A Randomized, Double-blind, Sponsor Un-blinded, Placebo-controlled, Phase 2a Crossover Study to Evaluate the Effect of the TRPV4 Channel Blocker, GSK2798745, on Pulmonary Gas Transfer and Respiration in Patients With Congestive Heart Failure
Phase: PHASE2
Conditions: Heart Failure
Sponsor: GlaxoSmithKline

2014N221874_02
CONFIDENTIAL
The GlaxoSmithKline group of companies
201881
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Randomized, Double-blind, Sponsor un-blinded, Placebo-
controlled, Phase 2a Crossover Study to Evaluate the Effect of 
the TRPV4 Channel Blocker, GSK2798745, on Pulmonary Gas 
Transfer and Respiration in Patients with Congestive Heart 
Failure
Compound Number: GSK2798745
Development Phase:
II
Effective Date:
19-APR-2016
Protocol Amendment Number:  02
Author(s):
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2014N221874_00
2015-MAY-19
Original
2014N221874_01
2015-JUL-29
Amendment No. 1
This amendment incorporates the changes requested during the FDA review of the IND.
2014N221874_02
2016-APR-19
Amendment No. 2
This amendment incorporates minor changes to eligibility (NT proBNP, BMI).
PPD
Copyright 2016the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.

PPD
PPD
PPD

2014N221874_02
CONFIDENTIAL
201881
3
MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day T
ime 
Phone 
Number and 
ema
i
l 
address
After-hours 
Phone/Ce
l
l/
Pager 
Number
Fax 
Number
S
ite Address
Pr
imary 
Med
ica
l 
Mon
itor 
 
 MD
 
 G
laxoSm
ithK
l
ine
709 Swede
land Rd, 
K
ing of Pruss
ia, PA 
19406
Secondary 
Med
ica
l 
Mon
itor
 
 
MD
 
G
laxoSm
ithK
l
ine
709 Swede
land Rd, 
K
ing of Pruss
ia, PA 
19406
SAE contact  
informat
ion 
 
 MD
 
 G
laxoSm
ithK
l
ine
709 Swede
land Rd, 
K
ing of Pruss
ia, PA 
19406
Sponsor Legal Registered Address: 
PPD
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number:  IND 125361
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

2014N221874_02
CONFIDENTIAL
201881
4
PROTOCOL AGREEMENT PAGE
For protocol number 201881
Iconfirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date

2014N221874_02
CONFIDENTIAL
201881
5
TABLE OF CONTENTS
PAGE
1. PROTOCOL SYNOPSIS FOR STUDY 201881........................................................8
2. INTRODUCTION....................................................................................................10
2.1.
Study Rationale..........................................................................................10
2.2.
Brief Background........................................................................................11
3. OBJECTIVE(S) AND ENDPOINT(S)......................................................................11
4. STUDY DESIGN....................................................................................................13
4.1.
Overall Design............................................................................................13
4.2.
Treatment Arms, Duration and Assessments..............................................13
4.3.
Type and Number of Subjects.....................................................................15
4.4.
Design Justification.....................................................................................15
4.5.
Dose Justification........................................................................................15
4.6.
Benefit:Risk Assessment............................................................................16
4.6.1.
Risk Assessment.........................................................................17
5. SELECTION OF STUDY POPULATION ANDWITHDRAWAL CRITERIA.............22
5.1.
Inclusion Criteria.........................................................................................22
5.2.
Exclusion Criteria........................................................................................24
5.3.
Eligibility for Optional Sleep Apnea Sub-Study............................................25
5.4.
Screening/Baseline Failures.......................................................................26
5.5.
Withdrawal/Stopping Criteria.......................................................................26
5.5.1.
Liver Chemistry Stopping Criteria................................................26
5.5.1.1.
Study Treatment RestartorRechallenge....................27
5.5.2.
QTc Stopping Criteria..................................................................27
5.5.3.
Other Dose Adjustment/Stopping Safety Criteria.........................28
5.5.3.1.
Troponin Stopping Criteria..........................................28
5.5.3.2.
Digoxin Stopping Criteria............................................29
5.6.
Subject and Study Completion....................................................................29
6. STUDY TREATMENT............................................................................................29
6.1.
Investigational Product and Other Study Treatment....................................29
6.2.
Treatment Assignment................................................................................30
6.3.
Blinding.......................................................................................................31
6.4.
Packaging andLabeling..............................................................................31
6.5.
Preparation/Handling/Storage/Accountability..............................................31
6.6.
Compliance with Study Treatment Administration.......................................32
6.7.
Treatment of Study Treatment Overdose....................................................32
6.8.
Treatment after the End of the Study..........................................................33
6.9.
Lifestyle and/or Dietary Restrictions............................................................33
6.9.1.
Monitoring in the Unit...................................................................33
6.9.2. 
Meal and Dietary Restrictions......................................................33
6.9.3.
Caffeine and Alcohol....................................................................34
6.9.4.
Activity.........................................................................................34
6.10. Concomitant Medications and Non-Drug Therapies....................................34
6.10.1. Permitted Medications and Non-Drug Therapies..........................34
6.10.2. ProhibitedMedications and Non-Drug Therapies.........................34

2014N221874_02
CONFIDENTIAL
201881
6
7. STUDY ASSESSMENTS AND PROCEDURES.....................................................35
7.1.
Time and Events Table...............................................................................37
7.2.
Screening and Critical Baseline Assessments............................................40
7.3.
Pharmacodynamic Endpoints.....................................................................40
7.3.1.
DLco and DLno............................................................................40
7.3.2.
Submaximal Exercise Test..........................................................41
7.3.3.
Intravenous Saline Infusion..........................................................41
7.3.4.
Pulmonary Function Tests...........................................................42
7.3.5.
Dyspnea......................................................................................42
7.3.6.
Polysomnography........................................................................42
7.3.7.
Health Survey: SF-36 Acute.........................................................43
7.4.
Safety.........................................................................................................43
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........43
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................43
7.4.1.2.
Method of Detecting AEs and SAEs...........................44
7.4.1.3.
Follow-up of AEs and SAEs........................................44
7.4.1.4.
Cardiovascular and Death Events..............................44
7.4.1.5.
Regulatory Reporting Requirements for SAEs............44
7.4.2.
Pregnancy...................................................................................45
7.4.3.
Physical Examinations.................................................................45
7.4.4.
Vital Signs....................................................................................45
7.4.5.
Electrocardiogram (ECG).............................................................45
7.4.6.
Echocardiogram...........................................................................46
7.4.7.
Remote Monitoring......................................................................46
7.4.8.
Audiometry..................................................................................46
7.4.9.
Clinical Safety Laboratory Assessments......................................46
7.4.9.1.
Serum Collagen Type I Telopeptide (CTX).................48
7.4.9.2.
Fecal Occult Blood Test (FOBT).................................48
7.4.10. Suicidal Risk Monitoring...............................................................48
7.5.
Pharmacokinetics.......................................................................................49
7.5.1.
Blood Sample Collection..............................................................49
7.5.2.
Sample Analysis..........................................................................49
7.6.
Biomarker(s)...............................................................................................50
7.7.
Genetics.....................................................................................................50
8. DATA MANAGEMENT...........................................................................................50
9. STATISTICAL CONSIDERATIONS AND DATA ANALYSES.................................51
9.1.
Hypotheses.................................................................................................51
9.2.
Sample Size Considerations.......................................................................51
9.2.1.
Sample Size Assumptions...........................................................51
9.2.2.
Sample Size Sensitivity................................................................51
9.2.3.
Sample Size Re-estimation or Adjustment...................................52
9.3.
Data Analysis Considerations.....................................................................52
9.3.1.
AnalysisPopulations....................................................................52
9.3.2.
Interim Analysis...........................................................................52
9.4.
Key Elements of Analysis Plan...................................................................53
9.4.1.
Primary Analyses.........................................................................53
9.4.2.
Secondary Analyses....................................................................53
9.4.3.
Other Analyses............................................................................54
9.4.4.
Exploratory Analyses...................................................................54

2014N221874_02
CONFIDENTIAL
201881
7
10. STUDY GOVERNANCE CONSIDERATIONS........................................................55
10.1. Posting of Information on PubliclyAvailable Clinical Trial Registers............55
10.2. Regulatory and Ethical Considerations, Including the Informed 
Consent Process........................................................................................55
10.3. Quality Control (Study Monitoring)..............................................................56
10.4. Quality Assurance.......................................................................................56
10.5. Study and Site Closure...............................................................................56
10.6. Records Retention......................................................................................57
10.7. Provision of Study Results to Investigators, Posting of Information 
onPublically Available Clinical Trials Registers and Publication.................57
11.REFERENCES.......................................................................................................59
12.APPENDICES........................................................................................................62
12.1. Appendix 1:  Abbreviations and Trademarks...............................................62
12.2. Appendix 2: Liver Safety Required Actions and Follow up 
Assessments..............................................................................................65
12.3. Appendix 3: Genetic Research...................................................................68
12.4. Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................71
12.4.1. Definition of Adverse Events........................................................71
12.4.2. Definition of Serious Adverse Events...........................................72
12.4.3. Definition of Cardiovascular Events.............................................74
12.4.4. Recording of AEs and SAEs........................................................74
12.4.5. Evaluating AEs and SAEs............................................................75
12.4.6. Reporting of SAEs to GSK...........................................................76
12.5. Appendix 5: Collection of Pregnancy Information........................................78
12.6. Appendix 6: Dyspnea 5-Point Likert Scale..................................................79
12.7. Appendix 7: Columbia Suicide-Severity Rating Scale (C-SSRS).................80
12.8. Appendix 8: SF-36 Acute............................................................................97
12.9. Appendix 9: Intravenous Saline Infusion...................................................103
12.10.Appendix 10: Protocol Changes................................................................106
12.11.Appendix 11: Country Specific Requirements...........................................179

2014N221874_02
CONFIDENTIAL
201881
8
1.
PROTOCOL SYNOPSIS FOR STUDY 201881
Rationale
In blocking the transient receptor potential vanilloid 4 (TRPV4) ion channel and reducing 
pulmonary interstitial fluid, GSK2798745 may improve pulmonary function, respiration, 
and gas exchange as well as sleep-disordered breathing in patients with heart failure.  
Therefore, the current study is designed to investigate the effect of repeat administration 
of GSK2798745 on pulmonary gas exchange, respiration, and sleep architecture.  
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary
To assess the effect of GSK2798745 on 
pu
lmonary gas transfer
Change 
in the d
iffus
ing capac
ity for carbon 
monox
ide (DLco)
Secondary
To assess the effect of GSK2798745 on 
a
lveo
lar-cap
i
l
lary conductance (D
M)
To assess the effect of GSK2798745 on 
pu
lmonary gas transfer fo
l
low
ing exerc
ise 
and fo
l
low
ing an 
intravenous sa
l
ine 
infus
ion
To eva
luate the effect of GSK2798745 on 
vent
i
latory eff
ic
iency
To eva
luate the effect of GSK2798745 on 
pu
lmonary funct
ion
To assess the effect of GSK2798745 on 
resp
iratory rate
To assess the effect of GSK2798745 on 
dyspnea
To eva
luate the safety and to
lerab
i
l
ity of 
repeat adm
in
istrat
ion of GSK2798745
Change 
in the d
iffus
ing capac
ity for n
itr
ic 
ox
ide (DLno), membrane conductance (D
M), 
and cap
i
l
lary b
lood vo
lume (Vc) 
Change 
in d
iffus
ing capac
ity for carbon 
monox
ide (DLco)
Change 
in the vent
i
latory eff
ic
iency 
(VE/VCO
2s
lope) determ
ined dur
ing a 
standard
ized 3-m
inute step test
Changes 
in sp
irometry measures 
inc
lud
ing 
forced v
ita
l capac
ity (FVC) and forced 
exp
iratory vo
lume 
in 1 second (FEV
1) as 
we
l
l as forcedexp
iratory f
lows, FEF
25-75
FEF50, and FEF
75 
Change 
in funct
iona
l res
idua
l capac
ity 
(FRC) and end-exp
iratory 
lung vo
lume 
(EELV) measured by body p
lethysmograph
Change 
in resp
iratory rate cont
inuous
ly 
measured by body sensor (Prevent
ice 
BodyGuard
ian)
Change 
in dyspnea score
C
l
in
ica
l mon
itor
ing of v
ita
l s
igns, ECGs, and 
c
l
in
ica
l 
laboratory safety data 
inc
lud
ing 
l
iver 
funct
ion tests (LFTs) and tropon
in, as we
l
l 

2014N221874_02
CONFIDENTIAL
201881
9
Objectives
Endpoints
To assess the effect of GSK2798745 on 
qua
l
ity of 
l
ife
To character
ize the pharmacok
inet
ic prof
i
le 
of GSK2798745 
in sub
jects w
ith heart 
fa
i
lure
as report
ing of adverse events (AEs) 
Change 
in SF-36 acute score
Area under the concentrat
iont
ime curve 
(AUC), max
imum drug concentrat
ion 
(Cmax), t
ime to max
imum observed p
lasma 
concentrat
ion (tmax), and e
l
im
inat
ion ha
lf-
l
ife (T½)
Overall Design
This is a randomized, double-blind, sponsor-unblinded, placebo-controlled, 2 by 2 
crossover study in adults with heart failure.  Approximately14 days (up to 25 days) 
beforethe start of PeriodI, subjects will begin a screening evaluation to determine 
eligibility for entry into the study.  Eligible subjects will be randomized to one of two 
treatment sequences.  Subjects will receive either GSK2798745 2.4 mg or placebo once 
daily for a period of 7 days.  After at least a 14-day washout period (preferably not 
greater than 30 days from last dose in Period I), subjectswill participate in a second, 
identical 7-day treatmentperiod and receive the alternate study medication.
The main objectives of the current study are to investigate the effect of repeat 
administration of GSK2798745 on pulmonary gas exchange and pulmonary function.

2014N221874_02
CONFIDENTIAL
201881
10
2.
INTRODUCTION
GSK2798745 isa potent and selective transient receptor potential vanilloid 4 (TRPV4) 
channel blocker being developed for the treatment of heart failure.
2.1.
Study Rationale
Patients with heart failure (HF) have a reduced capacity to perform exercise concurrent 
with numerous defects in ventilatory function including decreased lung compliance and 
abnormal gas transfer across the alveolar-vascular membrane.  These elements can lead 
to the sensation of dyspnea.  
In blocking the TRPV4 ion channel and reducing pulmonary interstitial fluid, 
GSK2798745 may improve pulmonary function, respiration, and gas exchange as well as 
sleep-disordered breathing in patients with heart failure.  Therefore, the main objectives 
of the current study are to investigate the effect of repeat administration of GSK2798745 
on pulmonary gas exchange and pulmonary function.  
The overall resistance of the lung to gas transfer is presented by the inverse of the 
diffusing capacity of the lung to carbon monoxide (DLco).  Changes in DLco and the 
diffusing capacity of the lung to nitric oxide (DLno) reflect the alveolar-capillary 
membrane conductance (DM).  DLco has been shown to be decreased in patients with 
chronic heart failure [Magini, 2015; Guazzi, 2008; Olsen, 2006; Agostoni, 2003].  Acute 
pulmonary congestion also causes a reduction in DLco, which is reversible.  With 
exercise, patients with chronic heart failure demonstrate a reduced rate of increase in 
DLco and a decrease near peak exertion that is consistent with the limitation of alveolar-
capillary recruitment and progressive interstitial edema [Olsen, 2006].  Moreover, there is 
a direct correlation between hemodynamic changes due to stressors [Andersen, 2015] and 
DM, which has been shown to decrease after exercise [Agostoni, 2003]and infusion of 
saline [Guazzi, 1999].  Therefore, the effects of GSK2798745 treatment on gas exchange 
following exercise and intravenous saline infusion challenges will also be investigated.
Additionally, measures of pulmonary function including FEV
1, FVC and DLco have been 
shown to predict prognosis in patients with heart failure [Olson, 2013].  In this placebo-
controlled crossover study, the pulmonary function of subjects will be characterized prior 
to treatment, after short-term treatment with GSK2798745, and again after the 
discontinuation of drug administration.  
Further, polysomnography will be utilized to characterize sleep-disordered breathing 
patterns in these subjects with heart failure who participate in the optional sleep apnea 
sub-study.  These patients frequently display sleep-disordered breathing often 
characterized by Cheyne-Stokes respiration (CSR) with central sleep apnea (CSA).  This 
sleep-disordered breathing is characterized by recurrent cycles of apnea with a crescendo-
decrescendo pattern of tidal volume.  Although obstructive sleep apnea (OSA) is also 
prevalent, CSA is uniquely associated with heart failure and recognized as one of the 
independent risk factors for disease progression [Costanzo, 2015; Somers, 2008].  In 
those willing to participate in this aspect of the study, a baseline assessment of the apnea-
hypopnea index will identify those subjects with sleep-disordered breathing for inclusion 

2014N221874_02
CONFIDENTIAL
201881
11
into the sub-study.  These subjects will undergo two additional sleep studies to determine 
whether TRPV4 channel blockade with GSK2798745 treatment (as compared to placebo) 
has an effect on sleep architecture. 
2.2.
Brief Background
Multiple lines of evidence from animal models have identified an important role for the 
TRPV4 Ca2+-permeating ion channel in mediating the development of cardiogenic 
pulmonary edema.  TRPV4channels are expressed atthe alveolar septal barrier, which 
functions to limit the movement of intravascular fluid into the interstitial and alveolar air 
spaces of the lung.  The TRPV4 channel is activated inresponse to increased pulmonary 
venous pressure, resulting in structural changes in the endothelial cells that affect the 
integrity of the alveolar barrier; the enhanced permeability results in pulmonary edema 
and associated symptoms of dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and 
reduced exercise tolerance.  
Preclinical studies have demonstrated that TRPV4 channel blockade inhibits structural 
changes in endothelial cells, reduces pressure-dependent lung permeability, and prevents 
and resolves pulmonary edema in heart failure models.  Furthermore, the TRPV4 channel 
is expressed in the endothelium of small pulmonary vessels in human lungs and appears 
to be increased in individuals with congestive heart failure [Thorneloe, 2012].  Based on 
the role of the TRPV4 channel in the mediation of cardiogenic pulmonary edema, it is 
postulated that blockade of this channel may provide therapeutic benefit in patients with 
heart failure (HF) and manifestations of increased extravascular lung fluid.    
To date, GSK2798745 has been administered to healthy volunteers as single doses of 
0.25, 1, 5, and 12.5 mg.  No clinically significant safety concerns were noted.  
Additionally, repeat doses of GSK2798745 5 mg once daily were administered to healthy 
volunteers.  No clinically significant safetyconcerns were observed with repeat 
administration.  For detailed information please refer to the Investigator’s Brochure for 
GSK2798745 [GlaxoSmithKline Document Number 2013N162862_01].
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary
To assess the effect of GSK2798745 on 
pu
lmonary gas transfer
Change 
in the d
iffus
ing capac
ity for carbon 
monox
ide (DLco)
Secondary
To assess the effect of GSK2798745 on 
a
lveo
lar-cap
i
l
lary conductance (D
M)
To assess the effect of GSK2798745 on 
pu
lmonary gas transfer fo
l
low
ing exerc
ise 
and fo
l
low
ing an 
intravenous sa
l
ine 
infus
ion
Change 
in the d
iffus
ing capac
ity for n
itr
ic 
ox
ide (DLno), membrane conductance (D
M), 
and cap
i
l
lary b
lood vo
lume (Vc)
Change 
in d
iffus
ing capac
ity for carbon 
monox
ide (DLco)

2014N221874_02
CONFIDENTIAL
201881
12
Objectives
Endpoints
To eva
luate the effect of GSK2798745 on 
vent
i
latory eff
ic
iency
To eva
luate the effect of GSK2798745 on 
pu
lmonary funct
ion
To assess the effect of GSK2798745 on 
dyspnea 
To assess the effect of GSK2798745 on 
resp
iratory rate
To eva
luate the safety and to
lerab
i
l
ity of 
repeat adm
in
istrat
ion of GSK2798745
To assess the effect of GSK2798745 on 
qua
l
ity of 
l
ife
To character
ize the pharmacok
inetic prof
i
le 
of GSK2798745 
in sub
jects w
ith heart 
fa
i
lure
Change 
in the VE/VCO2s
lope determ
ined 
dur
ing a standard
ized 3-m
inute step test
Changes 
in sp
irometry measures 
inc
lud
ing 
forced v
ita
l capac
ity (FVC) and forced 
exp
iratory vo
lume 
in 1 second (FEV
1) as 
we
l
l as forced exp
iratory f
lows, FEF25-75
FEF50, and FEF
75 
Change 
in funct
iona
lres
idua
l capac
ity 
(FRC) and end-exp
iratory 
lung vo
lume 
(EELV) measured by body p
lethysmograph 
Change 
in dyspnea score 
Change 
in resp
iratory rate cont
inuous
ly 
measured by body sensor (Prevent
ice 
BodyGuard
ian)
C
l
in
ica
l mon
itor
ing of v
ita
l s
igns, ECGs, and
c
l
in
ica
l 
laboratory safety data, 
inc
lud
ing 
LFTs and tropon
in as we
l
l as report
ing of 
adverse events (AEs) 
Change 
in SF-36 acute score
Area under the concentrat
ion t
ime curve 
(AUC), max
imum drug concentrat
ion 
(Cmax), t
ime to max
imum observed p
lasma 
concentrat
ion (tmax), and e
l
im
inat
ion ha
lf-
l
ife (T½)
Exploratory 
To determ
ine the effect of GSK2798745 on 
oxygen saturat
ion
To assess effect of GSK2798745 on s
leep-
d
isordered breath
ing patterns
To determ
ine whether GSK2798745 affects 
s
leep-d
isordered breath
ing 
lead
ing to an 
Change 
in m
in
imum O2saturat
ion 
measured dur
ing po
lysomnography
Change 
in apnea-hypopnea 
index (AHI) 
determ
ined by po
lysomnography
Change 
in the centra
l, obstruct
ive and 
m
ixed apnea 
indexes as determ
ined by 
po
lysomnography
Change 
in resp
iratory tempora
l dynam
ics 

2014N221874_02
CONFIDENTIAL
201881
13
Objectives
Endpoints
improvement 
in sympathoadrena
l act
iv
ity
To determ
ine whether GSK2798745 affects 
e
lectrocard
iograph
ic parameters
To exp
lore the 
impact of GSK2798745 on 
the exposure of HMG-CoA reductase 
inh
ib
itors
dur
ing 
in-house s
leep apnea eva
luat
ion
Change 
in p
lasma and ur
inary 
catecho
lam
ine concentrat
ions 
in sub
jects 
w
ith s
leep-d
isordered breath
ing
Changes 
in t
ime and frequency doma
in 
ana
lyses of ECG:  HR var
iab
i
l
ity to def
ine 
sympathet
ic act
iv
ity 
AUC of HMG-CoA reductase 
inh
ib
itors and 
the
ir key metabo
l
ites
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomized, double-blind, sponsor-unblinded, placebo-controlled, 2 by 2 
crossover study in adults with heart failure (Figure 1).  
Figure 1
Study Schematic
4.2.
Treatment Arms, Duration and Assessments
Approximately14 days (up to 25 days) beforethe start of PeriodI, subjects will begin a 
screening evaluation to determine eligibility for entry into the study.  Eligible subjects 
will be randomized to one of two treatment sequences.  Subjects will receive either 
GSK27987452.4 mgor placebo once daily for a period of 7 days.  After at least a 14-day 

2014N221874_02
CONFIDENTIAL
201881
14
washout period (preferably not greater than 30 days from last dose in Period I), subjects
will participate in a second, identical 7-day treatment period and receive the alternate 
study medication.  
During both study periods, the first 6 subjects will remain in the unit (i.e. clinical research 
unit, CRU) overnight for the first 2 days (Days1 and 2) to allow for continuous safety 
monitoring.  Subsequently, these initial subjects will remain in the unit for a minimum of 
4 hours after the administration of study medication (Days 3 through 7).  All subjects will 
be equipped with the Preventice BodyGuardian for continuous remote monitoring of 
ECG, heart rate, and respiration rate (Day -1 to Day 7).  Subjects may remain in the unit
for the durationof eachof the7 day treatment periodsfor convenience.  
After the first 6 randomized subjects have completed the two-day, in-house safety 
monitoring during Periods I and II, subsequent subjects enrolled into the study will 
remain in the unit for a minimum of 4 hours after the administration of study medication 
on all study days (Days 1 through 7).  However, subjects may remain in the unit for the 
duration of each of the 7 day treatment periods as determined on a case by case basis with 
the Investigator(s).This is not a requirement for successful completion of the study, but 
is mainly for purposes of subject convenience only.
Prior to the start of each study period, all subjects will undergo an assessment of 
pulmonary function testing (PFTs), gas transfer measurements including DLco, DLno 
and Vc, breath-by-breath measurements of minute ventilation, O2consumption and VCO
2
production during a metered 3-minute step exercise to establish ventilatory efficiency 
(V
E/VCO
2), and a dyspnea assessment.  Additionally, a measurement of N-terminal pro-
B-type Natriuretic Peptide (NT-proBNP) concentration, clinical laboratory tests, patient-
reported health status (SF-36 Acute), and general safety assessments will be obtained.  
Only for subjects willing to participate in the sleep apnea sub-study, they will undergo a 
sleep study to ascertain whether sleep-disordered breathing patterns are apparent prior to 
the firststudy period (Period I).  Subjects with sleep-disordered breathing, defined as an 
apnea-hypopnea index (AHI) >5 based on polysomnography, will undergo a repeat sleep 
study after 6days of treatment in eachof the two study periods.  
Pharmacokinetic profiles will be obtained during both study periods.  On Day 4 and 
Day7 of each study period, the assessments of pulmonary function will be repeated.  On 
Day 5 of each study period, subjects will receive an intravenous saline infusion, and 
DLco and DLno measurements will be performed before and after the procedure.  On 
Day 5 of each study period, subjects will remain in the unit for a minimum of 4 hours 
after completion ofthe intravenous saline infusion.  On Day 7 of each study period, the 
step-exercise challenge and gas transfer measurements, dyspnea assessment, 
measurement of NT-proBNP concentration, clinical laboratory tests, patient-reported 
health status (SF-36 Acute), and general safety assessments will be repeated.  
All subjects will return for a Follow-up Visit approximately 2 weeks after completion of 
the second study period; pulmonary and safety assessments will be repeated at this visit.

