24h profile)
Add footnote ‘Planned Relative Time is 
based on last dose of GSK2798745 but 
the timing of the last dose of 
Atorvastatin may vary.’
SAC [2]
4.14.
PK
PKCF6 (PK24)
Individual Atorvastatin Metabolite Plasma Concentration–Time 
Plot
(Linear and Semi-log)
Limit to 12 subjects per graphic split 
over pages (e.g. 2 pages for N=24, 
3 pages for N=36)
Add footnote ‘Planned Relative Time is 
based on last dose of GSK2798745 but 
the timing of the last dose of 
Atorvastatin may vary.’
SAC [2]
4.15.
PK
PKCF2 (PK17)
Mean Plasma Atorvastatin Metabolite Concentration-Time Plot 
(Linear and Semi-Log)
Add footnote ‘Planned Relative Time is 
based on last dose of GSK2798745 but 
the timing of the last dose of 
Atorvastatin may vary.’
SAC [2]
4.16.
PK
PKCF3 (PK18)
Median Plasma Atorvastatin Metabolite Concentration-Time 
Plot (Linear and Semi-Log)
Add footnote ‘Planned Relative Time is 
based on last dose of GSK2798745 but 
the timing of the last dose of 
Atorvastatin may vary.’
SAC [2]
 
 
 
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12.11.10. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC [2]
2.
All Subjects
ES2
Listing of Reasons for Study Withdrawal
ICH E3
SAC [2]
3.
All Subjects
SD3
Listing of Reasons for Study Treatment Discontinuation
ICH E3
SAC [2]
4.
All Subjects
BL2
Listing of Participants for Whom the Treatment Blind was Broken
ICH E3
SAC [2]
5.
All Subjects
CP_RA1x
Listing of Planned and Actual Treatments
IDSL
SAC [2]
Protocol Deviations
6.
All Subjects
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC [2]
7.
All Subjects
IE4
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
ICH E3
SAC [2]
Populations Analysed
8.
All Subjects
SP3a
Listing of Participants Excluded from Any Population
ICH E3
SAC [2]
Demographic and Baseline Characteristics
9.
All Subjects
DM4
Listing of Demographic Characteristics
ICH E3
SAC [2]
10.
All Subjects
DM10
Listing of Race
ICH E3
SAC [2]
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Prior and Concomitant Medications
11.
All Subjects
CP_CM4
Listing of Concomitant Medications
IDSL
SAC
Exposure and Treatment Compliance
12.
All Subjects
EX4
Listing of Exposure Data
ICH E3
SAC [2]
Adverse Events
13.
All Subjects
AE9CP
Listing of All Adverse Events
ICH E3
SAC [2]
14.
All Subjects
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC [2]
Serious and Other Significant Adverse Events
15.
All Subjects
AE9CPa
Listing of Serious Adverse Events
ICH E3
SAC [2]
16.
All Subjects
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3. Provides additional detail from 
SAE form e.g hospitalisation (Y/N) etc
SAC [2]
17.
All Subjects
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
SAC [2]
All Laboratory
18.
All Subjects
LB6
Listing of All Clinical Chemistry Data for Participants with Any 
Value of Potential Clinical Importance/Outside Normal Range
ICH E3
SAC [2]
19.
All Subjects
LB6
Listing of Clinical Chemistry Values of Potential Clinical 
Importance
SAC [2]
20.
All Subjects
LB6
Listing of All Hematology Data for Participants with Any Value of 
Potential Clinical Importance/Outside Normal Range
SAC [2]
21.
All Subjects
LB6
Listing of Hematology Values of Potential Clinical Importance
SAC [2]
22.
All Subjects
LB14
Listing of Laboratory Data with Character Results
ICH E3
SAC [2]
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
23.
All Subjects
UR2B
Listing of Urinalysis Data for Participants with Any Value of 
Potential Clinical Importance
ICH E3
SAC [2]
ECGs
24.
All Subjects
EG4
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance
IDSL
SAC [2]
25.
All Subjects
EG4
Listing of ECG Values of Potential Clinical Importance
IDSL
SAC [2]
26.
All Subjects
EG6
Listing of All ECG Findings for Participants with an Abnormal 
ECG Finding
IDSL
SAC [2]
27.
All Subjects
EG6
Listing of Abnormal ECG Findings
IDSL
SAC [2]
Vital Signs
28.
All Subjects
VS5
Listing of All Vital Signs Data for Participants with Any Value of 
Potential Clinical Importance
IDSL
SAC [2]
29.
All Subjects
VS5
Listing of Vital Signs of Potential Clinical Importance
IDSL
SAC [2]
 
 
 
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12.11.11. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
30.
All Subjects
EF_L1
Listing of Hourly and Total Cough Counts
SAC GSK [1]
31.
All Subjects
EF_L2
Listing of Severity and Urge to Cough (VAS)
SAC [2]
32.
All Subjects
EF_L3
Listing of Leicester Cough Questionnaire (LCQ)
SAC [2]
33.
All Subjects
-
Listing of SAS Output for 10h Total Cough Count Analysis
SAC GSK [1]
34.
All Subjects
-
Listing of SAS Output for 24h Total Cough Count Analysis
SAC GSK [1]
35.
All Subjects
-
Listing of SAS Output for CFB Severity to Cough Analysis
SAC [2]
36.
All Subjects
-
Listing of SAS Output for CFB Urge to Cough Analysis
SAC [2]
37.
All Subjects
-
Listing of SAS Output for CFB Leicester Cough Questionnaire 
Analysis
SAC [2]
38.
PK
PKCL1X 
(PK08)
Listing of GSK2798745 Plasma Pharmacokinetic 
Concentration–Time Data
SAC [2]
39.
PK
PKPL1X 
(PK14)
Listing of Derived GSK2798745 Plasma Pharmacokinetic 
Parameters
SAC [2]
40.
PK
PKCL1X 
(PK08)
Listing of GSK2798745 Metabolite M1 Plasma Pharmacokinetic 
Concentration–Time Data
SAC [2]
41.
PK
PKPL1X 
(PK14)
Listing of Derived GSK2798745 Metabolite M1 Plasma 
Pharmacokinetic Parameters
SAC [2]
42.
PK
PKCL1X 
(PK08)
Listing of Atorvastatin Plasma Pharmacokinetic Concentration–
Time Data
SAC [2]
43.
PK
PKPL1X 
(PK14)
Listing of Derived Atorvastatin Plasma Pharmacokinetic 
Parameters
SAC [2]
 
 
 
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Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
44.
PK
PKCL1X 
(PK08)
Listing of Atorvastatin Metabolite Plasma Pharmacokinetic 
Concentration–Time Data
Add footnote ‘Planned Relative Time is 
based on last dose of GSK2798745 but 
the timing of the last dose of 
Atorvastatin may vary.’
SAC [2]
45.
PK
PKPL1X 
(PK14)
Listing of Derived Atorvastatin Metabolite Plasma 
Pharmacokinetic Parameters
Add footnote ‘Planned Relative Time is 
based on last dose of GSK2798745 but 
the timing of the last dose of 
Atorvastatin may vary.’
SAC [2]
 
 
 
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12.12.
Appendix 12: Example Mock Shells for Data Displays
Data Display Specification will be made available on Request
 
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