2014N221874_02
CONFIDENTIAL
201881
15
The duration of participation in this study is expected to be approximately 8 weeks from 
Screening to the Follow-up Visit.
4.3.
Type and Number of Subjects
A sufficient number of subjects with heart failure will be enrolled so that 12 subjects 
complete the two study periods and critical assessments.  If subjects prematurely 
discontinue the study, additional replacement subjects may be randomised and assigned 
to the same treatment sequence at the discretion of the Sponsor in consultation with the 
Investigators.
After the first 12 subjects complete both study periods, an interim analysis will be 
performed to assess the intra-subject variability:  (a) if the actual variability is less than or 
equal to the assumed value, the study will be completed with 12 subjects; or (b) if the 
actual variability is greater than the assumed value, additional subjects may need to be 
enrolled.
If an insufficient number of subjects participate in the sleep sub-study, additional subjects 
who meet the criterion for the sleep apnea sub-study may be enrolled to undergo the 
polysomnography investigation at the discretion of the Sponsor and in consultation with 
the Investigators.  
In addition, another (separate) cohort of subjects may be enrolled to allow for the 
evaluation of an additional dose level at the discretion of the Sponsor in consultation with 
the Investigators.  
4.4.
Design Justification
The crossover design has been selected to provide greater statistical power with a smaller 
number of subjects.  Each subject serves as his or her own matched control avoiding 
issues of comparability of groups with regard to confounding variables such as age, sex, 
and disease severity.  The use of a placebo control allows for a more rigorous assessment 
of the effects of the drug treatment on physiologic measures and symptom assessments.  
Subjects selected for thisstudy have chronic heart failure and are stable on standard 
treatment to ensure that their disease status does not change significantly during the 
course of the study.  Additionally, the limited 7-day treatment period is not expected to 
alter the disease status of the subjects.  The 14-day washout period alleviates the 
possibility of carryover effects from one period to the other.  Given the short duration of 
the study, it is expected that subjects will complete the study in order to have data in each 
period of the crossover for all subjects.
4.5.
Dose Justification
Based on the no observed adverse effect level (NOAEL) of 3mg/kg/day established in the 
3-month dog study and a ≥30-fold safety margin from that NOAEL exposure, the daily 
exposure will not intentionally exceed a Cmax of 0.049 µg/mL and/or an AUC of 
0.448µg*hr/mL on an individual basis.  The planned dosage of GSK2798745 will be 
2.4mg administered once daily as a capsule formulation without any meal restrictions.  
This dosage was selected on the basis of pharmacokinetic and safety profiles in healthy 

2014N221874_02
CONFIDENTIAL
201881
16
volunteers who received repeat administration in the first time in human study, 
TR4117387. The dose may be adjusted based on emerging data. 
For detailed information please refer to the Investigator’s Brochure for GSK2798745 
[GlaxoSmithKline Document Number 2013N162862_01]
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2798745 can be found in the Investigator’s Brochure.  The following section 
outlines the risk assessment and mitigation strategy for this protocol: 

2014N221874_02
CONFIDENTIAL
201881
17
4.6.1.
Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product(IP) GSK2798745
Vascu
lar 
les
ions 
Dogs (4-week study):  At 30mg/kg/day, 2 ma
les had arter
ia
l 
les
ions
One ma
le: Heart –Coronary artery 
inf
lammat
ion; 
Thymus –Arter
io
le 
inf
lammat
ion w
ith f
ibrop
las
ia 
One ma
le:  Ep
id
idym
ides –Artery 
degenerat
ion/necros
isw
ith 
inf
lammat
ion
Dogs (12-week study):  At 10mg/kg/day, 1 ma
le and 1 fema
le 
had arter
ia
l 
les
ions
One ma
le: Ep
id
idym
ides –Arter
io
le 
degenerat
ion/necros
is w
ith 
lymphocyt
ic 
inf
lammat
ion
One fema
le: B
ladder –Arter
io
le degenerat
ion/necros
is 
w
ith 
lymphocyt
icinf
lammat
ion
The arter
ia
l 
les
ions noted 
in heart, thymus, ep
id
idym
ides, 
and ur
inary b
ladder cannot be mon
itored d
irect
ly.  There 
is 
current
ly no human trans
lat
ion b
iomarker or understand
ing 
of the under
ly
ing mechan
ism.
S
ince these effects cannot be mon
itored d
irect
ly 
in c
l
in
ica
l 
stud
ies, a coverage of ≥30 fo
ld w
i
l
l be ma
inta
ined from the 
no-effect dose (3mg/kg/day); exposure w
i
l
l not exceed the 
average da
i
ly AUC of 0.448hr*ug/mL and/or Cmax of 
0.049ug/mL on an 
ind
iv
idua
l bas
is. 
Myocard
ia
l tox
ic
ity 
Dogs (4-week study):  At 30mg/kg/day, myof
iber 
degenerat
ion/necros
is & 
inf
lammat
ion (2 an
ima
ls)
.
Sub
jects w
ith h
istory of acute coronary syndromes
(
inc
lud
ing unstab
le ang
ina), coronary ang
iop
lasty, or 
stent
ing w
ith
in the past 6 months w
i
l
l be exc
luded.
Tropon
in 
leve
ls w
i
l
l be mon
itored throughout the study.
A safety marg
in of ≥50 fo
ld w
i
l
l be ma
inta
ined from the no-
effect dose (10mg/kg/day) observed 
in dogs.
Morta
l
ity/mor
ibund 
Dogs (4-week study):  At 30 mg/kg/day one ma
le term
inated 
We
ight and adverse events reported by sub
jects w
i
l
l be 

2014N221874_02
CONFIDENTIAL
201881
18
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
cond
it
ion; poor v
iab
i
l
ity
ear
ly (Day 6) due to poor c
l
in
ica
l cond
it
ion.  Another ma
le had 
trans
ient who
le body shak
ing on Days 8 and 9.
Dogs (13-week study): At 10 mg/kg/day one ma
le was 
term
inated ear
ly (Day 74) due to we
lfare reasons.
Rats (m
icronuc
leus and comet study):  morta
l
ity occurred 
fo
l
low
ing 1 to 3 doses at ≥600mg/kg/day
mon
itored.
Gastro
intest
ina
l and/or 
hepat
ic  tox
ic
ity
GI tox
ic
ity -≥3mg/kg/day 
in dogs and at 30 and 300mg/kg/day 
in rats, cons
ist
ing of mucosa
l eros
ion/u
lcerat
ion 
in the stomach 
and/or duodenum.
Hepat
ic Tox
ic
ity:  B
i
l
iary ep
ithe
l
ia
l hypertrophy/hyperp
las
ia and 
per
iducta
l m
ixed 
inf
lammatory ce
l
l 
inf
i
ltrate 
into the 
l
iver was 
observed at 300mg/kg/day 
in rat (7-day study) and foca
l 
hepatoce
l
lu
lar degenerat
ion 
in 1 ma
le dog at 30mg/kg/day (4-
week study)
Sub
jects w
ith act
ive u
lcer d
isease or GI b
leed
ing w
i
l
l be 
exc
luded.  Assessment of feca
l occu
lt b
lood w
i
l
l be 
performed pr
ior to Day 1 of the f
irst study per
iod and 
fo
l
low
ing Day 7 of each study per
iod.
Sub
jects w
i
l
l be mon
itored for GI 
into
lerance and 
sequent
ia
l c
l
in
ica
l chem
istry ana
lys
is 
inc
lud
ing 
l
iver 
enzymes.  
Test
icu
lar tox
ic
ity
Rats (4-week study): Spermat
id retent
ion at ≥60mg/kg/day.  Not 
assoc
iated w
ith degenerat
ive changes 
in testes or ep
id
idym
ides.
No spermatogen
ic abnorma
l
it
ies were observed 
in dogs
A safety marg
in of ≥40fo
ld w
i
l
l be ma
inta
ined fromthe no
effect dose (10 mg/kg/day) 
in rats.
Ske
leta
l musc
le tox
ic
ity
Rat (4-week study): Myof
iber necros
is: myof
iber 
degenerat
ion/regenerat
ion; f
ibrop
las
ia, at 300mg/kg/day 
in the 
so
leus musc
le
CPK 
leve
ls w
i
l
l be mon
itored throughout the study.
Se
izures and 
Rats (m
icronuc
leus and comet study):  Convu
ls
ions observed at Sub
jects w
ith a h
istory of se
izure d
isorder or stroke w
ith
in 

2014N221874_02
CONFIDENTIAL
201881
19
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
convu
ls
ions
≥600mg/kg/day.  Convu
ls
ions were not re
lated to Cmax, nor 
occurred at any pred
ictab
le t
ime from dose adm
in
istrat
ion.
Dogs:  No CNS f
ind
ings at 12mg/kg/day 
in the dog 7-day 
EEG/CV study.  In other compounds 
in the same ser
ies, 
convu
ls
ions have been observed.
the 
last 5 years w
i
l
l be exc
luded from the study. 
Low  food consumpt
ion Dogs (4-week study):  30mg/kg/day reduced food consumpt
ion.  
Two ma
les were term
inated ear
ly (Day 10) due to extreme
ly 
reduced food consumpt
ion.
Rats (4-week study):  300mg/kg/day had decreased food 
consumpt
ion.
We
ight and appet
ite w
i
l
l be mon
itored.
Effects on macrophages 
(Phospho
l
ip
id 
accumu
lat
ion)
Rats (4-week study):  60mg/kg/day 
in the 
lung (prom
inent 
a
lveo
lar macrophages); 300mg/kg/day 
in the mesenter
ic 
lymph 
node (
increased ce
l
lu
lar
ity of s
inus macrophages) and thymus 
(macrophage vacuo
lat
ion; 
increased thymus we
ight).  
Cons
istent w
ith phospho
l
ip
id accumu
lat
ion (phospho
l
ip
idos
is) 
based on u
ltrastructura
l appearance of mesenter
ic 
lymph nodes 
at 300mg/kg/day.  F
ind
ings were not assoc
iated w
ith 
degenerat
ive changes.
A safety margin of 
≥40 fo
ld w
i
l
l be ma
inta
ined from the no 
effect dose (10 mg/kg/day) 
in rats.
Study Procedures
Exerc
ise
S
ide effects can 
inc
lude shortness of breath, 
l
ight-headedness, 
decrease 
in b
lood pressure, or abnorma
l heart rhythm.  In rare 
cases, these s
ide effects can be ser
ious or 
l
ife-threaten
ing.  A
lso 
poss
ib
le are d
irect 
in
jur
ies such as bru
ises, spra
ins, and stra
ins 
and 
ind
irect prob
lems such as worsen
ing of pa
in from arthr
it
is.
Sub
jects w
i
l
l have cont
inuous breath-by-breath mon
itor
ing 
of v
ita
l s
igns as we
l
l as mon
itor
ing of b
lood pressure.  A 
med
ica
l
ly tra
ined profess
iona
l w
i
l
l be d
irect
ing the exerc
ise 
test
ing.

2014N221874_02
CONFIDENTIAL
201881
20
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
NaC
l Infus
ion
S
ide effects of a per
iphera
l 
infus
ion of NaC
l may 
inc
lude pa
in or 
redness at the 
infus
ion s
ite and per
iphera
l ve
in trauma (ve
in 
thrombos
is, or extravasat
ion of sa
l
ine).  Sub
jects may a
lso 
exper
ience symptoms such as genera
l
ized swe
l
l
ing, 
increase 
in 
ur
ine output, dyspnea, or exacerbat
ion of congest
ive heart 
fa
i
lure. 
The 
infus
ion w
i
l
l be performed by a med
ica
l
ly tra
ined 
profess
iona
l and sub
jects w
i
l
l be mon
itored dur
ing and 
after the 
infus
ion.

2014N221874_02
CONFIDENTIAL
201881
21
Other Theoretical Risks:
Potential effects on vasoregulation: TRPV4 mediates prostaglandin release from isolated 
human endothelial cells and in vivo in rats, supporting the potential forTRPV4 blockade 
to modulate blood pressure via prostaglandin release. No effect of GSK2798745 on blood 
pressure was observed in preclinical studies. Blood pressure will be monitored 
throughout the study.
Genetic deletion of TRPV4 in mice has been shown to effect hearing.  TRPV4 knockout 
(KO) mice at age 8 weeks exhibited normal hearing thresholds but at age 24 weeks, had 
delayed-onset hearing loss; additionally, the cochlea was found to be vulnerable to 
acoustic injury with sound overexposure [Tabuchi, 2005].  Patients with Charcot-Marie-
Tooth disease Type 2C (CMT2C), an autosomal dominant axonal neuropathy related to 
TRPV4 gene mutations, demonstrate symptoms that include hearing loss caused by nerve 
damage in the innerear (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, thesefindings are academic, and have not been observed in any drug 
induced model. There is potential for benefit with GSK2798745, in that withcells 
(HEK293) expressing the CMT2C mutant channel, inhibitors of the TRPV4 channel were 
found to block the increasedintracellular calcium concentrations and resultant cell death 
[Landouré, 2010].  Despite the very low risk that hearing will be affected, audiometry 
will be conducted during the study at baseline, Day 7 and at Follow-up.  A repeat dose 
investigative mouse hearing study with a TRPV4 antagonist is planned to further 
characterize this theoretical risk.
Genetic deletion of TRPV4 in mice has also been shown to alter bone metabolism. 
Specifically, congenital TRPV4 KO micedisplayed impaired bone resorption due to 
decreased osteoclast number and activity; osteoblast and osteocyte numbers were not 
affected [Masuyama, 2008; Mizoguchi, 2008; van der Eerden, 2013].  These changes in 
osteoclast function resulted in increased bone mass and intracortical porosity along with 
reduced bone elasticity and hind-limb unloading-induced bone loss.  Consistent witha 
role for TRPV4 in modulating osteoclast function, TRPV4 KO mice exhibited altered 
serum Collagen Type I C-Telopeptide (CTX) and urinary deoxypyridinoline (DPD), 
specific markers of bone resorption, while no changes in procollagen type 1 amino-
terminal propeptide (P1NP), a specific marker of bone formation, were observed.  In 
addition, no differences in serum calcium or parathyroid hormone (PTH) were noted, 
suggesting no major changes in external calcium balance.  Consistent with these latter 
findings, rats treated for 7 days with the TRPV4 inhibitor GSK2193874 exhibited no 
changes in plasma calcium or urinary calcium excretion [Thorneloe, 2012].  Osteoclast 
function, however, has not been assessed in any drug-induced model.  As a result of the 
findings in TRPV4 KO mice, associations between genetic variants in the TRPV4 gene 
locus with fracture risk were assessed.  Whereas risk of osteoporotic fracture was 1.9 
times higher in men homozygous for an intronic SNP in the TRPV4 gene (T-allele of 
rs1861809) in the Rotterdam Study population, these results were not replicated in other 

2014N221874_02
CONFIDENTIAL
201881
22
cohorts and no trends were observed for women [van der Eerden, 2013].  In spite of the 
low riskthat GSK2798745 will alter bone metabolism in mature adult patients, fasted 
serum CTX will be assessed at baseline and on Day 7 of each study period.
Taking into account the measures taken to minimize the risk to subjects participating in 
this study, including a 30-fold exposure margin from the NOAEL in dogs, the potential 
risks identified in association with GSK2798745 are justified by the anticipated benefits 
that may be afforded to subjects with heart failure.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the Investigator’s Brochure.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified inthe protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if allof the following criteria 
apply: 
AGE
1. ≥ 21 years of age at the time of signing the informed consent form
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Diagnosis of heart failure (New York Heart Association Class II-IV) for a minimum 
of 3 months prior to screening
3. Clinically stable with no changes in optimized guidance-directed medications and no 
hospitalizations for heart failure for at least 1 month prior to Screening
4. NT-proBNP >400 pg/mL measured within 6 months prior to OR at Screening 
5. Average DLco measurements outside the normal range (% Predicted DLco < 80%) 
during the Screening Period 
WEIGHT
6. Body mass index (BMI) ≥18 and ≤45kg/m2

2014N221874_02
CONFIDENTIAL
201881
23
SEX
7. Male or female of non-childbearing potential
Male patients with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until at least five half-lives of study medication OR for a cycle of spermatogenesis 
following five terminal half-lives after the last dose of study medication.
a.Vasectomy with documentation of azoospermia.  
b.Male condom plus partner use of one of the contraceptive options below:

Contraceptive subdermal implant that meets the standard operating 
procedure (SOP) effectiveness criteria including a <1% rate of failure per 
year, as stated in the product label

Intrauterine device or intrauterine system that meets the SOP effectiveness 
criteria including a <1% rate of failure per year, as stated in the product 
label [Hatcher, 2007a]

Oral contraceptive, either combined or progestogen alone [Hatcher, 2007a]

Injectable progestogen [Hatcher, 2007a]

Contraceptive vaginal ring [Hatcher, 2007a]

Percutaneous contraceptive patches [Hatcher, 2007a]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
A female subject is eligible to participate if at least one of the following conditions 
applies:
a. Non-reproductive potential defined as:
Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented bilateral oophorectomy
b. Postmenopausal defined as 12 months of spontaneous amenorrhea.  Females 
on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the highly effective contraception 
methods if they wish to continue their HRT during the study.  Otherwise, 
they must discontinue HRT to allow confirmation of post-menopausal status 
prior to study enrolment.

2014N221874_02
CONFIDENTIAL
201881
24
INFORMED CONSENT
8. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the consent form and in this protocol
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if anyof the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. History of acute coronary syndromes including unstable angina or myocardial 
infarction within 6 months of screening
2. Coronary revascularization including angioplasty and stenting within 6 months of 
Screening 
3. History of stroke or seizure disorder within 5 years of Screening
4. Diagnosis of asthma
5. Diagnosis of chronic obstructive pulmonary disease (COPD) with FEV
1<50% of 
predicted measured within 4 weeks of Screening 
6. History of a condition that required radiation therapy to the thorax
7. History of any type of malignancy within the past five years with the exception of 
successfully treated basal cell cancer of the skin
8. Active ulcer disease or gastrointestinal bleedingat the time of screening
9. Current or chronic history of liver disease, known hepatic impairment, or biliary 
abnormalities (with the exception of Gilbert
's syndrome or asymptomatic gallstones)
10.Alanine transaminase (ALT) >2x Upper Limit of Normal (ULN) and bilirubin 
>1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and 
direct bilirubin <35%)
11.QTc > 450 msec or QTc > 480 msec in subjects with Bundle Branch Block

The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method, 
machine-read or manually over-read.

The sameQT correction formula mustbe used for each individual subject
throughout the study.  This formula maynot be changed or substituted once 
the subject has been enrolled.

For purposes of data analysis, QTcB, QTcF, another QT correction 
formula, or a composite of available values of QTc will be used as specified 
in the Reporting and Analysis Plan (RAP).
12.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 

2014N221874_02
CONFIDENTIAL
201881
25
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
GlaxoSmithKline (GSK) medical monitor, make the subject unsuitable for inclusion 
in this study
CONCOMITANT MEDICATIONS
13. Use of medications specified for the treatment of COPD including short-and long-
acting bronchodilators (β-agonists and anticholinergics) and inhaled glucocorticoids 
as well as oxygen therapy
14.Use of a listed prohibited medication (Section 6.10.2) within the restricted timeframe 
relative to the first dose of study medication
15.Use of a strong inhibitors or inducers of cytochrome P450 (CYP) 3A or p-
glycoprotein (see Section 6.10.2)
RELEVANT HABITS
16.Current smoker
17.History of alcoholabuse within 6 months of the studyin the opinion of the 
investigator(s).  
CONTRAINDICATIONS 
18.History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
19.Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result atscreening or within 3 months of screening.  For potent immunosuppressive 
agents, subjects with presence of hepatitis B core antibody (HBcAb) should also be 
excluded
20.A positive pre-study drug/alcohol screen(excluding prescribed medications)
21.Use of anotherinvestigational product in a clinical study within the following time 
period prior to the first administration of study medication in the current study: 30 
days, 5half-lives or twice the duration of the biological effect of the investigational 
product (whichever is longer)
22.Exposure to more than 4 investigational medicinal products within 12 months prior to 
the first administration of study medication
5.3.
Eligibility for Optional Sleep Apnea Sub-Study
Subjects eligible for the main study will be eligible for the sleep apnea sub-study, if the 
following inclusion criteriaaremet:

2014N221874_02
CONFIDENTIAL
201881
26
An apnea-hypopnea index (AHI) ≥5 events/hour based on polysomnography 
conducted prior to the first study period (Period I)
Agreement to participate in the sub-study by signing a separate informed consent 
form
5.4.
Screening/Baseline Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are not subsequently randomized.In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and any Serious Adverse Events.
5.5.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:
The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 
The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contactattempts should be documented 
in the subject’s medical record. 
Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. If a subject is withdrawn from study treatment, that subject will be 
withdrawn from the study.
5.5.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteriahave been designed to 
assure subject safety and evaluate liver eventetiology(in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf

2014N221874_02
CONFIDENTIAL
201881
27
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, 
if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver 
injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly 
for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist 
for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not 
applicable to subjects on anticoagulant
s
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in 
 the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: 
ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, 
if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2
5.5.1.1.
Study Treatment Restart orRechallenge
Study treatmentrestart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.5.2.
QTc Stopping Criteria

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the subject has been enrolled.
For example, if a subject is eligible for the protocol based on QTcB, then QTcB must 
be used for discontinuation of this individual subject as well.
Once the QT correction formula has been chosen for a subject’s eligibility, the same 
formula must continue to be used for that subject for all QTc data being collected for 
data analysis.  Safety ECGs and other non-protocol specified ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minutes) recording period.  
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:

2014N221874_02
CONFIDENTIAL
201881
28
QTc > 500 msec OR Uncorrected QT > 600 msec
Change from baseline of QTc > 60 msec
For patients 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
5.5.3.
Other Dose Adjustment/Stopping Safety Criteria
For an individual study participant, additional stopping criteria include, but are not 
limited to:
Significant changes to medication (e.g., diuretics) as judged by the Principal 
Investigator in consultation with the Medical Monitor if necessary
An emergency room (ER) visit or hospitalization for treatment of an episode of acute 
decompensated heart failure (ADHF)
Severe signs or symptoms or significant changes in any of the safety assessments 
(e.g.,ECG, vital signs, laboratory tests) that put the safety of the individual at risk, as 
judged by the Principal Investigator in consultation with the Medical Monitor if 
necessary.
5.5.3.1.
Troponin Stopping Criteria
If after screening, the local cardiac troponin (cTn) is > 2 times the subject’s baseline 
value and > ULN for the assay, it is recommended that subject undergo repeat troponin 
testing and urgent evaluation if symptoms suggestive of cardiac ischemia are present.

2014N221874_02
CONFIDENTIAL
201881
29
Asymptomatic Subject:
If the second value of cTn is below the ULN for the assay or less than 2 times the 
subject’s baseline value, the subject can continue in the study with close follow-up of 
symptoms.  ECG and further cTn measurements should be performed as clinically 
indicated.
If the second valueof cTn remains > ULN and > 2 times the subject’s baseline value, 
treatment with GSK2798745 should be interrupted.  The subject should be evaluated by a 
cardiologist and undergo any clinically appropriate testing.  Any re-start of study 
treatment must be discussed with the GSK Medical Monitor.
Symptomatic Subject:
Cardiology consultation should be obtained immediately for any subject with new signs 
or symptoms suggestive of cardiac ischemia, including chest pain, increased shortness of 
breath, and diaphoresis.  GSK2798745 should be discontinued permanently, and the 
subject should be withdrawn from the study.
5.5.3.2.
Digoxin Stopping Criteria
For subjects who are taking digoxin, concentrations will be monitored prior to 
administration of study medication daily.  If the digoxin concentrations are observed to 
be significantly lower or higher following study drug administration, the dose of digoxin 
may be titrated if possible in consultation with the Medical Monitor and Investigator.  In 
case the digoxin dose cannot be titrated, the subject may be withdrawn from the study or 
continue in the study with the withdrawal of the digoxin treatment, as clinically 
appropriate.  Any follow-up and safety observations will be collected and monitored in 
these subjects.
5.6.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
Follow-up Visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe the product 
received by the subject as indicated in the protocol design. 

2014N221874_02
CONFIDENTIAL
201881
30
Study Treatment
Product name:
GSK2798745
P
lacebo
Formulation description:
Granu
le f
i
l
led capsu
le
P
lacebo b
lend f
i
l
led capsu
le
Dosage form:
Capsu
le
Capsu
le
Unit dose 
strength(s)/Dosage 
level(s):
2.4 mg
1
NA
Route of Administration
Ora
l
Ora
l
Dosing instructions:
Dose w
ith 240mL water
Dose w
ith 240mL water.
Physical description:
S
ize one Wh
ite Opaque capsu
le  
conta
in
ing  wh
ite to a
lmost wh
ite 
so
l
id
S
ize one Wh
ite Opaque capsu
le  
conta
in
ing wh
ite to a
lmost wh
ite 
so
l
id
Method for individualizing 
dosage:
Pharmacy to assemb
le
Pharmacy to assemb
le
1. In the event of a dose ad
justment, dosage 
leve
ls for capsu
les f
i
l
led w
ith GSK2798745 granu
les w
i
l
l be accord
ing
ly 
ad
justed.
6.2.
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomization 
schedule generated in RandAll NG by Clinical Statisticsprior to the start of the study, 
using validatedinternal software.
Subjects will be randomized into the study by means of an interactive web response 
system (IWRS) i.e. RAMOS NG, to receive one the two treatment regimens shown below 
in Table 1.
Table 1
Treatment Sequences
Sequence
Period 1
Period 2
AP
GSK2798745 2.4mg
Placebo
PA
Placebo
GSK2798745 2.4mg

2014N221874_02
CONFIDENTIAL
201881
31
6.3.
Blinding
This will be a double-blind study where the sponsor and clinical pharmacist are un-
blinded and the following will apply. 
The investigator or treating physician may unblind a subject’s treatment assignment 
only in the case of an emergencyOR in the event of a serious medical condition 
when knowledge of the study treatment is essential for the appropriate clinical 
management orwelfare of the subject as judged by the investigator. 
Investigators have direct access to the subject’s individual study treatmentvia the 
IWRS (RAMOS NG). 
It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment. 
If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the treatment 
assignment of the unblinded subject, unless that information is important for the 
safety of subjects currently in the study. 
The date and reason for the unblinding must be fully documented in the CRF 
A subject may continue in the study if that subject’s treatment assignment is 
unblinded by the discretion of the Investigator in consultation with the Medical 
Monitor.  
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with a Serious Adverse Event (SAE). If the 
SAE requires that an expedited regulatory report be sent to one or more regulatory 
agencies, a copy of the report, identifying the subject’s treatment assignment, may be 
sent to investigators in accordance with local regulations and/or GSK policy.
6.4.
Packaging andLabeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.5.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for preparation of GSK2798745 or 
placebo capsules will be detailed in a Technical Agreement.  The capsules will be 
extemporaneously prepared as per instructions that will be reviewed and approved by 
GSK prior to use.
Only subjects enrolled in the study may receive study treatment and only authorized 
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 labelled storage conditions with access limited to the 

2014N221874_02
CONFIDENTIAL
201881
32
investigator and authorized site staff.  Please see Study Reference Manual (SRM) for 
additional information regarding storage.
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).  
Further guidance and information for final disposition of unused study treatment are 
provided in the SRM. 
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact.
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.
Precaution will be taken to avoid direct contact with the study treatment.  A MSDS 
describing occupational hazards and recommended handling precautions will be provided 
to the investigator.In the case of unintentional occupational exposure notify the monitor, 
Medical Monitor and/or GSK study contact.
6.6.
Compliance with Study Treatment Administration
When subjects are administered study treatment at the study site, they will receive the 
treatment directly from the Investigator or designee, under medical supervision.  The date 
and time of each dose administered in the clinic will be recorded.  The dose of study 
treatment and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.  
Study site personnel will examine each subject’s mouth to ensure that the study treatment 
was ingested.
6.7.
Treatment of Study Treatment Overdose
GSK does not recommend specific treatment for an overdose. The Investigator (or 
physician in charge of the subject at the time) will use clinical judgment to treat any 
overdose. 
In the event of an overdose the investigator or treating physicianshould:
1. Contact the Medical Monitor immediately.
2. Closely monitor the subject for adverse events (AEs)/serious adverse events (SAEs) 
and laboratory abnormalities until GSK2798745 can no longer be detected 
systemically (at least 5 days for GSK2798745).

2014N221874_02
CONFIDENTIAL
201881
33
3. Obtain a plasma sample for pharmacokinetic (PK) analysis within 1 day from the 
date of the last dose of study treatment if requested by the Medical Monitor 
(determined on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.8.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.9.
Lifestyle and/or Dietary Restrictions
6.9.1.
Monitoring in the Unit
The first six subjects who participate in the study will be admitted to the unit to be 
monitored for the first two days (Day 1 and Day 2) following the first administration of 
study medication in both study periods.  Subsequently, these subjects will remain in the 
unit for a minimum of 4 hours after the administration of study medication on eachof the 
remaining 5 days (Days 3 through 7) of each study period.  On Day 5, subjects will 
remain in the unit for a minimum of 4 hours after the completion of the saline infusion.
For the remainder of subjects participating in the study, they will remain in the unit for a 
minimum of 4 hours after the administration of study medication on eachof the 7 days of 
each study period.  
Following the completion of all assessments on each study day, subjects may return 
home.  For subjects who cannot return home each evening for multiple reasons including 
but not limited to distance from clinical site or transportation issues, housing will be 
providedor they may opt to remain in the unit for the durationof the study period.  
Housing should be consistent in both study periods.All subjects will be continuously 
monitored remotely (see Section 7.4.7). 
6.9.2.
Meal and Dietary Restrictions
Subjects 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 
prior to the first dose of study medication until their discharge from the unit after their 
last dose ofstudy medication in each period.
Three meals per day will be provided by dietary department either in the unit or as a 
boxed meal(s) to go.
No meal restrictions will be placed with regard to drug administration.  Subjects will be 
allowed to consume a standard breakfast prior to drug administration.

2014N221874_02
CONFIDENTIAL
201881
34
6.9.3.
Caffeine and Alcohol
During each study period, it is recommended that subjects minimizeingestion of
caffeine-or xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 
24 hours prior to the start of dosinguntil completion of all assessments.
During each study period, subjects will abstain from alcohol for 24 hours prior to the start 
of dosing until completion of all assessments.
6.9.4.
Activity
Subjects should refrain from strenuous activity 48 hours prior to each study period and 
throughout the study (except when in the exercise portion of the study).  Subjects may 
participate in light recreational activities during studies (e.g., watch television, read).
6.10.
Concomitant Medications and Non-Drug Therapies
6.10.1.
Permitted Medications and Non-Drug Therapies
Acetaminophen at doses of ≤ 3 grams/day is permitted for use any time during the study.
The patients may stay on all regular prescription medications unless specified in Section 
6.10.2.  Digoxin is permitted, but with close monitoring to maintain the therapeutic 
window.  Other concomitant medication may be considered on a case by case basis by the 
Investigator in consultation with the GSK Medical Monitor.
6.10.2.
Prohibited Medications and Non-Drug Therapies
Except for the permitted medications noted above (Section 6.10.1), subjects must abstain 
from taking 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) prior to the first dose of study medication until 
completion of the follow-up visit, unless in the opinion of the Investigator and sponsor 
the medication will not interfere with the study.
Subjects must provide to the investigator information/list of all medications they are 
currently taking. 
GSK2798745 has weak CYP3A4 inhibition potential.  There is a likelihood that the 
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 are likely to be taken by the eligible patients as part of their medications. 
The concentrations of these statins will be monitored during the study.  The investigators 
may also consider substitutions of these medications.  
Subjects should avoid using drugs that are strong inhibitors or inducersof 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 2;consider therapeutic 
substitutions for these medications.  

2014N221874_02
CONFIDENTIAL
201881
35
GSK2798745 systemic concentrations will be monitored to detect any drug interactions 
with moderate CYP3A4 inhibitors or P-gP inhibitors (see SRM for a detailed list).
It is strongly recommended that patients 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 subjects for loss of efficacy or consider substitutions of 
these medications.  See SRM for a detailed list.  The list may be modified based on 
emerging data.  All concomitant medications maybe reviewed by the Medical Monitor 
and it will be up to the discretion of the Investigator andif necessary theMedical 
Monitor,whether the medication can be continued and/or the subject can participate in 
the study.
Table 2 
Strong inducers/inhibitors of CYP3A and P-gp
Antiretrovirals:
atazanavir, danoprevir, elvitegravir, fosamprenavir, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir, 
tipranavir
Antibiotics:
clarithromycin, telithromycin, troleandomycin, rifampin
Oral antifungals:
ketoconazole, itraconazole, voriconazole
Antidepressant
nefazadone 
Immunosuppressant
cyclosporine
Anti-Epileptic
carbamazepine, phenytoin
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1
Assessments scheduled for the same nominal time, should occur in the 
following order:
1.12-lead ECG
2.Vital signs
3.Blood samples  

2014N221874_02
CONFIDENTIAL
201881
36
Note: The timing of the assessments should allow the blood draw to occur at the 
exact time each day.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic and biomarker assessmentsmay 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. 

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the 
relevant GSK study team member and then archived in the study sponsor 
and site study files, but this will not constitute a protocol amendment. 

The institutional review board (IRB) will be informed of any safety issues 
that require alteration of the safety monitoring scheme or amendment of the 
Informed Consent Form (ICF).

No more than 500 mL of blood will be collected over the duration of the 
study, including any extra assessments that may be required. 

2014N221874_02
CONFIDENTIAL
201881
37
7.1.
Time and Events Table
Procedure
Screening 
Period
Treatment Periods I and II (Day)
Follow-up
Day -25  
to Day -1 
pr
ior to 
Per
iod I
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9
14 ± 4 days 
after 
last 
dose of 
study 
med
icat
ion
Informed consent
X
Inc
lus
ion and exc
lus
ion 
cr
iter
ia
X
Demography
X
Fu
l
l phys
ica
l exam
inat
ion
inc
lud
ing he
ight & we
ight
X
Br
ief phys
ica
l exam
inc
lud
ing we
ight
X
X
X
X
Med
ica
l 
h
istory/Med
icat
ion h
istory
X
Hepat
it
is B &C screen
X
Echocard
iogram16
X
Ur
ine drug and a
lcoho
l 
test
X 
X
C
l
in
ica
l 
lab 
assessments
14
X 
X
X
X
X
NT-proBNP 
X
X
X
Serum CTX11
X
X
Feca
l Occu
lt B
lood Test12
X
X
Pharmacok
inet
icsamp
le
1
X
X
X
X
X
X
X
X
X
D
igox
in samp
le2
X
X
X
X
X
X
X
X
X
Tropon
in
X
X
X
X
X
X
DLco/DLno10
X15
X
X
X
X
X
12-lead ECG/  
t
ime & frequency 
doma
ins
3
X9
X9
X
X
X

2014N221874_02
CONFIDENTIAL
201881
38
Procedure
Screening 
Period
Treatment Periods I and II (Day)
Follow-up
Day -25  
to Day -1 
pr
ior to 
Per
iod I
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9
14 ± 4 days 
after 
last 
dose of 
study 
med
icat
ion
V
ita
l s
igns
X 
X 
X 
X 
X 
X 
X 
X 
X
X
We
ight
X 
X 
X
X 
X
Genet
ic samp
le 
For sub
jects who prov
ide consent, samp
le co
l
lected after start of treatment
Study treatment4
X
X
X
X
X
X
X
AE/SAE rev
iew
X
==============================================================
X
Concom
itant med rev
iew
X
==============================================================
X
Pu
lmonary funct
ion tests 
X
X
X
X
Step exerc
ise test/breath-
by-breath gas exchange 
X
X
X
Dyspneaassessment
X
X
X
X
Orthopnea
X
SF-36 Acute
X
X
X
Po
lysomnography 
inc
lud
ing ox
imetry (S
leep 
Apnea C
l
in
ic)5,13
      =========
      =========
P
lasma and 8-hour ur
ine 
catecho
lam
ines
6
X
X
Sa
l
ine 
infus
ion
X
Adm
iss
ion to un
it
7
X
D
ischarge from un
it
7
X
Meals
8
X
X
X
X
X
X
X
X
Appet
ite Assessment 
(SNAQ)
X
X
X
X
CSSRS (Su
ic
ida
l
ity) 
X
X
X
Aud
iometry
X13
X17
X
BodyGuard
ian Mon
itor 
(Prevent
ice)
============================Cont
inuous===================================

2014N221874_02
CONFIDENTIAL
201881
39
1. Pharmacokinetic samples to determine GSK2798745 and any metabolite(s) concentrations will be obtained at the following times on Day 1 of 
each treatment period:  Predose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours and at the following times on Day 7 of each treatment period: Predose, 0.5, 1, 
1.5, 2, 3, 5 and 10 hours.  On Day 2 of each treatment period, samples will be collected predose and at 12 hours post dose. On Days 3 through 6, 
PK samples will be collected predose.  On Days 8 and 9, samples will be collected at24 and 48 hours, respectively, after the last dose of study 
medication administered on Day 7. The time points may be modified based on emerging data.  Some of these timepoints willalso be utilized to 
collect samples to determine concentrations of other medications (e.g., atorvastatin and/or simvastatin).  See the SRM for detailed information.
2. Digoxin concentrations will be monitored only in those subjects who are taking digoxin.
3. Time and frequency domains assessed by ECG obtained on Day -1 and Day 7.
4. Subjects will remain in the unitfor a minimum of 4 hours after each administration of study medication.  [Note: The first 6 subjects enrolled will 
remain in the unitfor 52 hours after the first dose of study medication in each period]
5. Only for subjects participating in the sub-study: At Day -1 of the first study period only, subjects will undergo an overnight sleep study.  Only 
those subjects who are participating in the sub-study with sleep disordered breathing will undergo additional sleep studies on Day 6 of both study 
Periods I and II.
6. Only for subjects participating in the sub-study: Urinary norepinephrine (NE) and epinephrine (E) concentrations will be determined from 8-hour 
collections obtained during the overnight sleep study; urinary creatinine will also be measured to normalize the NE and E concentrations.  A blood 
sample to determine plasma concentrations of NE and E will be obtained the morning after the sleep study between the hours of9:00 am and 10:00 
am after the subject has been supine for 20 minutes in a quiet room.
7. The first 6 subjects enrolled will remain in the unitfor two days (Day 1 and Day 2) after the first dose of study medication in each period.
Subjects may remain in the unit for the duration of each of the 7 day treatment periods for convenience.  Housing should be consistent 
in both study periods.
8. Three meals per day will be provided by the dietary department either in the unitor as a boxed meal(s) to take home.
9. ECGs to be performed in triplicate
10.On the days whenexercise or the saline infusion is performed, DLco/DLno will be completed just prior to and after both exercise and the saline 
infusion.
11.Blood sample for analysis of Serum CTX must be collected when the subject is fasting.  See Section 7.4.9.1
12.Fecal Occult Blood Test (FOBT) cards will be provided to subjects at the end of the screening visit and must be completed andsent back to the 
laboratory prior to the baseline visit according to the laboratory’s standard collection procedures.  Similarly, subjects will be given FOBT cards at 
the end of the Day 7 visit of each study period with completion instructions.  See Section 7.4.9.2
13.Day -1 audiometry and sleep study assessments may be completed 7 days prior to Day -1.
14.Clinical laboratory assessments will be collected as a fasting sample.
15.The screening visit will only collect % Predicted DLco (DLco single breath)
16.If a subject has had an echocardiogram completed within the last 6 months prior toscreening, it does not need to be repeated
17.Day 7 Audiometry may be completed with a window of ± 2 days

2014N221874_02
CONFIDENTIAL
201881
40
7.2.
Screening and Critical Baseline Assessments
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/alcohol/family history will be assessed as related to the 
inclusion/exclusion criteria listed in Section 5.  Cardiovascular medical history/risk 
factors will also be assessed at screening, including the following items pertaining to 
medical and medicationhistory:

Onset and type of symptoms

Years since diagnosis of HF

New York Heart Association (NYHA) class

LVEF (%)

Years since diagnosis of sleep apnea (if applicable)

Degree of exercise intolerance: distance/ stairs/time prior to breathlessness

Presence of orthopnea and/or paroxysmal nocturnal dyspnea

Peripheral edema: presence and height beyond ankle; recent weight gains, 
level of peripheral pitting edema

Significant past medical history including onset, etiology, and results of any 
recent relevant investigations of heart failure, as applicable
Medication history
Procedures conducted as part of the subject’s routine clinical management and obtained 
prior to signing of informed consent may be utilized for Screening or baseline purposes 
provided the procedure meets the protocol-defined criteria and has been performed in the 
timeframe of the study.
During the Screening Period prior to the first study period (Period I), subjects will have 
the following assessments performed to determine eligibility for enrollment:
NT-proBNP
% Predicted DLco
Polysomnography (eligibility into sub-study)
7.3.
Pharmacodynamic Endpoints
7.3.1.
DLco and DLno
The diffusing capacity of the lung to carbon monoxide (DLco) or nitric oxide (DLno) is a 
measure of the ability of a gas to transfer from the alveoli across the alveolar epithelium 
and the capillary endothelium to the red blood cells.  Changes in DLco and DLno reflect 
the alveolar-capillary membrane conductance (D
M).  Since nitric oxide has a greater 

2014N221874_02
CONFIDENTIAL
201881
41
affinity for hemoglobin, the diffusion of nitric oxide is mainly limited by the transfer of 
gas across the alveolar capillary membrane.  Measurements are made simultaneously. 
Acute pulmonary congestion causes a reduction in DLco.  In patients withheart failure, 
DLco is decreased and serves as a predictor of disease progression.  An impairment in the 
diffusing capacity of the lung may be related to the symptoms and exercise intolerance 
associated with heart failure.  
DLco will be measured during the Screening Period to determine eligibility for 
enrollment into the study.  Subjects must have a % Predicted DLco <80%. 
During each study period, DLco and DLno will be measured just prior to and after the 3-
minute step test on Days -1, and 7 and at the Follow-up Visit.  Measurements will also be 
made just prior to and after an intravenous saline infusion on Day 5.  
Details of the pulmonary testing methodology including diffusing capacity and measured 
components are included in the SRM.  Refer to the instruction manual(s) for the 
equipment for further details.
7.3.2.
Submaximal Exercise Test
Blockade of the TRPV4 channel with GSK2798745 may decrease pulmonary edema 
resulting in an increase in exercise capacity and/or oxygen uptake.  
Subjects will be asked to participate in a submaximal exercise test that consists of 3 parts: 
a 2-minute resting baseline, a 3-minute step exercise, and a 1-minute recovery period 
[Woods, 2011].  Throughout the test, breathing pattern, gas exchange, and heart rate will 
be monitored using a simplified gas analysis system (i.e. SHAPE Medical Systems, Inc).  
Respiratory exchange ratio (RER) and the Borg Rating of Perceived Exertion (RPE) 
measures will be utilized to ensure subjects perform progressiveexercise while 
maintaining a submaximal level throughout the exercise period.  Minute ventilation, 
breath frequency, tidal volume, oxygen consumption, carbon dioxide production, RER 
and end tidal CO
2will be obtained from the breath-by-breath gas measurements.  The 
ventilation/carbon dioxide production (VE/VCO2) slope and other variables will be 
derived from this data.  
The exercise protocol will be completed on Day -1 and Day 7 of each study period.  
DLco/DLno measurements will be obtained before and after the exercise challenge.  
Additional details of the exercise protocol for the 3-minute step test are provided in the 
SRM. 
7.3.3.
Intravenous Saline Infusion
In patients with chronic HF, intravenously infused saline elicited a reduction of D
M [Puri, 
1999] suggesting that the abnormal pulmonary diffusion in this population may have a 
variable component that could be amenable to therapeutic intervention.  Similarly, an 
infusion of saline into the pulmonary artery significantly reduced both DLco and D
M in 
patients with chronic HF but not in control subjects [Guazzi, 1999]; the changes in D
M
were inversely related to VE/VCO2[Guazzi, 2001].  The hemodynamic effects of volume

2014N221874_02
CONFIDENTIAL
201881
42
expansionwith saline loading has been shown to be associated with increases in left and 
right heart filling pressures and pulmonary artery pressures in patients with HF 
[Andersen, 2015].  In this latter study, no patient developed dyspnea or any evidence of 
pulmonary congestion despite increase in cardiac filling pressures. 
All subjects will undergo an intravenous 0.9% NaCl infusion on Day 5 of both study 
periods in the presence of a cardiologist. The procedure will be conducted only if the 
subject is without any signs of obvious congestion as determined by the Investigator. 
Subjects will be carefully monitored both during and after the infusion and will be 
provided intravenous diuretics if necessary. Details of this procedure are described in 
Appendix 9.
DLco and DLno measurements will be obtained prior to the initiation of the infusion and 
after the completion of the infusion.  Additional details are included in the SRM.
7.3.4.
Pulmonary Function Tests
Measures of pulmonary function have been shown to predict prognosis in patients with 
HF [Olson, 2013].
Spirometry measures will include forced vital capacity (FVC) and forced expiratory 
volume in 1 second (FEV1) as well as forced expiratory flows, FEF
25-75FEF50, and FEF
75 
Functional residual capacity (FRC) and end-expiratory lung volume (EELV) will be 
measured by body plethysmography.
7.3.5.
Dyspnea
Dyspnea will be assessed using a standardised, validated 5-point scale [Mebazaa, 2010] 
on Days -1 and 7 of each study period as well as at the Follow-up Visit.  Additional 
details regarding the scale and the assessment are provided in Appendix 6and the SRM.
7.3.6.
Polysomnography
Only subjects participating in the sleep apnea substudy will undergo overnight 
polysomnography during the Screening Period.  Consenting subjects who meet all the 
eligibility criteria for the main study and have an apnea/hypopnea index (AHI) ≥5 
events/hour based on polysomnography will participate in subsequent sleep studies on 
Day 6 of both study periods. 
Multiple recordings will be monitored including electroencephlogram (EEG), 
electrooculogram (EOG), electromyogram (EMG), electrocardiogram (ECG), and 
oximetry.  Sleep stages and arousals, respiratory rate, and O
2saturation will be measured.  
Disordered breathing events will be classified as apneas or hypopneas and as either 
obstructive or central.
Additional details outlining the polysomnography procedure are detailed in the SRM.  

2014N221874_02
CONFIDENTIAL
201881
43
7.3.7.
Health Survey: SF-36 Acute
The SF-36 Acute health survey is validated questionnaire, which provides a profile of 
functional health and well-being.  Eight multifunctional scales are employed as well as a 
single-item evaluation of changes in health status and two summary component scales.   
The SF-36 Acute has a 1-week recall period for 6 of the 8 scales, which is appropriate for 
the length of this study.  The SF-36 Acute will be administered on Days -1 and 7 of each 
study period as well as at the Follow-up Visit.  Additional details regarding the 
administration of the scale are provided in Appendix 8and the SRM. 
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical 
examinations and clinical laboratory safety tests) may be added during the course of the 
study based on newly available data to ensure appropriate safety monitoring.
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.4.1.1.
Time period and Frequency for collecting AE and SAE information
AEs and SAEs will be collected fromthe start of Study Treatment until the follow-
up contact (see Section 7.4.1.3), at the timepoints specified in the Time and Events 
Table (Section 7.1).
Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.
Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact. 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 5.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the investigator 
must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEsand SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 5

2014N221874_02
CONFIDENTIAL
201881
44
7.4.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:
“How are you feeling?” 
“Have you had any (other) medical problems since your last visit/contact?” 
“Have you takenany new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.4.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.5). Further information on follow-up procedures is given in 
Appendix 4.
7.4.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4and 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 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 withinone 
week of when the death is reported.
7.4.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to 
study treatment (even for non-interventional post-marketing studies) is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety 
of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.

2014N221874_02
CONFIDENTIAL
201881
45
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.4.2.
Pregnancy
Details of all pregnancies in female partners of male subjects will be collected after 
the start of dosing and until the follow up visit. 
If a pregnancy is reported then the investigator should inform GSK within 2 weeks 
of learning of the pregnancy and should follow the procedures outlined in Appendix 
5.
7.4.3.
Physical Examinations
A complete physical examination will include, at a minimum, assessment of the 
head, eyes, ears, nose, throat, skin, thyroid, lymph nodes, extremities, and the 
cardiovascular, respiratory, gastrointestinal and neurological systems.  Height and 
weight will also be measured and recorded.
A brief physical examination will include, at a minimum assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).  Peripheral edema 
(height and severity above ankle, non-dependant limb), as well as jugular venous 
distention and should be assessed.  Weight will also be measured and recorded.
Weight will also be measured once daily as indicated in the Time and Events Table.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
7.4.4.
Vital Signs
Vital signs will be measured in a semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressures, heart rate, respiratory 
rate, and pulse oximetry.
7.4.5.
Electrocardiogram (ECG)
Triplicate 12-Lead ECGs will be obtained during the Screening Period and at 
baseline(Day -1)and single 12-lead ECGs will be obtained on Days 4 and 7 and the 
Follow-up Visit using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTcF or QTcB intervals.  
Refer to Section 5.5.2for QTc withdrawal criteria and additional QTc readings that 
may be necessary.
Resting and stationary measures will also be collected to determine heart rate 
variability and time domains

2014N221874_02
CONFIDENTIAL
201881
46
7.4.6.
Echocardiogram
A transthoracic echocardiogram will be performed during the Screening Period, unless 
the subject has had an echocardiogram completed within the 6 monthsprior to screening.
Images will be obtained in standard views (e.g., long axis parasternal, short axis 
parasternal, and apical 2, 3, 4 and 5 chamber).  The time to acquire images should not 
exceed 30minutes.
7.4.7.
Remote Monitoring
Continuousremote monitoring will be performed during each 7-day study period 
utilizing the Preventice BodyGuardian Remote Monitoring System.  The cardiac 
monitoring system is a portable, wireless body sensor that measures ECG, heart rate, 
respiratory rate, and activity level.  Data will be stored and transmitted to a 24-hour 
monitoring center.  Subjects will be instructed to wear the sensor throughout each study 
period.
7.4.8.
Audiometry
A hearing assessment will be conducted prior to the administration of study medication
and at the end of each study period as described in the Time and Events Table.  
Audiometry will be performed by authorized, trained staff.  Details of the audiometry 
testing may be found in the SRM.
7.4.9.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 3, must be conducted in 
accordance with the Laboratory Manual (if applicable), and Protocol Time and Events 
Schedule.All laboratory assessments will be collected as fasting samples.  Laboratory 
requisition forms must be completed and samples must be clearly labelled with the 
subject number, protocol number, site/centre number, and visit date.Details for the 
preparation and shipment of samples (if applicable) will be provided by the laboratory 
and are detailed in the SRM.  Reference ranges for all safety parameters will be provided 
to the study staff by the local laboratory.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 3. 

2014N221874_02
CONFIDENTIAL
201881
47
Table 3
Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
P
late
let Count
RBC Ind
ices: WBC count w
ith D
ifferent
ia
l:
RBC Count
MCV
Neutroph
i
ls
Hemog
lob
in
MCH
Lymphocytes
Hematocr
it
MCHC
Monocytes
WBC Count (abso
lute)
Eos
inoph
i
ls
Ret
icu
locyte count
Basoph
i
ls
Clinical 
Chemistry 
BUN
Potass
ium AST (SGOT)
Tota
l and d
irect 
b
i
l
irub
in
Creat
in
ine
Sod
ium
ALT (SGPT)
Tota
l Prote
in
G
lucose, 
fast
ing
Ca
lc
ium
A
lka
l
ine phosphat
ise
A
lbum
in
CPK
Ur
ic Ac
id
GGT
Ch
lor
ide
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Urinary norepinephrine and epinephrine (during sleep study)
Other 
Screening 
Tests
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody)
Digoxin concentrations (only in subjects treated with Digoxin)
Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)
HMG CoA Reductase Inhibitor concentration (only in subjects 
taking medication)
Biomarker(s)/ 
Other 
Assessments
N-terminal pro-B-type Natriuretic Peptide (NT-proBNP)
Norepinephrine and Epinephrine(substudy only)
Serum Collagen Type I C-Telopeptide (CTX), fasting
Fecal Occult Blood Test (FOBT)
Troponin
NOTES :
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 5.5.1and 
Appendix 2

2014N221874_02
CONFIDENTIAL
201881
48
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 14 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline.  If such values do not 
return to normal withina period judged reasonable by the investigator, theetiology
should be identified and the sponsor notified.
7.4.9.1.
Serum Collagen Type I Telopeptide (CTX)
Blood samples will be collected at the Baseline Visit (Day -1) and on Day 7 of each study 
period.  Approximately 1 mL will be collected as a fasting sample from the subject at the 
start of each of these visits.
7.4.9.2.
Fecal Occult Blood Test (FOBT)
Based on the gastric erosions found in a preclinical model (dogs at ≥3 mg/kg), FOBT will 
be performed to assess any possible drug-related GI blood loss.  Due to concomitant anti-
platelet therapy that many patients with heart failure receive, along with the common 
incidence of intestinal mucosal edema and associated diarrhea,findings of fecal blood 
would not be unexpected inthis population.  Subjects will be tested for the presence of 
fecal occult blood prior to the start of treatmentperiod I (between Screening and 
Baseline) and after each of the two treatmentperiods.  
Once subjects have signed the consent form and have been enrolled into the study based 
on meeting the eligibility criteria, they will be provided 3 FOBT cards at the end of the 
screening visit.  Study staff will provide the subjects with instructions for completing the 
tests and subsequent shipment of the tests back to the laboratory.  This assessment will be 
completed between Screening and Baseline (Day -1).  Additionally, subjects will be 
provided 3 FOBT cards on Day 7 of each treatment period with the same instructions for 
completion and shipment for laboratory analysis.
7.4.10.
Suicidal Risk Monitoring
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 this drug has 
not been shown to be associated with an increased risk of suicidal thinking or behaviour 
when given to this patient population, GSK considers it important to monitor for such 
events before or during clinical studies with compounds such as this.
Subjects 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 subjects who experience signs of suicidal ideation or 
behaviour.
The C-SSRS is a measure of suicidal ideation and behavior, with demonstrated predictive 
validity and reliability.  Improved assessments ofsuicidal ideation and behavior are 
necessary to better understand the relationship between suicidal AEs and medication 
treatment.  The FDA recommends the use of suicidality assessment instruments that map 

2014N221874_02
CONFIDENTIAL
201881
49
to the Columbia Classification Algorithm for Suicide Assessment (C-CASA).  One such 
instrument is the C-SSRS.  Sections of the C-SSRS include suicidal ideation, intensity of 
ideation, suicidal behavior, and actual suicide attempt(s).  The C-SSRS assesses lifetime 
and current suicidal thoughts and behaviors 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 Appendix 7and the SRM 
for details of the scale.
7.5.
Pharmacokinetics
7.5.1.
Blood Sample Collection
Blood samples for pharmacokinetic analysis of GSK2798745 will be collected at the time 
points indicated in Section 7.1Time and Events Table.
Approximately 2 mL of blood will be collected in EDTA tubes.  The actual date and time 
of eachblood 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.
Where possible, PK monitoring of relevant co-administered drugs and their metabolites 
willalso be undertaken (atorvastatin and simvastatin).  Approximately 2 mL of blood will 
be collected into sodium heparin tubes.  The actual date and time of each blood sample 
collection will be recorded.  The volume of such samples may be altered and additional 
time points may be added to ensure adequate statin PK monitoring.
Additional collection, processing, storage and shipping procedures are provided in the 
Study Reference Manual (SRM).
7.5.2.
Sample Analysis
Plasma analysis will be performed under the control of Platform Technologies and 
Science-Drug Metabolism and Pharmacokinetics (PTS-DMPK)/ GlaxoSmithKline, the 
details of which will be included in the Study Reference Manual (SRM).Concentrations 
of GSK2798745, and co-administered statins and corresponding metabolites (atorvastatin 
and metabolites,andsimvastatin and metabolites) will be determined in plasma samples 
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 metabolite M1 dependent upon the availability of an 
assay.  Until this time, GSK will store the remaining plasma from the PK plasma samples 
for future possible metabolite analysis.  

2014N221874_02
CONFIDENTIAL
201881
50
7.6.
Biomarker(s)
Blood samples will be taken for NT-proBNP measurement during the Screening Period 
and at the timepoints indicated in the Time and Event Table, Section 7.1.  
Details of sample collection, processing, storage, and shipment requirements are provided 
in the SRM.
7.7.
Genetics
Information regarding genetic research is included in Appendix 3.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.  
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.
Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.
CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted toGSK according to GSK policy.
For this study subject data will be collected using GSK defined case report forms and 
combined with data provided from other sources in a validated data system.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.
Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for RegulatoryActivities) and an internal validated medication 
dictionary, GSKDrug.  

Original CRFs will be retained by GSK, while the investigator will retain a copy.  
Subject initials will not be collected or transmitted to GSK according to GSK policy.

2014N221874_02
CONFIDENTIAL
201881
51
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
This is a double-blind study with the sponsor un-blinded, which allows data to be 
reviewed on an on-going basis by the sponsor.
9.1.
Hypotheses
An estimation approach will be used for the comparison between GSK2798745treatment 
and placebo for the change from baseline in DLco at Day 4 and Day 7.  Point estimates 
and associated 95% confidence intervals for the differences in means will be constructed 
to provide a plausible range of values for the true comparisons of interest.
9.2.
SampleSize Considerations
The sample size was determined using an estimation approach in order to provide 
sufficient precision for the estimation of the DLco comparison between the treatment and 
placebo groups.  A power statement has been calculated to put the sample size in a 
familiar context.
Based on the DLco measurements reported by [Olsen, 2006], the baseline mean DLco at 
rest is 15.3 mL/mmHg/min.  The within-subject variability (SDw) additionally provided 
by the Mayo Clinic Investigators is 1.9.  The corresponding change from baseline 
variance (SDw) estimation is 1.5.  If we assume the baseline values for HF subjects in the 
planned study will be similar to the values at rest in the HF group described in this 
reference, then a 15% increase from baseline would equate to an effect size of 2.3.
In a two-period crossover design (in which a subject receives placebo in one period and 
an active dose in the other period) with a sample size of 12 subjects, the estimates of the 
half-widths of the 95% confidence intervals for the difference in the mean change from 
baseline in DLco (active-placebo) is expected to be approximately 1.36 or less . That is, if 
the observed difference in the change from baseline for GSK2798745 and placebo is 2.3, 
then the 95% CI would be (0.94, 3.66).
In addition, 12 subjects would allow the detection of a 2.3 magnitude difference in the 
mean change from baseline for DLco under assumption that the SDw for change from 
baseline for DLco is 1.5, using a two-sided t-test with alpha=0.05 with more than 90% 
power.
9.2.1.
Sample Size Assumptions
If a subject is withdrawn from the study prior to completing both study periods, a subject 
may be enrolled as a replacement so that a total of 12 subjects complete all assessments
in the two study period.
9.2.2.
Sample Size Sensitivity
If the within-subject standard deviation is higher than expected, the precision of the 95% 
CI and the power of a two-sided t-test to detect an effect size of 2.3 (mean difference 

2014N221874_02
CONFIDENTIAL
201881
52
between the active dose andplacebo) with a 5% significance level would be as follows 
(with a two-period crossover design with 12 subjects):
SDw 
Power with Effect Size
of 2.3 mL/mmHg/min
Precision of the 95%
Confidence Interval
1.9
76%
1.73
2.4
56%
2.2
9.2.3.
Sample Size Re-estimation or Adjustment
When 12 subjects have completed both periods, an analysis will be performed to 
determine whether additional subjects (up to a maximum of 24 subjects) should be 
enrolled based on the estimate of within-subject variance for the change from baseline in 
DLco.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
All Subjects Population
The ‘All Subjects Population’ is defined as all randomized subjects who receive at least 
one dose of study medication.  
Per Protocol Population
The ‘Per Protocol Population’ will consist of any Analysis Population subjects who are 
compliant with protocol-specific criteria. Subjects with specified protocol deviations will 
be excluded.
9.3.2.
Interim Analysis
Safety, tolerabilityand efficacy data will be reviewed in-stream bythe sponsor.  These 
reviews may include individual subject data, summaries by treatment group and graphical 
displays.Subjects and all site personnel (except the un-blinded pharmacist) will be 
blinded to subject randomization.  The decision to continue or stop recruitment will be 
made based on the evaluation of all available safety and efficacy data.
After 12 subjects complete the study, a sample size re-estimation will be performed based 
on the estimate of within-subject variance for the change from baseline in the DLco 
measurement.  If the within-subject variance for the change from baseline in DLco is 
assumed reasonable, the study will be considered completed.  Otherwise, additional 
subjects up to a total of 24 may be enrolled into the study.  The finalanalyses and 
reporting of the study will be performed after all patients have completed the central 
formal study.

2014N221874_02
CONFIDENTIAL
201881
53
In addition, aBayesian predictive approach will be used to assess the futility of the 
percent change from baseline in DLco at Day 7 to help determine whether additional 
patients are needed after the sample size re-evaluation.  However, this alone will not be 
used as a basis for determining futility.  
The futility criteria for the change from baseline in DLco will be based on the predictive 
probability at the interim that the end of the study difference in the change from baseline 
in DLco between GSK2798745 treatment and placebo will meet the definition of a 
positive outcome.
9.4.
Key Elements of Analysis Plan
Final analysis will be provided when all subjects have finished the study and the database 
has been frozen.  The construction of analysis data sets will be performed in accordance 
with all applicable GlaxoSmithKline standards and procedures.
Adjustment for multiplicity of treatment group comparisons and endpoints is not planned.  
All available data will be used in the analyses as defined in the populations above. 
Missing values will not be imputed.
9.4.1.
Primary Analyses
Profiles for DLco will be summarized and presented graphically by treatment groupas 
appropriate for the data.The change from baseline in DLco at Day 4, Day 5and Day 7 
will be calculated and summarized in tabular format and/or graphically by treatment.For 
the change from baseline in DLco, a statistical analysis will be performed using a mixed 
effect model with repeated measures with a fixed effect term for treatment, period and 
day,with a random effect forsubject,day in the repeated statement with subject being 
subject by period, and baseline as a covariate, if data permit.Point estimates and 
associated 95% confidence intervals will be constructed for the differences between the 
active treatment and placebo.
Full details of analysis will be specified in the RAP.
9.4.2.
Secondary Analyses
For other diffusing capacitypharmacodynamic (PD) endpoints such as DLno, DM and 
Vc, similar analyses as in Section 9.4.1will be provided, as data permit.  For these PD 
endpoints, which may be log
etransformed prior to analysis to satisfy model assumptions, 
point estimates and their associated 95% confidence intervals will be back-transformed to 
provide point estimates and 95% confidence intervals for the ratios.
For pulmonary function measurement endpoints such as FVC, FEV1, FEF25-75FEF50, and 
FEF75, FRC and EELV, similar analysis as in Section 9.4.1will be provided, as data 
permit.  For these PD endpoints, which may be log
etransformed prior to analysis to 
satisfy model assumptions, point estimates and their associated 95% confidence intervals 
will be back-transformed to provide point estimates and 95% confidence intervals for the 
ratios.

2014N221874_02
CONFIDENTIAL
201881
54
For respiratory rate measurement and dyspnea score,similar analysis as in Section 9.4.1
will be provided, as data permit.  
In terms of DLco and DLno changes from baseline after saline challenge on Day 5and 
after exercise on Day 7, the change from baseline for the challenge (after-before) will be 
calculated and summarized in tabular format by treatment.  Astatistical analysis will be 
performed using a mixed effect model with a fixed effect term for treatment, period and 
sequence, random effect term for subject-within-sequence, and baseline as a covariate, if 
data permit.  Point estimates and associated 95% confidence intervals will be constructed 
for the differences between the active treatment and placebo.  
In terms of ventilatory efficiency, scatter plots for Ve/VCO2 at Baseline and Day 7 will 
be performed and the slope or correlation of Ve/VO2 provided.  Summary statistics for 
Ve and VCO2 and change from baseline measurement will be provided. 
Details on the analysis of other endpoints will be provided in RAP.
Pharmacokinetic analyses will be the responsibility of the Clinical Pharmacology 
Modeling & Simulation Department within GlaxoSmithKline.  Plasma GSK2798745 
concentration-time data will be analyzed by non-compartmental methods with the latest 
available version of WinNonlin software.  Calculations will be based on the actual 
sampling times recorded during the study.  From the plasma concentration-time data, the 
pharmacokinetic parameters such as Cmax and AUC may be determined, as data permit.
The details of the PK analysis will be listed in the RAP.
9.4.3.
Other Analyses
Safety datawill be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.  
No formal statistical analyses are planned for safety data.  Safety data will be listed and 
summarized.  All subjects who received an active dose of study medication will be 
included in the evaluation of clinical safety and tolerability.  Clinical monitoring and 
laboratory safety will be reviewed by the Investigator and vital signs will be summarized 
by treatment.
9.4.4.
Exploratory Analyses
Pharmacokinetic analysesfor the statins and any statin metabolites will be the 
responsibility of the Clinical Pharmacokinetics Modeling & Simulation Department 
within GlaxoSmithKline.  Calculations will be based on the actual sampling times 
recorded during the study.  The systemic concentrations of any HMG-CoA reductase 
inhibitors(e.g., simvastatin, atorvastatin) and their metabolites will be summarized, as 
data permit.  The details of the PK analysis will be listed in the RAP.
Data from the polysomnography sub-study will be presented in tablular and/or graphical 
format and summarized descriptively.

2014N221874_02
CONFIDENTIAL
201881
55
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers beforeenrollmentof subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:
IRB/IEC review andfavorableopinion/approval of the study protocol and 
amendments as applicable
Signed informed consent  to be obtained for each subject before participation in the 
study (and for amendments as applicable)
Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)
GSK will provide full details of the above procedures, either verbally, in writing, or 
both.
Signed informed consent must be obtained for each subject prior to participation in 
the study
The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  
Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  
Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, written 
approval of the clinical protocol should state that approval of optional assessments is 
being deferred and the study, with the exception of the optional assessments, can be 
initiated.

2014N221874_02
CONFIDENTIAL
201881
56
10.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  
When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK will monitor the study and site activity to verify that the:
Data are authentic, accurate, and complete.
Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 
In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure
Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures.
GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites.  
If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

2014N221874_02
CONFIDENTIAL
201881
57
If the study issuspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  
If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly andprovide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention
Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.  
The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.  

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 
institutional requirements or local laws or regulations, GSK standards/procedures, 
and/or institutional requirements.  
The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
ofthe records in the event the investigator is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.

2014N221874_02
CONFIDENTIAL
201881
58
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 subjects, 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.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.

2014N221874_02
CONFIDENTIAL
201881
59
11.
REFERENCES
AgostoniP, Cattadori G, Bianchi M, Wasserman K. Exercise-induced pulmonary edema 
in heart failure. Circ. 2003;108:2666-2671.Epub October 27, 2003.
Andersen MJ, Olson TP, Melenovsky V, Kane GC, Borlaug BA, MD. Differential 
hemodynamic effects of exercise and volumeexpansion in people with and without heart 
failure.  Circ Heart Fail. 2015;8:41-48. doi:10.1161/CIRCHEARTFAILURE.114.001731.
Costanzo MR, Khayat R, Ponikowski P, Augostini R, Stellbrink C, Mianulli M, Abraham 
WT. Mechanisms and Clinical Consequences of Untreated Central Sleep Apnea in Heart 
Failure. J Amer Coll Cardiol. 2015;65(1): 72-84.
Fujimoto N, Borlaug BA, Gregory D. Lewis GD, Hastings JL, Shafer KM, Bhella PS, 
Carrick-Ranson G, Levine BD.  Hemodynamic responses to rapid saline loading: the 
impact of age, sex, and heart failure. Circulation. 2013;127(1):55-62.
GlaxoSmithKline Document Number 2013N162862_01.  Investigator’s Brochure for 
GSK2798745.2015.
Guazzi M, Agostoni P, Bussotti M, Guazzi M. Impeded alveolar-capillary gas transfer 
with saline infusion in heart failure. Hypertension. 1999;34:1202-1207.
Guazzi M, Agostoni P, Guazzi M. Alveolar-capillary gas exchange and exercise 
performance in heart failure. Amer J Cardio. 2001;88:452-457.
Guazzi M. Alveolar Gas Diffusion Abnormalities in Heart Failure. Journal of Cardiac 
Failure. 2008;14(8):695-702.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(a): 24. Table 3-
2.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(b): 28
ICH Harmonized Tripartite Guideline.  Guidance on Nonclinical Safety Studies for the 
Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals M3 
(R2). Current Step 4 version 11 Jun 2009.
Landouré G, Zdebik AA, Martinez TL, Burnett BG, Stanescu HC, Inada H, Shi Y, Taye 
AA, Kong L, Munns CH, Choo SS, Phelps CB, Paudel R, Houlden H, Ludlow CL, 
Caterina MJ, Gaudet R, Kleta R, Fischbeck KH, Sumner CJ. Mutations in TRPV4 cause 
Charcot-Marie-Tooth disease type 2C. Nat Genet. 2010;42(2):170-4. doi: 
10.1038/ng.512. Epub 2009 Dec 27.
Magini A, Apostolo A, Salvioni E, Italiano G, Veglia F, Agostoni P. Alveolar–capillary 
membrane diffusion measurement by nitric oxide inhalation in heart failure. Eur J Prev 
Cardiol. 2015;22(2):206-12. Epub 2013 Oct 28.

2014N221874_02
CONFIDENTIAL
201881
60
Masuyama R, Vriens J, Voets T, Karashima Y, Owsianik G, Vennekens R, et al. TRPV4-
mediated calcium influx regulates terminal differentiation of osteoclasts. Cell Metab. 
2008;8:257-65.
Mebazaa A, Pang PS, Tavares M, Collins SP, Storrow AB, Laribi S, et al. The impact of 
early standard therapy on dyspnoea in patients with acute heart failure: the URGENT-
dyspnoea study. European Heart Journal.2010;31:832-841.
Mizoguchi F, Mizuno A, Hayata T, Nakashima K, Heller S, Ushida T, et al. Transient 
receptor potential vanilloid 4 deficiency suppresses unloading-induced bone loss. J Cell 
Physiol. 2008;216:47-53.
Olsen LJ, Synder EM, Beck KC, Johnson BD. Reduced rate of alveolar-capillary 
recruitment and fall of pulmonary diffusing capacity during exercise in patients with 
heart failure.  Journal of Cardiac Failure. 2006;12(4):299-306.
Olson TP, Denzer DL, Sinnett WL, Wilson T, Johnson BD. Prognostic value of resting 
pulmonary function in heart failure. Clin Med Insights Circ Respir Pulm Med. 2013;7: 
35-43.
Puri S, Dutka DP, Baker BL, Hughes JMB, Cleland JGF. Acute saline infusion reduces 
alveolar-capillary membrane conductance and increases airflow obstruction in patients 
with left ventricular dysfunction. Circ. 1999;99:1190-1196.
Robbins IM, Hemnes AR, ME, Brittain EL, Zhao DX, Piana RN, Fong PP, Newman JH. 
High prevalence of occult pulmonary venous hypertension revealed by fluid challenge in 
pulmonary hypertension. Circ Heart Fail. 2014;7(1):116-22.
Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, et al. Sleep Apnea 
and Cardiovascular Diseases. J Amer Coll Cardiol. 2008;52(8):686-717.
Synder EM, Beck KC, Hulsebus ML, Breen JF, Hoffman EA, Johnson BJ. Short-term 
hypoxic exposure at rest andduring exercise reduces lung water in healthy humans. J 
Appl Physiol. 2006; 101: 1623–1632.
Tabuchi K, Suzuki M, Mizuno A, Hara A. Hearing impairment in TRPV4 knockout mice. 
Neurosci Lett. 2005;382(3):304-8. Epub 2005 Apr 13.
Thorneloe KS, Cheung M, Bao W, Alsaid H, Lenhard S, Jian MY, Costell M, 
Maniscalco-Hauk K, Krawiec JA, Olzinski A, Gordon E, Lozinskaya I, Elefante L, Qin 
P, Matasic DS, James C, Tunstead J, Donovan B, Kallal L, Waszkiewicz A, Vaidya K, 
Davenport EA, Larkin J, Burgert M, Casillas LN, Marquis RW, Ye G, Eidam HS, 
Goodman KB, Toomey JR, Roethke TJ, Jucker BM, Schnackenberg CG, Townsley MI, 
Lepore JJ, Willette RN.   An orally active TRPV4 channel blocker prevents and resolves 
pulmonary edema induced by heart failure.  Sci Transl Med. 2012;4(159):159ra148. doi: 
10.1126/scitranslmed.3004276.

2014N221874_02
CONFIDENTIAL
201881
61
van der Eerden BC, Oei L, Roschger P, Fratzl-Zelman N, Hoenderop JG, van Schoor 
NM, et al. TRPV4 deficiency causes sexual dimorphism in bone metabolism and 
osteoporotic fracture risk. Bone. 2013;57:443-54.
Woods PR, Frantz RP, Taylor BJ, Olson TP, Johnson BD. Usefulness of submaximal 
exercise gas exchange to define pulmonary arterial hypertension. J Heart Lung 
Transplant. Oct 2011; 30(10): 1133–1142.

2014N221874_02
CONFIDENTIAL
201881
62
12.
APPENDICES
12.1.
Appendix 1:  Abbreviations and Trademarks
Abbreviations
ADHF
Acute decompensated heart failure
AE
Adverse Event
AHI
Apnea-hypopnea index
ALT
Alanine transaminase
AST
Aspartate aminotransferase
AUC
Area under the curve
BMI
Body mass index
Ca2+
Calcium
C-CASA
Columbia Classification Algorithmfor Suicide Assessment
CHF
Chronic heart failure
CI
Confidence intervals
Cmax
Maximum concentration
CMT2C
Charcot-Marie-Tooth disease Type 2C 
CNS
Central nervous system
CO2
Carbon dioxide
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic obstructive pulmonary disease
CPK
Creatine phosphokinase
CRF
Case report form
CRU
Clinical research unit
CSA
Central sleep apnea
CSR
Cheyne-Strokes respiration
C-SSRS
Columbia Suicide Severity Rating Scale
cTn
Troponin (cardiac)
CTX
Collagen Type I Telopeptide
CV
Cardiovacsular
CYP
Cytochrome P450 enzyme
DLco
Diffusing capacity of the lung for carbon monoxide
DLno
Diffusing capacity of the lung for nitric oxide
DM
Alveolar-caplillary membrane conductance
DMPK
Drug Metabolism and Pharmacokinetics
DNA
Deoxyribonucleic acid
DPD
Deoxypyridinoline
E
Epinephrine
ECG
Electrocardiogram
EEG
Electroencephalography
EELV
End expiratory lung volume
EMG
Electromyogram
EOG
Electrooculogram
ER
Emergency Room

2014N221874_02
CONFIDENTIAL
201881
63
FDA
Food and Drug Administration
FEF
Forced expiratory flows
FEV1
Forced expiratory volume in 1 second
FOBT
Fecal Occult Blood Test
FRC
Forced residual capacity
FSH
Follicle stimulating hormone
FVC
Forced vital capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilence
GSK
GlaxoSmithKline
HBcAb
Hepatitis B core antibody
HbsAg
Hepatitis B surface antigen
HEK
Human embryonic kidney cells
HF
Heart failure
HR
Heart rate
HRT
Hormone Replacement Therapy
IDSL
Integrated Data Standards Library
IEC
Independent ethics committee
IgM
Immunoglobulin
INR
International normalized ratio
IP
Investigational Product
IRB
Institutional review board
IWRS
Interactive webresponse system
Kg
Kilogram
KO
Knockout
LDH
Lactate dehydrogenase
LFT
Liver function tests
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mL
Milliliter
MSDS
Material Safety Data Sheet
Na
Sodium
NaCl
Sodium chloride
NE
Norepinephrine
nM
Nanomolar
NO
Nitric oxide
NOAEL
No observed adverse event level 
NYHA
New York Heart Association
O2
Oxygen
OSA
Obstructive sleep apnea
P1NP
Procollagen type 1 amino-terminal propeptide
PD
Pharmacodynamic
PFT
Pulmonary function tests
P-gp
P-glycoprotein
PGx
Pharmacogenomics
PK
Pharmacokinetics

2014N221874_02
CONFIDENTIAL
201881
64
PTH
Parathyroid hormone
PTS-DMPK
Platform Technologies and Sciences-Drug Metabolism and 
Pharmacokinetics
QTc
QT interval corrected
QTcB
QT interval corrected according to Bazett’s formula
QTcF
QT interval corrected according to Fridericia’s formular
RAP
Reporting and analysis plan
RER
Respiratory exchange ratio 
RPE
Rating of perceived exertion
SAE
Serious Adverse Event
SDw
Within-subject variability
SOP
Standard Operating Procedure
SRM
Study reference manual
t½
Half-life 
tmax
Time to maximum observed plasma concentration
TRPV4
Transient receptor potential vanilloid 4
µg
Micrograms
ULN
Upper limit of normal
VCO2
Volume of carbon dioxide production
Vc
Capillary blood volume
VE
Ventilation
VO2
Volume of oxygen
WBC
White blood cells
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Preventice BodyGuardian
WinNonlin

2014N221874_02
CONFIDENTIAL
201881
65
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteriahave been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria –Liver Stopping Event
ALT-absolute ALT 5xULN
ALT Increase
ALT 3xULN pers
ists for 4 weeks
Bilirubin1, 2
ALT 3xULN andb
i
l
irub
in 2xULN (>35% d
irect b
i
l
irub
in)
INR2
ALT 3xULN andINR>1.5, 
if INR measured
Cannot Monitor ALT 3xULN and cannot be mon
itored week
ly for 4 weeks
Symptomatic3
ALT  3xULN assoc
iated w
ith symptoms (new or worsen
ing) be
l
ieved to be 
re
lated to 
l
iver 
in
jury or hypersens
it
iv
ity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments
Immediately d
iscont
inue  study treatment 
Report the event to GSKwithin 24 hours
Comp
lete the 
l
iver event CRF and comp
lete an 
SAE data co
l
lect
ion too
l 
if the event a
lso meets 
the cr
iter
ia for an SAE
2
Perform 
l
iver event fo
l
low up assessments 
Mon
itor the sub
ject unt
i
l 
l
iver chem
istr
ies
reso
lve, stab
i
l
ize, or return to w
ith
in base
l
ine 
(see MONITORINGbe
low)
Do not restart/rechallengesub
ject w
ith study 
treatment un
less a
l
lowed per protoco
l and GSK 
Med
ica
l Governance approva
l is granted  
If restart/recha
l
lenge not allowed per protocol 
or not granted, permanent
ly d
iscont
inue study 
treatment and may cont
inuesub
ject 
in the study 
V
ira
l hepat
it
is sero
logy4
B
lood samp
le for pharmacok
inet
ic (PK) 
ana
lys
is, obta
ined 24 hours after 
last 
dose
5
Serum creat
ine phosphok
inase (CPK) 
and 
lactate dehydrogenase (LDH).
Fract
ionate b
i
l
irub
in, 
if tota
l 
b
i
l
irub
in2xULN
Obta
in comp
lete b
lood count w
ith 
d
ifferent
ia
l to assess eos
inoph
i
l
ia
Record the appearance or worsen
ing of 
c
l
in
ica
l symptomsof 
l
iver 
in
jury, or 
hypersens
it
iv
ity, on the AE report form
Record use of concom
itant med
icat
ions 
on the concom
itant med
icat
ions report 

2014N221874_02
CONFIDENTIAL
201881
66
Liver Chemistry Stopping Criteria –Liver Stopping Event
for any protoco
l spec
if
ied fo
l
low up assessments 
MONITORING:
For bilirubin or INR criteria:
Repeat 
l
iver chem
istr
ies(
inc
lude ALT, AST, 
a
lka
l
ine phosphatase, b
i
l
irub
in) and perform 
l
iver event fo
l
low up assessments w
ith
in  
24 hrs
Mon
itor sub
jects tw
ice week
ly unt
i
l 
l
iver 
chem
istr
ies reso
lve, stab
i
l
ize or return to w
ith
in 
base
l
ine 
A spec
ia
l
ist or hepato
logyconsu
ltat
ion 
is 
recommended
For All other criteria:
Repeat 
l
iver chem
istr
ies(
inc
lude ALT, AST, 
a
lka
l
ine phosphatase, b
i
l
irub
in)and perform 
l
iver event fo
l
low up assessments w
ith
in  
24-72 
hrs 
Mon
itor sub
jects week
ly unt
i
l 
l
iver chem
istr
ies 
reso
lve, stab
i
l
ize or return to w
ith
in base
l
ine
form 
inc
lud
ing acetam
inophen, herba
l 
remed
ies, other over the counter 
med
icat
ions.
Record a
lcoho
l use on the 
l
iver event 
a
lcoho
l 
intake case report form
For bilirubin or INR criteria:
Ant
i-nuc
lear ant
ibody, ant
i-smooth 
musc
le ant
ibody, Type 1 ant
i-l
iver 
k
idney m
icrosoma
l ant
ibod
ies, and 
quant
itat
ive tota
l 
immunog
lobu
l
in G 
(IgG or gamma g
lobu
l
ins).
Serum acetam
inophen adduct HPLC 
assay (quant
if
ies potent
ia
l 
acetam
inophen contr
ibut
ion to 
l
iver 
in
jury 
in sub
jects w
ith def
in
ite or 
l
ike
ly 
acetam
inophen use 
in the preced
ing 
week [James, 2009]). NOTE: not 
required in China
L
iver 
imag
ing (u
ltrasound, magnet
ic 
resonance, or computer
ised 
tomography) and /or 
l
iver b
iopsy to 
eva
luate 
l
iver d
isease; comp
lete L
iver 
Imag
ing and/or L
iver B
iopsy CRF 
forms.
1. Serum b
i
l
irub
in fract
ionat
ion shou
ld be performed 
if test
ing 
is ava
i
lab
le. If serum b
i
l
irub
in fract
ionat
ion 
is not 
immed
iate
ly ava
i
lab
le, d
iscont
inue study treatment for that sub
ject 
if ALT 3xULN andb
i
l
irub
in 2xULN.. 
Add
it
iona
l
ly, 
if serum b
i
l
irub
in fract
ionat
ion test
ing 
is unava
i
lab
le, record presence of detectable urinary 
bilirubin on dipstick, 
ind
icat
ing d
irect b
i
l
irub
in e
levat
ions and suggest
ing 
l
iver 
in
jury. 
2. A
l
l events of ALT 3xULN andb
i
l
irub
in 2xULN (>35% d
irect b
i
l
irub
in) or ALT 3xULN andINR>1.5, 
if INR 
measured wh
ich may 
ind
icate severe 
l
iver 
in
jury (poss
ib
le 
‘Hy
’s Law
’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement 
is not requ
ired and the thresho
ld va
lue stated 
w
i
l
l not app
ly to sub
jects rece
iv
ing ant
icoagu
lants
3. New or worsen
ing symptoms be
l
ieved to be re
lated to 
l
iver 
in
jury (such as fat
igue, nausea, vom
it
ing, r
ight upper 
quadrant pa
in or tenderness, or 
jaund
ice) or be
l
ieved to be re
lated to hypersens
it
iv
ity (such as fever, rash or 
eos
inoph
i
l
ia)
4. Inc
ludes: Hepat
it
is A IgM ant
ibody; Hepat
it
is B surface ant
igen and Hepat
it
is B Core Ant
ibody (IgM); Hepat
it
is C 
RNA; Cytomega
lov
irus IgM ant
ibody;  Epste
in-Barr v
ira
l caps
id ant
igen IgM ant
ibody (or 
if unava
i
lab
le, obta
in 
heteroph
i
le ant
ibody or monospot test
ing);  Hepat
it
is E IgM ant
ibody 
5. PK samp
le may not be requ
iredfor sub
jects known to be rece
iv
ing p
lacebo or non-GSK comparator treatments.)  
Record the date/t
ime of the PK b
lood samp
le draw and the date/t
ime of the 
last dose of study treatment pr
ior to 
b
lood samp
le draw on the CRF. If the date or t
ime of the 
last dose 
is unc
lear, prov
ide the sub
ject
’s best 
approx
imat
ion. If the date/t
ime of the 
last dose cannot be approx
imated OR a PK samp
le cannot be co
l
lected 
in 

2014N221874_02
CONFIDENTIAL
201881
67
the t
ime per
iod 
ind
icated above, do not obta
in a PK samp
le. Instruct
ions for samp
le hand
l
ing and sh
ipp
ing are 
in 
the SRM.
Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria –Liver Monitoring Event
Criteria
Actions
ALT 3xULN and<5xULN andb
i
l
irub
in 
<2xULN, withoutsymptoms be
l
ievedto 
be re
lated to 
l
iver 
in
jury or 
hypersens
it
iv
ity, andwho can be 
mon
itored week
ly for 4 weeks
Not
ify the GSK med
ica
l mon
itor within 24 hoursof 
learn
ing of the abnorma
l
ity to d
iscuss sub
ject safety. 
Sub
ject can cont
inue study treatment 
Sub
ject must return week
ly for repeat 
l
iver 
chem
istr
ies (ALT, AST, a
lka
l
ine phosphatase, 
b
i
l
irub
in) unt
i
l they reso
lve, stab
i
l
ise or return to 
w
ith
in base
l
ine 
If at any t
ime sub
ject meets the 
l
iver chem
istry 
stopp
ing cr
iter
ia, proceed as descr
ibed above
If, after 4 weeksof mon
itor
ing, ALT <3xULN and 
b
i
l
irub
in <2xULN, mon
itor sub
jects tw
ice month
ly 
unt
i
l 
l
iver chem
istr
ies norma
l
ize or return to w
ith
in 
base
l
ine.
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.

2014N221874_02
CONFIDENTIAL
201881
68
12.3.
Appendix 3: Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 
Response to medicine, including GSK2798745 or any concomitant medicines;
Heart Failure susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis.  Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received anallogeneicbone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priorihypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  
A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A 
Blood sample is collected at the baseline visit, after the subject has been randomized 
and provided informed consent for genetic research. Instructions for collection and 
shipping of the genetic sample are described in the laboratory manual. The DNA 
from the blood sample may undergo quality control analyses to confirm the integrity 
of the sample. If there are concerns regarding the quality of the sample, then the 
sample may be destroyed. The blood sample is taken on a single occasion unless a 
duplicate sample is required due to an inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 

2014N221874_02
CONFIDENTIAL
201881
69
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:
Continue to participate in the genetic research in which case the genetic DNA sample 
is retained
Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 
If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  
Genetic data that has been analyzed at the time of withdrawn consent will continue 
to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.

2014N221874_02
CONFIDENTIAL
201881
70
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.

2014N221874_02
CONFIDENTIAL
201881
71
12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:
An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.
NOTE: An AE can therefore be anyunfavorableand unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meetingAE definition include:
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinicalsequelae of a suspected interaction.
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.

2014N221874_02
CONFIDENTIAL
201881
72
Events NOTmeeting definition of an AE include:
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 subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.4.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above,then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
atany dose:
a. Results in death
b. Is life-threatening
NOTE:
The term 
'life-threatening
' in the definition of 
'serious
' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c. Requires hospitalization or prolongation of existing hospitalization
NOTE:
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patientsetting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization orfulfillsany 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 

2014N221874_02
CONFIDENTIAL
201881
73
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
atany dose:
from baseline is not considered an AE.
d. Results in disability/incapacity
NOTE:
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting,diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e. Is a congenital anomaly/birth defect
f. Other situations:
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g. Is associated with liver injury andimpaired liver function defined as:
ALT 3xULN and total bilirubin*2xULN (>35% direct), or
ALT 3xULN and INR**> 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
Refer to Appendix 2for the required liver chemistry follow-up instructions

2014N221874_02
CONFIDENTIAL
201881
74
12.4.3.
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
12.4.4.
Recording of AEs and SAEs
AEs and SAE Recording:
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.
The investigator will then record all relevant information regarding an AE/SAE in 
the CRF
It is notacceptable for the investigator to send photocopies of the subject’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 instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.
Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 

2014N221874_02
CONFIDENTIAL
201881
75
AEs and SAE Recording:
the scale’s developer.
The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.4.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:
Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.
Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities
Severe:  An event that prevents normal everyday activities. -an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality
The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.
A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.
The investigator will use clinical judgment to determine the relationship.
Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.
The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator mustdocument in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 

2014N221874_02
CONFIDENTIAL
201881
76
Assessment of Causality
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.
The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.
The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.
The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.4.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool
Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool
If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor.
Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.
After the study is completed at a given site, the electronic data collection tool 
(InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data
If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

2014N221874_02
CONFIDENTIAL
201881
77
SAE reporting to GSK via electronic data collection tool
Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.

2014N221874_02
CONFIDENTIAL
201881
78
12.5.
Appendix 5: Collection of Pregnancy Information
Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the 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.

2014N221874_02
CONFIDENTIAL
201881
79
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected 
by third party copyright laws and therefore have been excluded.
12.6.
Appendix 6: Dyspnea 5-Point Likert Scale

2014N221874_02
CONFIDENTIAL
201881
80
12.7.
Appendix 7: Columbia Suicide-Severity Rating Scale (C-
SSRS)
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.

2014N221874_02
CONFIDENTIAL
201881
90
COLUMBIA SUICIDE-SEVERITY 
RATING SCALE (C-SSRS)
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded.

2014N221874_02
CONFIDENTIAL
201881
97
12.8.
Appendix 8: SF-36 Acute
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.

2014N221874_02
CONFIDENTIAL
201881
103
12.9.
Appendix 9: Intravenous Saline Infusion
Rapid intravenous saline infusion has been employed to elicit fluid extravasation from the 
vasculature to the pulmonary interstitium.  This methodology has been previously utilized 
in studies with healthy volunteers [Synder, 2006] and patients with heart failure 
[Fujimoto, 2013; Robbins, 2014; Andersen, 2015].
Subject Evaluation Prior to Infusion
On Day 5 of both study periods, the subject will be admitted to the unit and undergo 
routine weight measurement and vital sign assessments including temperature, systolic 
and diastolic blood pressures, heart rate, respiratory rate, and pulse oximetry to assess O
2
saturation.  The subject will also undergo a pulmonary examination.  
While in a sitting position, a dyspnea assessment, utilizing a standardized 5-point Likert 
scale, will be obtained to document the subject’s current status.  A subject who is not 
severely or very severely short of breath will undergo an orthopnea test (placed supine 
with head ≤ 20 degrees relative to horizontal).  After an equilibration period of 2 minutes, 
the 5-point scale will be repeated.  A subject who reports a worse dyspnea score when 
supine compared to sitting will be categorized as having orthopnea.  Subjects categorized 
ashaving orthopnea will not be eligible to participate in the saline infusion. 
Study treatment will be administered after all planned pre-dose assessments for Day 5 are 
completed.  
Saline Infusion Procedure
A subject who is judged by the Investigator to be in a stable condition and without 
obvious congestion will then undergo the intravenous saline infusion procedure.  This 
procedure will be conducted in the unit, in the presence of a cardiologist and monitoring 
personnel.  A crash cart will be accessible, and intravenous diuretic will be available, if 
necessary.  
A venous catheter will be inserted while the subject is semi-recumbent (approximately 
45°).  The subject will remain in a semi-recumbent position throughout the procedure.
DLco and DLno measurements and simple spirometry assessments will be obtained prior 
to the initiation of the infusion.
0.9% normal saline will be infused intravenously at a rate of approximately 150 mL/min 
to a total volume of 500mL.  During the saline infusion, blood pressure, heart rate, 
respiratory rate, and O
2saturation will be continuously monitored, and any physical 
symptoms recorded.  
DLco and DLno measurements and spirometry assessments will be obtained after the 
completion of the infusion.Additional details are provided in the SRM.

2014N221874_02
CONFIDENTIAL
201881
104
Post-infusion Monitoring
Following the completion of the saline infusion procedure, the subject will remain in the 
unit for the next 4 hours.  Blood pressure, heart rate, respiratory rate, and O2saturation 
will be continuously monitored, and any physical symptoms recorded.  The subject will 
also be assessed for dyspnea and orthopnea, as described above, at hourly intervals.
After the 4-hour period, the subject will be eligible to leave the unitif heart rate and 
respiratory rate are within 20% of the baseline value, O
2saturation is within 2% of the 
baseline value, and if the dyspnea score is the same as the baseline score.  
The subject will continue to be monitored by the Preventice BodyGuardian Remote 
Monitoring System as described in Section 7.4.7of the protocol; ECG, heart rate, 
respiratory rate and activity level will be measured continuously.  
Any worsening of heart failure that requires treatment in the 48 hours subsequent to the 
saline infusion will be reported as a serious adverse event.
Individual Stopping Criteria During the Saline Infusion Procedure
If the subject demonstrates oneof the following changes during the saline infusion, the 
infusion should be discontinued:
Decrease in O2 saturation of >4% compared to baseline 
Increase in respiratory rate of >20% compared to baseline
Any increase in dyspnea perceived by the patient 
If the subject has met one of these criteria during or immediately after the infusion, the 
subject should be carefully monitored and given intravenous diuretic treatment, 
intravenous or sublingual nitrates, or other treatment as required.  
The subject may continue in the study.  However, if this response occurred in the first 
study period, the subject should not undergo a second saline infusion in the subsequent 
study period.
Discontinuation of Saline Infusion Procedure
If during the conduct of the study, twosubjects meet the individual stopping criteria 
during the infusion or demonstrate a worsening of heart failure in the 48 hours after 
completion of the infusion, this challenge procedure will be removed from the study 
design.  No other subjects will undergo this assessment. 
Reporting of Adverse Outcomes Associated with the Saline Infusion
Any of the following outcomes must be reported to the sponsor as a serious adverse 
event:
Treatment with intravenous diuretic subsequent to the saline infusion

2014N221874_02
CONFIDENTIAL
201881
105
Need for continued monitoring in the unitbeyond the 4-hour mandated 
observation period 
Any worsening of heart failure that requires treatment during the 48-hour 
monitoring period after the saline infusion procedure
These events will be reported by the investigator as serious adverse events in the InForm 
electronic data collection tool.  They will be reported by the sponsor to the FDA as an 
Expedited Report via electronic submission in eCTD format to the IND, as a 7-day or 15-
day IND safety report, as applicable per timeframe specified in 21 CFR 312.32(c)(1).  
The completed report will also be provided to the IRB.

2014N221874_02
CONFIDENTIAL
201881
106
12.10.
Appendix 10: Protocol Changes
Protocol Amendment 1
Summary of Amendment Changes 
This amendment incorporates the changes requested during the FDA review of the IND.
List of Specific Changes
Section 4.2 Treatment Arms, Duration and Assessments
PREVIOUS TEXT
Pharmacokinetic profiles will be obtained during both study periods.  On Day 4 and 
Day7 of each study period, the assessments of pulmonary function will be repeated.  On 
Day 6 of each study period, subjects will receive an intravenous saline infusion, and 
DLco and DLno measurements will be performed before and after the procedure.  On 
Day 7 of each study period, the step-exercise challenge and gas transfer measurements, 
dyspnea assessment, measurement of NT-proBNP concentration, clinical laboratory tests, 
patient-reported health status (SF-36 Acute), and general safety assessments will be 
repeated.
REVISED TEXT
Pharmacokinetic profiles will be obtained during both study periods.  On Day 4 and 
Day7 of each study period, the assessments of pulmonary function will be repeated.  On 
Day 56of each study period, subjects will receive an intravenous saline infusion, and 
DLco and DLno measurements will be performed before and after the procedure.  On 
Day 7 of each study period, the step-exercise challenge and gas transfer measurements, 
dyspnea assessment, measurement of NT-proBNP concentration, clinical laboratory tests, 
patient-reported health status (SF-36 Acute), and general safety assessments will be 
repeated.
Section 4.6.1 Risk Assessment
PREVIOUS TEXT
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK2798745
Vascu
lar 
les
ions 
Dogs (4-week study):  At 30mg/kg/day, 
2 ma
les had arter
ial 
les
ions
One ma
le: Heart –Coronary 
artery 
inf
lammat
ion; Thymus –
The arter
ia
l 
les
ions noted 
in heart, 
thymus,ep
id
idym
ides, and ur
inary 
b
ladder cannot be mon
itored 
d
irect
ly.  There 
is current
ly no 

2014N221874_02
CONFIDENTIAL
201881
107
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Arter
io
le 
inf
lammat
ion w
ith 
f
ibrop
las
ia 
One ma
le:  Ep
id
idym
ides –
Artery degenerat
ion/necros
is 
w
ith 
inf
lammat
ion
Dogs (12-week study):  At 
10mg/kg/day, 1 ma
le and 1 fema
le had 
arter
ia
l 
les
ions
One ma
le: Ep
id
idym
ides –
Arter
io
le degenerat
ion/necros
is 
w
ith 
lymphocyt
ic 
inf
lammat
ion
One fema
le: B
ladder –
Arter
io
le degenerat
ion/necros
is 
w
ith 
lymphocyt
ic 
inf
lammat
ion
Rats: No vascu
lar 
les
ions observed
human trans
lat
ion b
iomarker or 
understand
ing of the under
ly
ing 
mechan
ism.
S
ince these effects cannot be 
mon
itored d
irect
ly 
in c
l
in
ica
l 
stud
ies, a coverage of ≥30 fo
ld wi
l
l 
be ma
inta
ined from the no-effect 
dose (3mg/kg/day); exposure w
i
l
l 
not exceed the average da
i
ly AUC 
of 0.448hr*ug/mL and/or Cmax of 
0.049ug/mL on an 
ind
iv
idua
l bas
is. 
Myocard
ia
l tox
ic
ity Dogs (4-week study):  At 30mg/kg/day, 
myof
iber degenerat
ion/necros
is & 
inf
lammat
ion (2 an
ima
ls)
Rats: No myocard
ia
l tox
ic
ity observed
Sub
jects w
ith h
istory of acute 
coronary syndromes(
inc
lud
ing 
unstab
le ang
ina), coronary 
ang
iop
lasty, or stent
ing w
ith
in the 
past 6 months w
i
l
l be exc
luded.
Tropon
in 
leve
ls w
i
l
l be mon
itored 
throughout the study.
A safety marg
in of ≥50 fo
ld w
i
l
l be 
ma
inta
ined from the no-effect dose 
(10mg/kg/day) observed 
in dogs.
Morta
l
ity/mor
ibund 
cond
it
ion; poor 
v
iab
i
l
ity
Dogs (4-week study):  At 30 mg/kg/day 
one ma
le term
inated ear
ly (Day 6) due 
to poor c
l
in
ica
l cond
it
ion.  Another ma
le 
had trans
ient who
le body shak
ing on 
Days 8 and 9.
Dogs (13-week study): At 10 mg/kg/day 
one ma
le was term
inated ear
ly (Day 
74) due to we
lfare reasons.
Rats (m
icronuc
leus and comet study):  
morta
l
ity occurred fo
l
low
ing 1 to 3 
doses at ≥600mg/kg/day
We
ight and adverse events 
reported by sub
jects w
i
l
l be 
mon
itored.
.

2014N221874_02
CONFIDENTIAL
201881
108
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Gastro
intest
ina
l 
and/or hepat
ic  
tox
ic
ity
GI tox
ic
ity -≥3mg/kg/day 
in dogs and 
at 30 and 300mg/kg/day 
in rats, 
cons
ist
ing of mucosa
l 
eros
ion/u
lcerat
ion 
in the stomach 
and/or duodenum.
Hepat
ic Tox
ic
ity:  B
i
l
iary ep
ithe
l
ia
l 
hypertrophy/hyperp
las
ia and per
iducta
l 
m
ixed 
inf
lammatory ce
l
l 
inf
i
ltrate 
into 
the 
l
iver was observed at 
300mg/kg/day 
in rat (7-day study) and 
foca
l hepatoce
l
lu
lar degenerat
ion 
in 1 
ma
le dog at 30mg/kg/day (4-week 
study)
Sub
jects w
ith act
ive u
lcer d
isease 
or GI b
leed
ing w
i
l
l be exc
luded.  
Sub
jects w
i
l
l be mon
itored for GI 
into
lerance and sequent
ia
l c
l
in
ica
l 
chem
istry ana
lys
is 
inc
lud
ing 
l
iver 
enzymes.  
REVISED TEXT
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK2798745
Vascu
lar 
les
ions 
Dogs (4-week study):  At 30mg/kg/day, 
2 ma
les had arter
ia
l 
les
ions
One ma
le: Heart –Coronary 
artery 
inf
lammat
ion; Thymus –
Arter
io
le 
inf
lammat
ion w
ith 
f
ibrop
las
ia 
One ma
le:  Ep
id
idym
ides –
Artery degenerat
ion/necros
is 
w
ith 
inf
lammat
ion
Dogs (12-week study):  At 
10mg/kg/day, 1 ma
le and 1 fema
le had 
arter
ia
l 
les
ions
One ma
le: Ep
id
idym
ides –
Arter
io
le degenerat
ion/necros
is 
w
ith 
lymphocyt
ic 
inf
lammat
ion
One fema
le: B
ladder –
Arter
io
le degenerat
ion/necros
is 
The arter
ia
l 
les
ions noted 
in heart, 
thymus, ep
id
idym
ides, and ur
inary 
b
ladder cannot be mon
itored 
d
irectly.  There 
is current
ly no 
human trans
lat
ion b
iomarker or 
understand
ing of the under
ly
ing 
mechan
ism.
S
ince these effects cannot be 
mon
itored d
irect
ly 
in c
l
in
ica
l 
stud
ies, a coverage of ≥30 fo
ld w
i
l
l 
be ma
inta
ined from the no-effect 
dose (3mg/kg/day); exposure w
i
l
l 
not exceed the average da
i
ly AUC 
of 0.448hr*ug/mL and/or Cmax of 
0.049ug/mL on an 
ind
iv
idua
l bas
is. 

2014N221874_02
CONFIDENTIAL
201881
109
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
w
ith 
lymphocyt
ic 
inf
lammat
ion
Rats: No vascular lesions observed
Myocard
ia
l tox
ic
ity Dogs (4-week study):  At 30mg/kg/day, 
myof
iber degenerat
ion/necros
is & 
inf
lammat
ion (2 an
ima
ls)
Rats: No myocardial toxicity 
observed
Sub
jects w
ith h
istory of acute 
coronary syndromes(
inc
lud
ing 
unstab
le ang
ina), coronary 
ang
iop
lasty, or stent
ing w
ith
in the 
past 6 months w
i
l
l be exc
luded.
Tropon
in 
leve
ls w
i
l
l be mon
itored 
throughout the study.
A safety marg
in of ≥50 fo
ld w
i
l
l be 
ma
inta
ined from the no-effect dose 
(10mg/kg/day) observed 
in dogs.
Morta
l
ity/mor
ibund 
cond
it
ion; poor 
v
iab
i
l
ity
Dogs (4-week study):  At 30 mg/kg/day 
one ma
le term
inated ear
ly (Day 6) due 
to poor c
l
in
ica
l cond
it
ion.  Another ma
le 
had trans
ient who
le body shak
ing on 
Days 8 and 9.
Dogs (13-week study): At 10 mg/kg/day 
one ma
le was term
inated ear
ly (Day 
74) due to we
lfare reasons.
Rats (m
icronuc
leus and comet study):  
morta
l
ity occurred fo
l
low
ing 1 to 3 
doses at ≥600mg/kg/day
We
ight and adverse events 
reported by sub
jects w
i
l
l be 
mon
itored.
.

2014N221874_02
CONFIDENTIAL
201881
110
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Gastro
intest
ina
l 
and/or hepat
ic  
tox
ic
ity
GI tox
ic
ity -≥3mg/kg/day 
in dogs and 
at 30 and 300mg/kg/day 
in rats, 
cons
ist
ing of mucosa
l 
eros
ion/u
lcerat
ion 
in the stomach 
and/or duodenum.
Hepat
ic Tox
ic
ity:  B
i
l
iary ep
ithe
l
ia
l 
hypertrophy/hyperp
las
ia and per
iducta
l 
m
ixed 
inf
lammatory ce
l
l 
inf
i
ltrate 
into 
the 
l
iver was observed at 
300mg/kg/day 
in rat (7-day study) and 
foca
l hepatoce
l
lu
lar degenerat
ion 
in 1 
ma
le dog at 30mg/kg/day (4-week 
study)
Sub
jects w
ith act
ive u
lcer d
isease 
or GI b
leed
ing w
i
l
l be exc
luded.  
Assessment of fecal occult 
blood will be performed prior to 
Day 1 of the first study period 
and following Day 7 of each 
study period.
Sub
jects w
i
l
l be mon
itored for GI 
into
lerance andsequent
ia
l c
l
in
ica
l 
chem
istry ana
lys
is 
inc
lud
ing 
l
iver 
enzymes.  
Genetic deletion of TRPV4 in mice has also been shown to alter bone metabolism. 
Specifically, congenital TRPV4 KO mice displayed impaired bone resorption due to 
decreased osteoclast number and activity; osteoblast and osteocyte numbers were 
not affected [Masuyama, 2008; Mizoguchi, 2008; van der Eerden, 2013].  These 
changes in osteoclast function resulted in increased bone mass and intracortical 
porosity along with reduced bone elasticity and hind-limb unloading-induced bone 
loss.  Consistent with a role for TRPV4 in modulating osteoclast function, TRPV4 
KO mice exhibited altered serum Collagen Type I C-Telopeptide (CTX) and 
urinary deoxypyridinoline (DPD), specific markers of bone resorption, while no 
changes in procollagen type 1 amino-terminal propeptide (P1NP), a specific marker 
of bone formation, were observed.  In addition, no differences in serum calcium or 
parathyroid hormone (PTH) were noted, suggesting no major changes in external 
calcium balance.  Consistent with these latter findings, rats treated for 7 days with 
the TRPV4 inhibitor GSK2193874 exhibited no changes in plasma calcium or 
urinary calcium excretion [Thorneloe, 2012].  Osteoclast function, however, has not 
been assessedin any drug-induced model.  As a result of the findings in TRPV4 KO 
mice, associations between genetic variants in the TRPV4 gene locus with fracture 
risk were assessed.  Whereas risk of osteoporotic fracture was 1.9 times higher in 
men homozygous for an intronic SNP in the TRPV4 gene (T-allele of rs1861809) in 
the Rotterdam Study population, these results were not replicated in other cohorts 
and no trends were observed for women [van der Eerden, 2013].  In spite of the low 
risk that GSK2798745 will alter bone metabolism in mature adult patients, fasted 
serum CTX will be assessed at baseline and on Day 7 of each study period.

2014N221874_02
CONFIDENTIAL
201881
111
Section 5.1 Inclusion Criteria
ADDED TEXT
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
9. Diagnosis of heart failure (New York Heart Association Class II-IV)for a 
minimum of 3 months prior to screening
10.Clinically stable with no changes in optimized guidance-directed medications and no 
hospitalizations for heart failure for at least 1 month prior to Screening
11.NT-proBNP >1000 pg/mL measured within 6 months prior to OR atScreening 
12.Average DLco measurements outside the normal range (% Predicted DLco < 80%) 
during the Screening Period 
Section 6.9.1 Monitoring in the Clinical Research Unit
ADDED TEXT
The first six subjects who participate in the study will be admitted to the Clinical 
Research Unit to be monitored for the first two days (Day 1 and Day 2) following the 
first administration of study medication in both study periods.  Subsequently, these 
subjects will remain in the unit for a minimum of 4 hours after the administration of study 
medication on eachof the remaining 5 days (Days 3 through 7) of each study period.  On 
Day 5, subjects will remain in the unit for a minimum of 4 hours after the 
completion of the saline infusion.

2014N221874_02
CONFIDENTIAL
201881
112
Section 7.1 Time and Events Table
PREVIOUS TEXT
Procedure
Screening 
Period
Treatment Periods I and II (Day)
Follow-up
Day -25  to 
Day -1 pr
ior 
to Per
iod I
-1
1
2
3
4
5
6
7
14 ± 4 days 
after 
last 
dose of 
study 
med
icat
ion
Informed consent
X
Inc
lus
ion and 
exc
lus
ion cr
iter
ia
X
Demography
X
Fu
l
l phys
ica
l 
exam
inat
ion
inc
lud
ing he
ight and 
we
ight
X
Br
ief phys
ica
l 
exam
inat
ion
inc
lud
ing we
ight
X
X
X
X
Med
ica
l 
h
istory/Med
icat
ion 
h
istory
X
Hepat
it
is B and 
Hepat
it
is C screen
X
Echocard
iogram
X
Ur
ine drug and 
a
lcoho
l breath test
X
X
C
l
in
ica
l 
laboratory 
assessments 
X
X
X
X
X
NT-proBNP 
X
X
X
Pharmacok
inet
ic 
samp
le
1
X
X
X
X
X
X
X
X
D
igox
in sample
2
X
X
X
X
X
X
X
X
X

2014N221874_02
CONFIDENTIAL
201881
113
Procedure
Screening 
Period
Treatment Periods I and II (Day)
Follow-up
Day -25  to 
Day -1 pr
ior 
to Per
iod I
-1
1
2
3
4
5
6
7
14 ± 4 days 
after 
last 
dose of 
study 
med
icat
ion
Tropon
in
X
X
X
X
X
X
DLco/DLno10
X
X
X
X
X
X
12-lead ECG/  
t
ime and frequency 
doma
ins
3
X9
X9
X
X
X
V
ita
l s
igns
X
X
X
X
X
X
X
X
X
X
We
ight
X
X
X
X
X
Genet
ic samp
le 
For sub
jects who prov
ide consent, samp
leco
l
lected after start of treatment
Study treatment4
X
X
X
X
X
X
X
AE/SAE rev
iew
X
================================================================
X
Concom
itant 
med
icat
ion rev
iew
X
================================================================
X
Pu
lmonary funct
ion 
tests 
X
X
X
X
Step exerc
ise 
test/breath-by-breath 
gas exchange 
X
X
X
Dyspneaassessment
X
X
X
SF-36 Acute
X
X
X
Po
lysomnography 
inc
lud
ing ox
imetry 
(S
leep Apnea C
l
in
ic)
5
      =========
     =========
P
lasma and 8-hour 
ur
ine 
catecho
lam
ines
6
X
X
Sa
l
ine 
infus
ion
X
Adm
iss
ion to CRU7
X
D
ischarge from CRU7
X

2014N221874_02
CONFIDENTIAL
201881
114
Procedure
Screening 
Period
Treatment Periods I and II (Day)
Follow-up
Day -25  to 
Day -1 pr
ior 
to Per
iod I
-1
1
2
3
4
5
6
7
14 ± 4 days 
after 
last 
dose of 
study 
med
icat
ion
Mea
ls8
X
X
X
X
X
X
X
X
Appet
ite Assessment 
(SNAQ)
X
X
X
X
CSSR (Su
ic
ida
l
ity 
Assessment)
X
X
X
Aud
iometry
X
X
X
BodyGuard
ian 
Mon
itor (Prevent
ice)
============================Cont
inuous========================================
1. Pharmacokinetic samples to determine GSK2798745 and any metabolite(s) concentrations will be obtained at the following times on Day 1 of each treatment 
period:  Predose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours and at the following times on Day 7 of each treatment period: Predose,0.5, 1, 1.5, 2, 3 and 5 hours.  On Day 2 
of each treatment period, samples will be collected predose and at 12 hours post dose. On days 3 through 6, PK samples will be collected predose. The time 
points may be modified based on emerging data.  Some of these timepoints may also be utilized to collect samples to determineconcentrations of other 
medications (e.g., atorvastatin and/or simvastatin).  See the SRM for detailed information.
2. Digoxin concentrations will be monitored only in those subjects who are taking digoxin
3. Time and frequency domains assessed by ECG obtained on Day -1 and Day 7
4. Subjects will remain in the CRU for a minimum of 4 hours after each administration of study medication.  [Note: The first 6 subjects enrolled will remain in the 
CRU for 52 hours after the first dose of study medication in each period]
5. Only for subjects participating in the sub-study: At Day -1 of the first study period only, subjects will undergo an overnight sleep study.  Only those subjects who 
are participating in the sub-study with sleep disordered breathing will undergo additional sleep studieson Day 6 of both study Periods I and II.
6. Only for subjects participating in the sub-study: Urinary norepinephrine (NE) and epinephrine (E) concentrations will be determined from 8-hour collections 
obtained during the overnight sleep study; urinary creatinine will also be measured to normalize the NE and E concentrations.  A blood sample to determine 
plasma concentrations of NE and E will be obtained the morning after the sleep study between the hours of 9:00 am and 10:00 am after the subject has been 
supine for 20 minutes in a quiet room.
7. The first 6 subjects enrolled will remain in the CRU for two days (Day 1 and Day 2) after the first dose of study medication in each period.
8. Three meals per day will be provided by the dietary department either in the CRU or as a boxed meal(s) to take home.
9. ECGs to be performed in triplicate
10.On the days where exercise or the saline infusion is performed, DLco/DLno will be completed just prior to and after both exercise and the saline infusion.

2014N221874_02
CONFIDENTIAL
201881
115
REVISED TEXT
Procedure
Screening 
Period
Treatment Periods I and II (Day)
Follow-up
Day -25  
to Day -1 
pr
ior to 
Per
iod I
-1 
1 
2 
3 
4 
5 
6 
7
8 
9
14 ± 4 days 
after 
last 
dose of 
study 
med
icat
ion
Informed consent
X
Inc
lus
ion and exc
lus
ion 
cr
iter
ia
X
Demography
X
Fu
l
l phys
ica
l exam
inat
ion
inc
lud
ing he
ight & we
ight
X
Br
ief phys
ica
l exam
inc
lud
ing we
ight
X
X
X
X
Med
ica
l 
h
istory/Med
icat
ion h
istory
X
Hepat
it
is B & C screen
X
Echocard
iogram
X
Ur
ine drug and a
lcoho
l 
breath test
X 
X
C
l
in
ica
l 
lab 
assessments
14
X 
X
X
X
X
NT-proBNP 
X
X
X
Serum CTX11
X
X
Fecal Occult Blood 
Test12
X
X
Pharmacok
inet
ic samp
le1
X
X
X
X
X
X
X
X
X
X
D
igox
in samp
le2
X
X
X
X
X
X
X
X
X
Tropon
in
X
X
X
X
X
X
DLco/DLno10
X
X
X
X
X
X
X
12-lead ECG/  
t
ime & frequency 
doma
ins
3
X9
X9
X
X
X

2014N221874_02
CONFIDENTIAL
201881
116
Procedure
Screening 
Period
Treatment Periods I and II (Day)
Follow-up
Day -25  
to Day -1 
pr
ior to 
Per
iod I
-1 
1 
2 
3 
4 
5 
6 
7
8 
9
14 ± 4 days 
after 
last 
dose of 
study 
med
icat
ion
V
ita
l s
igns
X 
X 
X 
X 
X 
X 
X 
X 
X
X
We
ight
X 
X 
X
X 
X
Genet
ic samp
le 
For sub
jects who prov
ide consent, samp
le co
l
lected after start of treatment
Study treatment4
X
X
X
X
X
X
X
AE/SAE rev
iew
X
==============================================================
X
Concom
itant med rev
iew
X
==============================================================
X
Pu
lmonary funct
ion tests 
X
X
X
X
Step exerc
ise test/breath-
by-breath gas exchange 
X
X
X
Dyspneaassessment
X
X
X
X
Orthopnea
X
SF-36 Acute
X
X
X
Po
lysomnography 
inc
lud
ing ox
imetry (S
leep 
Apnea C
l
in
ic)5,13
      =========
      =========
P
lasma and 8-hour ur
ine 
catecho
lam
ines
6
X
X
Sa
l
ine 
infus
ion
X
X
Adm
iss
ion to CRU7
X
D
ischarge from CRU7
X
Mea
ls8
X
X
X
X
X
X
X
X
Appet
ite Assessment 
(SNAQ)
X
X
X
X
CSSRS (Su
ic
ida
l
ity) 
X
X
X
Aud
iometry
X13
X
X
BodyGuard
ian Mon
itor 
(Prevent
ice)
============================Cont
inuous===================================

2014N221874_02
CONFIDENTIAL
201881
117
1. Pharmacokinetic samples to determine GSK2798745 and any metabolite(s) concentrations will be obtained at the following times on Day 1 of 
each treatment period:  Predose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours and at the following times on Day 7 of each treatment period: Predose, 0.5, 1, 
1.5, 2, 3, and5 and 10hours.  On Day 2 of each treatment period, samples will be collected predose and at 12 hours post dose. On Days 3 through 
6, PK samples will be collected predose.  On Days 8 and 9, samples will be collected at 24 and 48 hours, respectively, after the last dose of 
study medication administered on Day 7.The time points may be modified based on emerging data.  Some of these timepoints may also be 
utilized to collect samples to determine concentrations of other medications (e.g., atorvastatin and/or simvastatin).  See the SRM for detailed 
information.
2. Digoxin concentrations will be monitored only in those subjects who are taking digoxin
3. Time and frequency domains assessed by ECG obtained on Day -1 and Day 7
4. Subjects will remain in the CRU for a minimum of 4 hours after each administration of study medication.  [Note: The first 6 subjects enrolled will 
remain in the CRU for 52 hours after the first dose of study medication in each period]
5. Only for subjects participating in the sub-study: At Day -1 of the first study period only, subjects will undergo an overnight sleep study.  Only 
those subjects who are participating in the sub-study with sleep disordered breathing will undergo additional sleep studies on Day 6 of both study 
Periods I and II.
6. Only for subjects participating in the sub-study: Urinary norepinephrine (NE) and epinephrine (E) concentrations will be determined from 8-hour 
collections obtained during the overnight sleep study; urinary creatinine will also be measured to normalize the NE and E concentrations.  A blood 
sample to determine plasma concentrations of NE and E will be obtained the morning after the sleep study between the hours of9:00 am and 10:00 
am after the subject has been supine for 20 minutes in a quiet room.
7. The first 6 subjects enrolled will remain in the CRU for two days (Day 1 and Day 2) after the first dose of study medication in each period.
8. Three meals per day will be provided by the dietary department either in the CRU or as a boxed meal(s) to take home.
9. ECGs to be performed in triplicate
10.On the days where exercise or the saline infusion is performed, DLco/DLno will be completed just prior to and after both exercise and the saline 
infusion.
11.Blood sample for analysis of Serum CTX must be collected when the subject is fasting.  See Section 7.4.9.1
12.Fecal Occult Blood Test (FOBT) cards will be provided to subjects at the end of the screening visit and must be completed andsent back 
to the laboratory prior to the baseline visit according to the laboratory’s standard collection procedures.  Similarly, subjects will be given 
FOBT cards at the end of the Day 7 visit of each study period with completion instructions.  See Section 7.4.9.2
13.Day -1 audiometry and sleep study assessments may be completed 7 days prior to Day -1.
14.Clinical laboratory assessments will be collected as a fasting sample.

2014N221874_02
CONFIDENTIAL
201881
118
Section 7.3.3 Intravenous Saline Infusion
PREVIOUS TEXT
In patients with chronic HF, intravenously infused saline elicited a reduction of D
M [Puri, 
1999] suggesting that the abnormal pulmonary diffusion in this population may have a 
variable component that could be amenable to therapeutic intervention.  Similarly, an 
infusion of saline into the pulmonary artery significantly reduced both DLco and D
M in 
patients with chronic HF but not in control subjects [Guazzi, 1999]; the changes in DM 
were inversely related to VE/VCO2 [Guazzi, 2001].  The hemodynamic effects of 
volumeexpansionwith saline loading has been shown to be associated with increases in 
left and right heart filling pressures and pulmonary artery pressures in patients with HF 
[Andersen, 2015].  This intervention has not been associated with any significant clinical 
safety signal in stable HF patients. 
All subjects will undergo an intravenous 0.9% NaCl infusion on Day 6 of both study 
periods in the presence of a cardiologist and only if determined by the Investigator that 
subject is without any signs of obvious congestion.  Subjects will be carefully monitored 
both during and after the infusion and will be provided intravenous diuretics if necessary. 
Details of this procedure are described in the SRM.  DLco and DLno measurements will 
be obtained prior to the initiation of the infusion and after the completion of the infusion.
REVISED TEXT
In patients with chronic HF, intravenously infused saline elicited a reduction of D
M [Puri, 
1999] suggesting that the abnormal pulmonary diffusion in this population may have a 
variable component that could be amenable to therapeutic intervention.  Similarly, an 
infusion of saline into the pulmonary artery significantly reduced both DLco and D
M in 
patients with chronic HF but not in control subjects [Guazzi, 1999]; the changes in DM 
were inversely related to VE/VCO2 [Guazzi, 2001].  The hemodynamic effects of 
volumeexpansionwith saline loading has been shown to be associated with increases in 
left and right heart filling pressures and pulmonary artery pressures in patients with HF 
[Andersen, 2015].  In this latter study, no patient developed dyspnea or any evidence 
of pulmonary congestion despite increase in cardiacfilling pressures. This 
intervention has not been associated with any significant clinical safety signal in 
stable HF patients. 
All subjects will undergo an intravenous 0.9% NaCl infusion on Day 5 6of both study 
periods in the presence of a cardiologist specializing in heart failure. andThe 
procedure will be conductedonly if determined by the Investigatorthe subject is 
without any signs of obvious congestion as determined by the Investigator. Subjects 
will be carefully monitored both during and after the infusion and will be provided 
intravenous diuretics if necessary. Details of this procedure are described in Appendix 9
the SRM.
DLco and DLno measurements will be obtained prior to the initiation of the infusion and 
after the completion of the infusion.

2014N221874_02
CONFIDENTIAL
201881
119
Section 7.4.9 Clinical Laboratory Assessments
PREVIOUS TEXT
All protocol required laboratory assessments, as defined in Table 3, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisitionforms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the SRM.Reference ranges for all safety parameters will be provided to the 
site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 3. 
Table3
Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
P
late
let Count
RBC Ind
ices: WBC count w
ith D
ifferent
ia
l:
RBC Count
MCV
Neutroph
i
ls
Hemog
lob
in
MCH
Lymphocytes
Hematocr
it
MCHC
Monocytes
WBC Count (abso
lute)
Eos
inoph
i
ls
Ret
icu
locyte count
Basoph
i
ls
Clinical 
Chemistry 
BUN
Potass
ium AST (SGOT)
Tota
l and d
irect 
b
i
l
irub
in
Creatin
ine
Sod
ium
ALT (SGPT)
Tota
l Prote
in
G
lucose, 
fast
ing
Ca
lc
ium
A
lka
l
ine phosphat
ise
A
lbum
in
CPK
Ur
ic Ac
id
GGT
Tropon
in
Ch
lor
ide
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Urinary norepinephrine and epinephrine (during sleep study)
Other 
Screening 
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody)
Digoxin concentrations (only in subjects treated with Digoxin)

2014N221874_02
CONFIDENTIAL
201881
120
Laboratory 
Assessments
Parameters
Tests
Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)
HMG CoA Reductase Inhibitor concentration (only in subjects 
taking medication)
Biomarker(s)/ 
Other 
Assessments
N-terminal pro-B-type Natriuretic Peptide (NT-proBNP)
Norepinephrine and Epinephrine
NOTES :
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 5.5.1 and 
Appendix 2
REVISED TEXT
All protocol required laboratory assessments, as defined in Table 3, must be conducted in 
accordance with the Laboratory Manual (if applicable),and Protocol Time and Events 
Schedule.All laboratory assessments will be collected as fasting samples.  Laboratory 
requisition forms must be completed and samples must be clearly labelled with the 
subject number, protocol number, site/centre number, and visit date.Details for the 
preparation and shipment of samples (if applicable)will be provided by the laboratory 
and are detailed in the SRM. Reference ranges for all safety parameters will be provided 
to the study staffsiteby the locallaboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling ofsamples to avoid duplicate 
and/or additional blood draws.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 3. 

2014N221874_02
CONFIDENTIAL
201881
121
Table3
Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
P
late
let Count
RBC Ind
ices: WBC count w
ith D
ifferent
ia
l:
RBC Count
MCV
Neutroph
i
ls
Hemog
lob
in
MCH
Lymphocytes
Hematocr
it
MCHC
Monocytes
WBC Count (abso
lute)
Eos
inoph
i
ls
Ret
icu
locyte count
Basoph
i
ls
Clinical 
Chemistry 
BUN
Potass
ium AST (SGOT)
Total and d
irect 
b
i
l
irub
in
Creat
in
ine
Sod
ium
ALT (SGPT)
Tota
l Prote
in
G
lucose, 
fast
ing
Ca
lc
ium
A
lka
l
ine phosphat
ise
A
lbum
in
CPK
Ur
ic Ac
id
GGT
Tropon
in
Ch
lor
ide
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Urinary norepinephrine and epinephrine (during sleep study)
Other 
Screening 
Tests
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody)
Digoxin concentrations (only in subjects treated with Digoxin)
Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)
HMG CoA Reductase Inhibitor concentration (only in subjects 
taking medication)
Biomarker(s)/ 
Other 
Assessments
N-terminal pro-B-typeNatriuretic Peptide (NT-proBNP)
Norepinephrine and Epinephrine
Serum Collagen Type I C-Telopeptide (CTX), fasting
Fecal Occult Blood Test (FOBT)
NOTES :
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 5.5.1 and 
Appendix 2

2014N221874_02
CONFIDENTIAL
201881
122
ADDED SECTIONS
Section 7.4.9.1 Serum Collagen Type I Telopeptide (CTX)
Blood samples will be collected at the Baseline Visit (Day -1) and on Day 7 of each 
study period.  Approximately 1 mL will be collected as a fasting sample from the 
subject at the start of each of these visits.
Section 7.4.9.2 Fecal Occult Blood Test (FOBT)
Based on the gastric erosions found in a preclinical model (dogs at ≥3 mg/kg), FOBT 
will be performed to assess any possible drug-related GI blood loss.  Due to 
concomitant anti-platelet therapy that many patients with heart failure receive, 
along with the common incidence of intestinal mucosal edema and associated 
diarrhea,findings of fecal blood would not beunexpected in this population.  
Subjects will be tested for the presence of fecal occult blood prior to the start of 
study period I (between Screening and Baseline) and after each of the two study 
periods.  
Once subjects have signed the consent form and have been enrolled into the study 
based on meeting the eligibility criteria, they will be provided 3 FOBT cards at the 
end of the screening visit.  Study staff will provide the subjects with instructions for 
completing the tests and subsequent shipment of the tests back to the laboratory.  
This assessment will be completed between Screening and Baseline (Day -1).  
Additionally, subjects will be provided 3 FOBT cards on Day 7 of each study period 
with the same instructions for completion and shipment for laboratory analysis.
Section 7.5.2 Sample Analysis
PREVIOUS TEXT
Once the plasma has been analyzed for GSK2798745 any remaining plasma may be 
analyzed for other compound-related metabolites and the results reported under a 
separate PTS-DMPK GlaxoSmithKline protocol.
REVISED TEXT
Plasma samples may be analyzed for metabolite M1 dependent upon the availability 
of an assay.  Until this time, GSK will store the remaining plasma from the PK 
plasma samples for future possible metabolite analysis.  Once the plasma has been 
analyzed for GSK2798745 any remaining plasma may be analyzed for other 
compound-related metabolites and the results reported under a separate PTS-
DMPK GlaxoSmithKline protocol.

2014N221874_02
CONFIDENTIAL
201881
123
Section 11 References
ADDED TEXT
Fujimoto N, Borlaug BA, Gregory D. Lewis GD, Hastings JL, Shafer KM, Bhella 
PS, Carrick-Ranson G, Levine BD.  Hemodynamic responses to rapid saline 
loading: the impact of age, sex, and heart failure. Circulation. 2013;127(1):55-62.
Masuyama R, Vriens J, Voets T, Karashima Y, Owsianik G, Vennekens R, et al. 
TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts. 
Cell Metab. 2008;8:257-65.
Mizoguchi F, Mizuno A, Hayata T, Nakashima K, Heller S, Ushida T, et al. 
Transient receptor potential vanilloid 4 deficiency suppressesunloading-induced 
bone loss. J Cell Physiol. 2008;216:47-53.
Robbins IM, Hemnes AR, ME, Brittain EL, Zhao DX, Piana RN, Fong PP, Newman 
JH. High prevalence of occult pulmonary venous hypertension revealed by fluid 
challenge in pulmonary hypertension. CircHeart Fail. 2014;7(1):116-22.
Synder EM, Beck KC, Hulsebus ML, Breen JF, Hoffman EA, Johnson BJ. Short-
term hypoxic exposure at rest and during exercise reduces lung water in healthy 
humans. J Appl Physiol. 2006; 101: 1623–1632.
van der Eerden BC, Oei L, Roschger P, Fratzl-Zelman N, Hoenderop JG, van 
Schoor NM, et al. TRPV4 deficiency causes sexual dimorphism in bone metabolism 
and osteoporotic fracture risk. Bone. 2013;57:443-54.
ADDED APPENDIX
APPENDIX 9: Intravenous Saline Infusion
Rapid intravenous saline infusion has been employed to elicit fluid extravasation 
from the vasculature to the pulmonary interstitium.  This methodology has been 
previously utilized in studies with healthy volunteers [Snyder, 2006] and patients 
with heart failure [Fujimoto, 2013; Robbins, 2014; Andersen, 2015].
Subject Evaluation Prior to Infusion
On Day 5 of both study periods, the subject will be admitted to the clinical research 
unit (CRU) and undergo routine weight measurement and vital sign assessments 
including temperature, systolic and diastolic blood pressures, heart rate, respiratory 
rate, and pulse oximetry to assess O
2saturation.  The subject will also undergo a 
pulmonary examination.  
While in a sitting position, a dyspnea assessment, utilizing a standardized 5-point 
Likert scale, will be obtained to document the subject’s current status.  A subject, 
who is not severely or very severely short of breath, will undergo an orthopnea test 
(placed supine with head ≤ 20 degrees relative to horizontal).  After an equilibration 

2014N221874_02
CONFIDENTIAL
201881
124
period of 2 minutes, the 5-point scale will be repeated.  A subject who reports a 
worse dyspnea score when supine compared to sitting will be categorized as having 
orthopnea.  Subjects categorized with having orthopnea will not be eligible to 
participate in the saline infusion. 
Study treatment will be administered after all planned pre-dose assessments for Day 
5 are completed.  
Saline Infusion Procedure
A subject, who is judged by the Investigator to be in a stable condition and without 
obvious congestion, will then undergo the intravenous saline infusion procedure.  
This procedure will be conducted in the clinical research unit, which is adjacent to 
the catheterization laboratory, in the presence of a cardiologist and monitoring 
personnel.  A crash cart will be accessible, and intravenous diuretic will be 
available, if necessary.  
An 18-gauge venous catheter will be inserted into a prominent antecubital vein 
while the subject is semi-recumbent (approximately 45°).  The subject will remain in 
a semi-recumbent position throughout the procedure.
DLco and DLno measurements and simple spirometry assessments will be obtained 
prior to the initiation of the infusion.
Prewarmed 0.9% normal saline will be infused intravenously at a rate of 150 
mL/min to a total volume of 500 mL.  During the saline infusion, blood pressure, 
heart rate, respiratory rate, and O2saturation, will be continuously monitored, and 
any physical symptoms recorded.  
DLco and DLno measurements and spirometry assessments will be obtained after 
the completion of the infusion.
Post-infusion Monitoring
Following the completion of the saline infusion procedure, the subject will remain in 
the clinical research unit for the next 4 hours.  Blood pressure, heart rate, 
respiratory rate, and O
2saturation, will be continuously monitored, and any 
physical symptoms recorded.  The subject will also be assessed for dyspnea and 
orthopnea, as described above, at hourly intervals.
After the 4-hour period, the subject will be eligible to leave the CRU if heart rate 
and respiratory rate are within 20% of the baseline value, O2saturation is within 
2% of the baseline value, and if the dyspnea score is the same as the baseline score.  
The subject will continue to be monitored by the Preventice BodyGuardian Remote 
Monitoring System as described in Section 7.4.7 of the protocol; ECG, heart rate, 
respiratory rate and activity level will be measured continuously.  

2014N221874_02
CONFIDENTIAL
201881
125
Any worsening of heart failure that requires treatment in the 48 hours subsequent 
to the saline infusion will be reported as a serious adverse event.
Individual Stopping Criteria During the Saline Infusion Procedure
If the subject demonstrates oneof the following changes during the saline infusion, 
the infusion should be discontinued:
Decrease in O2 saturation of >4% compared to baseline 
Increase in respiratory rate of >20% compared to baseline
Any increase in dyspnea perceived by the patient 
If the subject has met one of these criteria during or immediately after the infusion, 
the subject should be carefully monitored and given intravenous diuretic treatment, 
intravenous or sublingual nitrates, or other treatment as required.  
The subject may continue in the study.  However, if this response occurred in the 
first study period, the subject should not undergo a second saline infusion in the 
subsequent study period.
Discontinuation of Saline Infusion Procedure
If during the conduct of the study, twosubjects meet the individual stopping criteria 
during the infusion or demonstrate a worsening of heart failure in the 48 hours after 
completion of the infusion, this challenge procedure will be removed from the study 
design.  No other subjects will undergo this assessment. 
Reporting of Adverse Outcomes Associated with the Saline Infusion
Any of the following outcomes must be reported to the sponsor as a serious adverse 
event:
Treatment with intravenous diuretic subsequent to the saline infusion
Need for continued monitoring in the CRU beyond the 4-hour mandated 
observation period 
Any worsening of heart failure thatrequires treatment during the 48-hour 
monitoring period after the saline infusion procedure
These events will be reported by the investigator as serious adverse events in the 
InForm electronic data collection tool.  They will be reported by the sponsor tothe 
FDA as an Expedited Report via electronic submission in eCTD format to the IND, 
as a 7-day or 15-day IND safety report, as applicable per timeframe specified in 21 
CFR 312.32(c)(1).  The completed report will also be provided to the IRB. 

2014N221874_02
CONFIDENTIAL
201881
126
Protocol Amendment 2
Summary of Amendment Changes 
This amendment incorporates minor changes to eligibility (NT proBNP, BMI).
List of Specific Changes
Title
ADDED TEXT
A Randomized, Double-blind, Sponsor un-blinded, Placebo-controlled, Phase 2a 
Crossover Study to Evaluate the Effect of the TRPV4 Channel Blocker, GSK2798745, on 
Pulmonary Gas Transfer and Respiration in Patients with Congestive Heart Failure
Section 1
PREVIOUS TEXT
Overall Design
This is a randomized, double-blind, sponsor-unblinded, placebo-controlled, 2 by 2 
crossover study in adults with heart failure.  The study will be conducted at a single 
center.
Within 14 days (up to 25 days) of the start of PeriodI, subjects will begin a screening 
evaluation to determine eligibility for entry into the study.  Eligible subjects will be 
randomized to one of two treatment sequences.  Subjects will receive either GSK2798745 
or placebo once daily for a period of 7 days.  After at least a 14-day washout period 

2014N221874_02
CONFIDENTIAL
201881
127
(preferably not greater than 30 days from last dose in Period I), subjectswill participate 
in a second, identical 7-day study period and receive the alternate study medication.
REVISED TEXT
Overall Design
This is a randomized, double-blind, sponsor-unblinded, placebo-controlled, 2 by 2 
crossover studyin adults with heart failure.  The study will be conducted at a single 
center.
Within Approximately14 days (up to 25 days) ofbeforethe start of PeriodI, subjects 
will begin a screening evaluation to determine eligibility for entry into the study.  Eligible 
subjects will be randomized to one of two treatment sequences.  Subjects will receive 
either GSK2798745 2.4 mgor placebo once daily for a period of 7 days.  After at least a 
14-day washout period (preferably not greater than 30 days from last dose in Period I), 
subjectswill participate in a second, identical 7-day studytreatmentperiod and receive 
the alternate study medication.
Section 4
PREVIOUS TEXT
4.1
Overall Design
This is a randomized, double-blind, sponsor-unblinded, placebo-controlled, 2 by 2 
crossover study in adults with heart failure (Figure 1).  The study will be conducted at a 
single center.

2014N221874_02
CONFIDENTIAL
201881
128
REVISED TEXT
4.1
Overall Design
This is a randomized, double-blind, sponsor-unblinded, placebo-controlled, 2 by 2 
crossover study in adults with heart failure (Figure 1).  The study will be conducted at a 
single center.
PREVIOUS TEXT
4.2
Treatment Arms, Duration and Assessments
Within 14 days (up to 25 days) of the start of PeriodI, subjects will begin a screening 
evaluation to determine eligibility for entry into the study.  Eligible subjects will be 
randomized to one of two treatment sequences.  Subjects will receive either GSK2798745 
or placebo once daily for a period of 7 days.  After at least a 14-day washout period 
(preferably not greater than 30 days from last dose in Period I), subjectswill participate 
in a second, identical 7-day study period and receive the alternate study medication.  
During both study periods, the first 6 subjects will remain in the clinical research unit 
(CRU) overnight for the first 2 days (Days 1 and 2) to allow for continuous safety 
monitoring.  Subsequently, subjects will remain in the research unit for a minimum of 4 
hours after the administration of study medication (Days 3 through 7).  Subjects will be 
equipped with the Preventice BodyGuardian for continuous remote monitoring of ECG, 
heart rate, and respiration rate (Day -1 to Day 7).
After the first 6 subjects have completed the two-day, in-house safety monitoring during 
Periods I and II, subsequent subjects enrolled into the study will remain in the research 
unit for a minimum of 4 hours after the administration of study medication on all study 
days (Days 1 through 7).  
Prior to the start of each study period, all subjects will undergo an assessment of 
pulmonary function testing (PFTs), gas transfer measurements including DLco, DLno 
and Vc, breath-by-breath measurements of minute ventilation, O2consumption and VCO
2
production during a metered 3-minute step exercise to establish ventilatory efficiency 
(V
E/VCO
2), and a dyspnea assessment.  Additionally, a measurement of N-terminal pro-
B-type Natriuretic Peptide (NT-proBNP) concentration, clinical laboratory tests, patient-
reported health status (SF-36 Acute), and general safety assessments will be obtained.  
Only for subjects willing to participate in the sleep apnea sub-study, they will undergo a 
sleep study to ascertain whether sleep-disordered breathing patterns are apparent prior to 
the firststudy period (Period I).  Subjects with sleep-disordered breathing, defined as an 
apnea-hypopnea index (AHI) >5 based on polysomnography, will undergo a repeat sleep 
study after 6days of treatment in each of the two study periods.  
Pharmacokinetic profiles will be obtained during both study periods.  On Day 4 and 
Day7 of each study period, the assessments of pulmonary function will be repeated.  On 
Day 5 of each study period, subjects will receive an intravenous saline infusion, and 
DLco and DLno measurements will be performed before and after the procedure.  On 

2014N221874_02
CONFIDENTIAL
201881
129
Day 7 of each study period, the step-exercise challenge and gas transfer measurements, 
dyspnea assessment, measurement of NT-proBNP concentration, clinical laboratory tests, 
patient-reported health status (SF-36 Acute), and general safety assessments will be 
repeated.  
All subjects will return for a Follow-up Visit approximately 2 weeks after completion of 
the second study period; pulmonary and safety assessments will be repeated at this visit.
The duration of participation in this study is expected to be approximately 8 weeks from 
Screening to the Follow-up Visit.
REVISED TEXT
4.2
Treatment Arms, Duration and Assessments
Within Approximately14 days (up to 25 days) ofbefore the start of PeriodI, subjects 
will begin a screening evaluation to determine eligibility for entry into the study.  Eligible 
subjects will be randomized to one of two treatment sequences.  Subjects will receive 
either GSK2798745 2.4 mgor placebo once daily for a period of 7 days.  After at least a 
14-day washout period (preferably not greater than 30 days from last dose in Period I), 
subjectswill participate in a second, identical 7-day study period and receive the alternate 
study medication.  
During both study periods, the first 6 subjects will remain in the clinical researchunit 
(i.e. clinical research unit,CRU) overnight for the first 2 days (Days 1 and 2) to allow 
for continuous safety monitoring.  Subsequently, these initialsubjects will remain in the 
researchunit for a minimum of 4 hours after the administration of study medication 
(Days 3 through 7).  All Ssubjects will be equipped with the Preventice BodyGuardian 
for continuous remote monitoring of ECG, heart rate, and respiration rate (Day -1 to Day 
7).  Subjects may remain in the unit for the duration of each of the 7day treatment 
periods for convenience.
After the first 6randomizedsubjects have completed the two-day, in-house safety 
monitoring during Periods I and II, subsequent subjects enrolled into the study will 
remain in the researchunit for a minimum of 4 hours after the administration of study 
medication on all study days (Days 1 through 7).  However, subjects may remain in the 
unit for the duration of each of the 7 day treatment periods as determined on a case 
by case basis with the Investigator(s).This is not arequirement for successful 
completion of the study, but is mainly for purposes of subject convenience only.
Prior to the start of each study period, all subjects will undergo an assessment of 
pulmonary function testing (PFTs), gas transfer measurements including DLco, DLno 
and Vc, breath-by-breath measurements of minute ventilation, O2consumption and VCO
2
production during a metered 3-minute step exercise to establish ventilatory efficiency 
(V
E/VCO
2), and a dyspnea assessment.  Additionally, a measurementof N-terminal pro-
B-type Natriuretic Peptide (NT-proBNP) concentration, clinical laboratory tests, patient-
reported health status (SF-36 Acute), and general safety assessments will be obtained.  
Only for subjects willing to participate in the sleep apneasub-study, they will undergo a 
sleep study to ascertain whether sleep-disordered breathing patterns are apparent prior to 

2014N221874_02
CONFIDENTIAL
201881
130
the firststudy period (Period I).  Subjects with sleep-disordered breathing, defined as an 
apnea-hypopnea index (AHI) >5 based on polysomnography, will undergo a repeat sleep 
study after 6days of treatment in each of the two study periods.  
Pharmacokinetic profiles will be obtained during both study periods.  On Day 4 and 
Day7 of each study period, the assessments of pulmonary function will be repeated.  On 
Day 5 of each study period, subjects will receive an intravenous saline infusion, and 
DLco and DLno measurements will be performed before and after the procedure.  On 
Day 5 of each study period, subjects will remain in the unit for a minimum of 4 
hours after completion of the intravenous saline infusion.  On Day 7 of each study 
period, the step-exercise challenge and gas transfer measurements, dyspnea assessment, 
measurement of NT-proBNP concentration, clinical laboratory tests, patient-reported 
health status (SF-36 Acute), and general safety assessments will be repeated.  
All subjects will return for a Follow-up Visit approximately 2 weeks after completion of 
the second study period; pulmonary and safety assessments will be repeated at this visit.
The duration of participation in this study is expected to be approximately 8 weeks from 
Screening to the Follow-up Visit.
PREVIOUS TEXT
4.3
Type and Number of Subjects
A sufficient number of subjects with heart failure will be enrolledso that 12 subjects 
complete the two study periods and critical assessments.  If subjects prematurely 
discontinue the study, additional replacement subjects may be randomised and assigned 
to the same treatment sequence at the discretion of the Sponsor in consultation with the 
Investigator.
After the first 12 subjects complete both study periods, an interim analysis will be 
performed to assess the intra-subject variability:  (a) if the actual variability is less than or 
equal to the assumed value, the study will be completed with 12 subjects; or (b) if the 
actual variability is greater than the assumed value, additional subjects may need to be 
enrolled.
If an insufficient number of subjects participate in the sleep sub-study, additional 
subjects, who meet the criterion for the sleep apnea sub-study, may be enrolled to 
undergo the polysomnography investigation at the discretion of the Sponsor and in 
consultation with the Investigator.  
In addition, another (separate) cohort of subjects may be enrolled to allow for the 
evaluation of an additional dose level at the discretion of the Sponsor in consultation with 
the Investigator.  

2014N221874_02
CONFIDENTIAL
201881
131
REVISED TEXT
4.3
Type and Number of Subjects
A sufficient number of subjects with heart failure will be enrolled so that 12 subjects 
complete the two study periods and critical assessments.  If subjects prematurely 
discontinue the study, additional replacement subjects may be randomised and assigned 
to the same treatment sequence at the discretion of the Sponsor in consultation with the 
Investigators.
After the first 12 subjects complete both study periods, an interim analysis will be 
performed to assess the intra-subject variability:  (a) if the actual variability is less than or 
equal to the assumed value, the study will be completed with 12 subjects; or (b) if the 
actual variability is greater than the assumed value, additional subjects may need to be 
enrolled.
If an insufficient number of subjects participate in the sleep sub-study, additional 
subjects,who meet the criterion for the sleep apnea sub-study,may be enrolled to 
undergo the polysomnography investigation at the discretion of the Sponsor and in 
consultation with the Investigators.  
In addition, another (separate) cohort of subjects may be enrolled to allow for the 
evaluation of an additional dose level at the discretion of the Sponsor in consultation with 
the Investigators.  
PREVIOUS TEXT
4.4 
Design Justification
The crossover design has been selected to provide greater statistical power with a smaller 
number of subjects.  Each subject serves as his or her own matched control avoiding 
issues of comparability of groups with regard to confounding variables such as age, sex, 
and disease severity.  The use of a placebo control allows a more rigorous assessment of 
the effects of the drug treatment on physiologic measures and symptom assessments.  
Subjects selected for this study have chronic heart failure and are stable on standard 
treatment to ensure that their disease status does not change significantly during the 
course of the study.  Additionally, the limited 7-day treatment period is not expected to 
alter the disease status of the subjects.  The 14-day washout period alleviates the 
possibility of carryover effects from one period to the other.  Given the short duration of 
the study, it is expected that subjects will complete the study in order to have data in each 
period of the crossover for all subjects.
REVISED TEXT
4.4 
Design Justification
The crossover design has been selected to provide greater statistical power with a smaller 
number of subjects.  Each subject serves as his or her own matched control avoiding 
issues of comparability of groups with regard to confounding variables such as age, sex, 

2014N221874_02
CONFIDENTIAL
201881
132
and disease severity.  The use of a placebo control allows fora more rigorous assessment 
of the effects of the drug treatment on physiologic measures and symptom assessments.  
Subjects selected for this study have chronic heart failure and are stable on standard 
treatment to ensure that their disease status does not change significantly during the 
course of the study.  Additionally, the limited 7-day treatment period is not expected to 
alter the disease status of the subjects.  The 14-day washout period alleviates the 
possibility of carryover effects from one period to the other.  Given the short duration of 
the study, it is expected that subjects will complete the study in order to have data in each 
period of the crossover for all subjects.
Section 5
PREVIOUS TEXT
5.1
Inclusion Criteria
A subject will be eligible for inclusion in this study only if allof the following criteria 
apply: 
AGE
13.≥ 21 years of age at the time of signing the informed consent form
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
14.Diagnosis of heart failure (New York Heart Association ClassII-IV) for a minimum 
of 3 months prior to screening
15.Clinically stable with no changes in optimized guidance-directed medications and no 
hospitalizations for heart failure for at least 1 month prior to Screening
16.NT-proBNP >1000 pg/mL measured within 6 months prior to OR at Screening 
17.Average DLco measurements outside the normal range (% Predicted DLco < 80%) 
during the Screening Period 
WEIGHT
18.Body mass index (BMI) ≥18 and ≤40 kg/m2

2014N221874_02
CONFIDENTIAL
201881
133
SEX
19.Male or female of non-childbearing potential
Male patients with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until at least five half-lives of study medication OR for a cycle of spermatogenesis 
following five terminal half-lives after the last dose of study medication.
h.Vasectomy with documentation of azoospermia.  
i.Male condom plus partner use of one of the contraceptive options below:

Contraceptive subdermal implant that meets the standard operating 
procedure (SOP) effectiveness criteria including a <1% rate of failure per 
year, as stated in the product label

Intrauterine device or intrauterine system thatmeets the SOP effectiveness 
criteria including a <1% rate of failure per year, as stated in the product 
label [Hatcher, 2007a]

Oral contraceptive, either combined or progestogen alone [Hatcher, 2007a]

Injectable progestogen [Hatcher, 2007a]

Contraceptive vaginal ring [Hatcher, 2007a]

Percutaneous contraceptive patches [Hatcher, 2007a]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
A female subject is eligible to participate if at least one of the following conditions 
applies:
c. Non-reproductive potential defined as:
Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 

Hysterectomy

Documented bilateral oophorectomy
d. Postmenopausal defined as 12 months of spontaneous amenorrhea.  Females 
on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the highly effective contraception 
methods if they wish to continue their HRT during the study.  Otherwise, 
they must discontinue HRT toallow confirmation of post-menopausal status 
prior to study enrolment.

2014N221874_02
CONFIDENTIAL
201881
134
INFORMED CONSENT
20. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the consent form and in this protocol
5.2
Exclusion Criteria
A subject will not be eligible for inclusion in this study if anyof the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
23.History of acute coronary syndromes including unstable angina or myocardial 
infarction within 6 months of screening
24.Coronary revascularization including angioplasty and stenting within 6 months of 
Screening 
25.History of stroke or seizure disorder within 5 years of Screening
26.Diagnosis of asthma
27.Diagnosis of chronicobstructive pulmonary disease (COPD) with FEV
1<50% of 
predicted measured within 4 weeks of Screening 
28.History of a condition that required radiation therapy to the thorax
29.History of any type of malignancy within the past five years with the exception of 
successfully treated basal cell cancer of the skin
30.Active ulcer disease or gastrointestinal bleeding
31.Current or chronic history of liver disease, known hepatic impairment, or biliary 
abnormalities (with the exception of Gilbert
's syndrome or asymptomatic gallstones)
32.Alanine transaminase (ALT) >2x Upper Limit of Normal (ULN) and bilirubin 
>1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and 
direct bilirubin <35%)
33.QTc > 450 msec or QTc > 480 msec in subjects with Bundle Branch Block
The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method, 
machine-read or manually over-read.

The sameQT correction formula mustbe used for each individual subject
throughout the study.  This formula may not be changed or substituted once 
the subject has been enrolled.

For purposes of data analysis, QTcB, QTcF, another QT correction 
formula, or a composite of available values of QTc will be used as specified 
in the Reporting and Analysis Plan (RAP).
34.History or current evidence of any serious or clinically significant gastrointestinal, 
renal, endocrine, neurologic, hematologic or other condition that is uncontrolled on 

2014N221874_02
CONFIDENTIAL
201881
135
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
permitted therapies or that would, in the opinion of the investigator or the 
GlaxoSmithKline (GSK) medical monitor, make the subject unsuitable for inclusion 
in this study
CONCOMITANT MEDICATIONS
35. Use of medications specified for the treatment of COPD including short-and long-
acting bronchodilators (β-agonists and anticholinergics) and inhaled glucocorticoids 
as well as oxygen therapy
36.Use of a listed prohibited medication (Section6.10.2) within the restricted timeframe 
relative to the first dose of study medication
37.Use of a strong inhibitors or inducers of cytochrome P450 (CYP) 3A or p-
glycoprotein (see Section 6.10.2)
RELEVANT HABITS
38.Current smoker
39.History of drug/substance abuse within the past 2 years
40.History of alcoholabuse within 6 months of the study.  Defined as an average 
weekly alcohol consumption of >14 drinks for men or >7 drinks for women.  One 
drink is equivalent to 12 g of alcohol: approximately 12 ounces (360 mL) of beer, 5 
ounces (150 mL) of wine, or 1.5 ounces of (45 mL) 80 proof distilled spirits
CONTRAINDICATIONS 
41.History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
42.Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months of screening.  For potent immunosuppressive 
agents, subjects with presence of hepatitis B core antibody (HBcAb) should also be 
excluded
43.A positive pre-study drug/alcohol screen
44.Use of another investigational product in a clinical study within the following time 
period prior to the first administration of study medication in the current study: 30 
days, 5half-lives or twice the duration of the biological effect of the investigational 
product (whichever is longer)
45.Exposure to more than 4 investigational medicinal products within 12 months prior to 
the first administration of study medication

2014N221874_02
CONFIDENTIAL
201881
136
REVISED TEXT
5.1
Inclusion Criteria
A subject will be eligible for inclusion in this study only if allof the following criteria 
apply: 
AGE
1. ≥ 21 years of age at the time of signing the informed consent form
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Diagnosis of heart failure (New York Heart Association Class II-IV) for a 
minimum of 3 months prior to screening
3. Clinically stable with no changes in optimized guidance-directed medications and 
no hospitalizations for heart failure for at least 1 month prior to Screening
4. NT-proBNP >1000400pg/mL measured within 6 months prior to OR at 
Screening 
5. Average DLco measurements outside the normal range (% Predicted DLco < 
80%) during the Screening Period 
WEIGHT
6. Body mass index (BMI) ≥18 and ≤40  45kg/m2
SEX
7. Male or female of non-childbearing potential
Male patients with female partners of child bearing potential must comply with 
the following contraception requirements from the time of first dose of study 
medication until at least five half-lives of study medication OR for a cycle of 
spermatogenesis following five terminal half-lives after the last dose of study 
medication.
a. Vasectomy with documentation of azoospermia.  
b. Male condom plus partner use of one ofthe contraceptive options below:
Contraceptive subdermal implant that meets the standard operating 
procedure (SOP) effectiveness criteria including a <1% rate of failure per 
year, as stated in the product label
Intrauterine device or intrauterine system that meets the SOP effectiveness 
criteria including a <1% rate of failure per year, as stated in the product 
label [Hatcher, 2007a]
Oral contraceptive, either combined or progestogen alone [Hatcher, 

2014N221874_02
CONFIDENTIAL
201881
137
SEX
2007a]
Injectable progestogen [Hatcher, 2007a]
Contraceptive vaginal ring [Hatcher, 2007a]
Percutaneous contraceptive patches [Hatcher, 2007a]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
A female subject is eligible to participate if at least one of the following 
conditions applies:
a. Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-
up confirmation of bilateral tubal occlusion 
Hysterectomy
Documented bilateral oophorectomy
b. Postmenopausal defined as 12 months of spontaneous amenorrhea.  Females on 
hormone replacement therapy (HRT) and whose menopausal status is in doubt 
will be required to use one of the highly effective contraception methods if they 
wish to continue their HRT during the study.  Otherwise, they must discontinue 
HRTto allow confirmation of post-menopausal status prior to study enrolment.
INFORMED CONSENT
8. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the consent form and in this protocol
5.2
Exclusion Criteria
A subject will not be eligible for inclusion in this study if anyof the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. History of acute coronary syndromes including unstable angina or myocardial 
infarction within 6 months of screening
2. Coronary revascularization including angioplasty and stenting within 6 months of 
Screening 

2014N221874_02
CONFIDENTIAL
201881
138
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
3. History of stroke or seizure disorder within 5 years of Screening
4. Diagnosis of asthma
5. Diagnosis of chronic obstructive pulmonary disease (COPD) with FEV
1<50% of 
predicted measured within 4 weeks of Screening 
6. History of a condition that required radiation therapy to the thorax
7.
History of any type of malignancy within the past five years with the exception 
of successfully treated basal cell cancer of the skin
8. Active ulcer disease or gastrointestinal bleedingat the time of screening
9.
Current or chronic history of liver disease, known hepatic impairment, or biliary 
abnormalities (with the exception of Gilbert
's syndrome or asymptomatic 
gallstones)
10. Alanine transaminase (ALT) >2x Upper Limit of Normal (ULN) and bilirubin 
>1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated 
and direct bilirubin <35%)
11.QTc > 450 msec or QTc > 480 msec in subjects with Bundle Branch Block

The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method, 
machine-read or manually over-read.

The sameQT correction formula mustbe used for each individual subject
throughout the study.  This formula may not be changed or substituted once 
the subject has been enrolled.
For purposes of data analysis, QTcB, QTcF, another QT correction 
formula, or a composite of available values of QTc will be used as specified 
in the Reporting and Analysis Plan (RAP).
12.History or current evidence of any serious or clinically significant gastrointestinal, 
renal, endocrine, neurologic, hematologic or other condition that is uncontrolled 
on permitted therapies orthat would, in the opinion of the investigator or the 
GlaxoSmithKline (GSK) medical monitor, make the subject unsuitable for 
inclusion in this study
CONCOMITANT MEDICATIONS
13.Use of medications specified for the treatment of COPD including short-and 
long-acting bronchodilators (β-agonists and anticholinergics) and inhaled 
glucocorticoids as well as oxygen therapy
14.Use of a listed prohibited medication (Section6.10.2) within the restricted 
timeframe relative to the first dose of study medication
15.Use of a strong inhibitors or inducers of cytochrome P450 (CYP) 3A or p-

2014N221874_02
CONFIDENTIAL
201881
139
glycoprotein (see Section6.10.2)
RELEVANT HABITS
16.Current smoker
17.History of drug/substance abuse within the past 2 years
17.History of alcoholabuse within 6 months of the studyin the opinion of the 
investigator(s).  Defined as an average weekly alcohol consumption of >14 
drinks for men or >7 drinks for women.  One drink is equivalent to 12 g of 
alcohol: approximately 12 ounces (360 mL) of beer, 5 ounces (150 mL) of 
wine, or 1.5 ounces of (45 mL) 80 proof distilled spirits
CONTRAINDICATIONS 
18.History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
19.Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody 
test result at screening or within 3 months of screening.  For potent 
immunosuppressive agents, subjects with presence of hepatitis B core antibody 
(HBcAb) should also be excluded
20.A positive pre-study drug/alcohol screen(excluding prescribed medications)
21.Use of another investigational product in a clinical study within the following 
time period prior to the first administration of study medication in the current 
study: 30 days, 5half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer)
22.Exposure to more than 4 investigational medicinal products within 12 months 
prior to the first administration of study medication
PREVIOUS TEXT
5.3
Eligibility for Optional Sleep Apnea Sub-Study
Subjects eligible for the main study will be eligible for the sleep apnea sub-study, if the 
following inclusion criterion is met:
REVISED TEXT
5.3
Eligibility for Optional Sleep Apnea Sub-Study
Subjects eligible for the main study will be eligible for the sleep apnea sub-study, if the 
following inclusion criterionaisaremet:

2014N221874_02
CONFIDENTIAL
201881
140
Section 6
PREVIOUS TEXT
6.2
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomization 
schedule generated in RandAll NG by Clinical Statisticsprior to the start of the study, 
using validated internal software.
Subjects will be randomized into the study by means of an interactive voiceresponse 
system (IVRS) i.e. RAMOS NG, to receive one the two treatment regimens shown below 
inTable 1.
REVISED TEXT
6.2
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomization 
schedule generated in RandAllNG by Clinical Statisticsprior to the start of the study, 
using validated internal software.
Subjects will be randomized into the study by means of an interactive voicewebresponse 
system (IVWRS) i.e. RAMOS NG, to receive one the two treatment regimensshown 
below inTable 1.
PREVIOUS TEXT
6.3
Blinding
This will be a double-blind study where the sponsor and clinical pharmacist are un-
blinded and the following will apply. 
The investigator or treating physician may unblind a subject’s treatment assignment 
only in the case of an emergencyOR in the event of a serious medical condition 
when knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator. 
Investigators have direct access to the subject’s individual study treatment. 
It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment. 
If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the treatment 
assignment of the unblinded subject, unless that information is important for the 
safety ofsubjects currently in the study. 
The date and reason for the unblinding must be fully documented in the CRF 

2014N221874_02
CONFIDENTIAL
201881
141
A subject may continue in the study if that subject’s treatment assignment is 
unblinded by the discretion of the Investigator in consultation with the Medical 
Monitor.  
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an Serious Adverse Event (SAE) . If the 
SAE requires that an expedited regulatory report be sent to one or more regulatory 
agencies, a copy of the report, identifying the subject’s treatment assignment, may be 
sent to investigators in accordance with local regulations and/or GSK policy.
REVISED TEXT
6.3
Blinding
This will be a double-blind study where the sponsorand clinical pharmacist are un-
blinded and the following will apply. 
The investigator or treating physician may unblind a subject’s treatment assignment 
only in the case of an emergencyOR in the event of a serious medical condition 
when knowledge of thestudy treatment is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator. 
Investigators have direct access to the subject’s individual study treatmentvia the 
IWRS (RAMOS NG). 
It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment. 
If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the treatment 
assignment of the unblinded subject, unless that information is important for the 
safety of subjects currently in the study. 
The date and reason for the unblinding must be fully documented in the CRF 
A subject may continue in the study if that subject’s treatment assignment is 
unblinded by the discretion of the Investigator in consultation with the Medical 
Monitor.  
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with anSerious Adverse Event (SAE). If the 
SAE requires that an expedited regulatory report be sent to one or more regulatory 
agencies, a copy of the report, identifying the subject’s treatment assignment, may be 
sent to investigators in accordance with local regulations and/or GSK policy.

2014N221874_02
CONFIDENTIAL
201881
142
PREVIOUS TEXT
6.7
Treatment of Study Treatment Overdose
GSK does not recommend specific treatment for an overdose. The Investigator (or 
physician in charge of the subject at the time) will use clinical judgment to treat any 
overdose. 
In the event of an overdose the investigator or treating physicianshould:
5. Contact the Medical Monitor immediately
6. Closely monitor the subject for adverse events (AEs)/seriousadverse events (SAEs) 
and laboratory abnormalities until GSK2798745 can no longer be detected 
systemically (at least 5 days for GSK2798745)
7. Obtain a plasma sample for pharmacokinetic (PK) analysis within 1 days from the 
date of the last dose of study treatment if requested by the Medical Monitor 
(determined on a case-by-case basis)
8. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
REVISED TEXT
6.7
Treatment of Study Treatment Overdose
GSK does not recommend specific treatment for an overdose. The Investigator (or 
physician in charge of the subject at the time) will use clinical judgment to treat any 
overdose. 
In the event of an overdose the investigator or treating physicianshould:
1. Contact the Medical Monitor immediately.
2. Closely monitor the subject for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities until GSK2798745 can no longer be detected 
systemically (at least 5 days for GSK2798745).
3. Obtain a plasma sample for pharmacokinetic (PK) analysis within 1 daysfrom the 
date of the last dose of study treatment if requested by the Medical Monitor 
(determined on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the 
overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.

2014N221874_02
CONFIDENTIAL
201881
143
PREVIOUS TEXT
6.9.1
Monitoring in the Clinical Research Unit
The first six subjects who participate in the study will be admitted to the Clinical 
Research Unitto be monitored for the first two days (Day 1 and Day 2) following the 
first administration of study medication in both study periods.  Subsequently, these 
subjects will remain in the unit for a minimum of 4 hours after the administration of study 
medication on eachof the remaining 5 days (Days 3 through 7) of each study period.  On 
Day 5, subjects will remain in the unit for a minimum of 4 hours after the completion of 
the saline infusion.
For the remainder of subjects participating in the study, they will remain in the unit for a 
minimum of 4 hours after the administration of study medication on eachof the 7 days of 
each study period.  
Following the completion of all assessments on each study day, subjects may return 
home.  For subjects who cannot return home each evening for multiple reasons including 
but not limited to distance from clinical site or transportation issues, housing will be 
provided.  All subjects will be continuously monitored remotely (see Section7.4.7). 
REVISED TEXT
6.9.1
Monitoring in the Clinical ResearchUnit
The first six subjects who participate in the study will be admitted to the Clinical 
Research Uunitto be monitored for the first two days (Day 1 and Day 2) following the 
first administration of study medication in both study periods.  Subsequently, these 
subjects will remain in the unit for a minimum of 4 hours after the administration of study 
medication on eachof the remaining 5 days (Days 3 through 7) of each study period.  On 
Day 5, subjects will remain in the unit for a minimum of 4 hours after the completion of 
the saline infusion.
For the remainder of subjects participating in the study, they will remain in the unit for a 
minimum of 4 hours after the administration of study medication on eachof the 7 days of 
eachstudy period.  
Following the completion of all assessments on each study day, subjects may return 
home.  For subjects who cannot return home each evening for multiple reasons including 
but not limited to distance from clinical site or transportation issues, housing will be 
providedorthey may opt to remain in the unit for the duration of the study period.  
Housing should be consistent in both study periods.  All subjects will be continuously 
monitored remotely (see Section7.4.7). 

2014N221874_02
CONFIDENTIAL
201881
144
PREVIOUS TEXT
6.9.2
Meal and Dietary Restrictions
Subjects 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 
prior to the first dose of study medication until their discharge from the unit after their 
last dose of study medication in each period.
Three meals per day will be provided by dietary department either in the clinical research 
unit or as a boxed meal(s) to go.
No meal restrictions will be placed with regard to drug administration.  Subjects will be 
allowed to consume a standard breakfast prior to drug administration.
REVISED TEXT
6.9.2
Meal and Dietary Restrictions
Subjects are not permitted to consume red wine, Seville oranges, grapefruit orgrapefruit 
juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days 
prior to the first dose of study medication until their discharge from the unit after their 
last dose of study medication in each period.
Three meals per day will be provided by dietary department either in the clinical 
researchunit or as a boxed meal(s) to go.
No meal restrictions will be placed with regard to drug administration.  Subjects will be 
allowed to consume a standard breakfast prior to drug administration.
PREVIOUS TEXT
6.9.3
Caffeine and Alcohol
During each study period, subjects will abstain from ingesting caffeine-or xanthine-
containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 hours prior to the 
start of dosinguntil completion of all assessments.
During each study period, subjects will abstain from alcohol for 24 hours prior to the start 
of dosing until completion of all assessments.
REVISED TEXT
6.9.3
Caffeine and Alcohol
During each study period, it is recommended that subjects will abstain from ingesting
minimize ingestion of caffeine-or xanthine-containing products (e.g., coffee, tea, cola 
drinks, and chocolate) for 24 hours prior to the start of dosinguntil completion of all 
assessments.

2014N221874_02
CONFIDENTIAL
201881
145
During each study period, subjects will abstain from alcohol for 24 hours prior to the start 
of dosing until completion of all assessments.
PREVIOUS TEXT
6.10.2.
Prohibited Medications and Non-Drug Therapies
Except for the permitted medications noted above (Section6.10.1), subjects must abstain 
from taking 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) prior to the first dose of study medication until 
completion of the follow-up visit, unless in the opinion of the Investigator and sponsor 
the medication will not interfere with the study.
Subjects must provide to the investigator information/list of all medications they are 
currently taking. 
GSK2798745 has weak CYP3A4 inhibition potential.  There is a likelihood that the 
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 are likely to be taken by the eligible patients as part of their medications. 
The concentrations of these statins will be monitored during the study.  The investigators 
may also consider substitutions of these medications.  
Subjects should avoid using drugs that are strong inhibitors or inducersof 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 2 consider therapeutic 
substitutions for these medications.  
GSK2798745 systemic concentrations will be monitored to detect any drug interactions 
with moderate CYP3A4 inhibitors or P-gP inhibitors (see SRM for a detailed list).
It is strongly recommended that patients 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 subjects for loss of efficacy or consider substitutions of 
these medications.  See SRM for a detailed list.  The list may be modified based on 
emerging data.  All concomitant medications should be reviewed by the Medical Monitor 
and will be to the discretion of the Investigator and Medical Monitor whether the 
medication can be continued and/or the subject can participate in the study.
REVISED TEXT
6.10.2.
Prohibited Medications and Non-Drug Therapies
Except for the permitted medications noted above (Section6.10.1), subjects must abstain 
from taking non-prescription drugs (including vitamins and dietary or herbal 

2014N221874_02
CONFIDENTIAL
201881
146
supplements), within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 
half-lives (whichever is longer) prior to the first dose of study medication until 
completion of the follow-up visit, unless in the opinion of the Investigator and sponsor 
the medication will not interfere with the study.
Subjects must provide to the investigator information/list of all medications they are 
currently taking. 
GSK2798745 has weak CYP3A4 inhibition potential.  There is a likelihood that the 
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 are likely to be taken by the eligible patients as part of their medications. 
The concentrations of these statins will be monitored during the study.  The investigators 
may also consider substitutions of these medications.  
Subjects should avoid using drugs that are strong inhibitors or inducersof 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 2 consider therapeutic 
substitutions for these medications.  
GSK2798745 systemic concentrations will be monitored to detect any drug interactions 
with moderate CYP3A4 inhibitors or P-gP inhibitors (see SRM for a detailed list).
It is strongly recommended that patients 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 subjects for loss of efficacy or consider substitutions of 
these medications.  See SRM for a detailed list.  The list may be modified based on 
emerging data.  All concomitant medications shouldmaybe reviewed by the Medical 
Monitor anditwill beupto the discretion of the Investigator and if necessary the 
Medical Monitor,whether the medication can be continued and/or the subject can 
participate in the study.

2014N221874_02
CONFIDENTIAL
201881
147
PREVIOUS TEXT
7.1.
Time and Events Table
Procedure
Screening 
Period
Treatment Periods I and II(Day)
Follow-up
Day -25  
to Day -1 
pr
ior to 
Per
iod I
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9
14 ± 4 days 
after 
last 
dose of 
study 
med
icat
ion
Informed consent
X
Inc
lus
ion and exc
lus
ion 
cr
iter
ia
X
Demography
X
Fu
l
l phys
ica
l exam
inat
ion
inc
lud
ing he
ight & we
ight
X
Br
ief phys
ica
l exam
inc
lud
ing we
ight
X
X
X
X
Med
ica
l 
h
istory/Med
icat
ion h
istory
X
Hepat
it
is B & C screen
X
Echocard
iogram
X
Ur
ine drug and a
lcoho
l 
breath test
X 
X
C
l
in
ica
l 
lab 
assessments
14
X 
X
X
X
X
NT-proBNP 
X
X
X
Serum CTX11
X
X
Feca
l Occu
lt B
lood Test12
X
X
Pharmacok
inet
ic samp
le1
X
X
X
X
X
X
X
X
X
X
D
igox
in samp
le2
X
X
X
X
X
X
X
X
X
Tropon
in
X
X
X
X
X
X
DLco/DLno10
X
X
X
X
X
X

2014N221874_02
CONFIDENTIAL
201881
148
Procedure
Screening 
Period
Treatment Periods I and II(Day)
Follow-up
Day -25  
to Day -1 
pr
ior to 
Per
iod I
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9
14 ± 4 days 
after 
last 
dose of 
study 
med
icat
ion
12-lead ECG/  
t
ime & frequency 
doma
ins
3
X9
X9
X
X
X
V
ita
l s
igns
X 
X 
X 
X 
X 
X 
X 
X 
X
X
We
ight
X 
X 
X
X 
X
Genet
ic samp
le 
For sub
jects who prov
ide consent, samp
le co
l
lected after start of treatment
Study treatment
4
X
X
X
X
X
X
X
AE/SAE rev
iew
X
==============================================================
X
Concom
itant med rev
iew
X
==============================================================
X
Pu
lmonary funct
ion tests 
X
X
X
X
Step exerc
ise test/breath-
by-breath gas exchange 
X
X
X
Dyspneaassessment
X
X
X
X
Orthopnea
X
SF-36 Acute
X
X
X
Po
lysomnography 
inc
lud
ing ox
imetry (S
leep 
Apnea C
l
in
ic)5,13
      =========
      =========
P
lasma and 8-hour ur
ine 
catecho
lam
ines
6
X
X
Sa
l
ine 
infus
ion
X
Adm
iss
ion to CRU7
X
D
ischarge from CRU7
X
Mea
ls8
X
X
X
X
X
X
X
X
Appet
ite Assessment 
(SNAQ)
X
X
X
X
CSSRS (Su
ic
ida
l
ity) 
X
X
X
Aud
iometry
X13
X
X

2014N221874_02
CONFIDENTIAL
201881
149
Procedure
Screening 
Period
Treatment Periods I and II(Day)
Follow-up
Day -25  
to Day -1 
pr
ior to 
Per
iod I
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9
14 ± 4 days 
after 
last 
dose of 
study 
med
icat
ion
BodyGuard
ian Mon
itor 
(Prevent
ice)
============================Cont
inuous===================================
1. Pharmacokinetic samples to determine GSK2798745 and any metabolite(s) concentrations will be obtained at the following times on Day 1 of 
each treatment period:  Predose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours and at the following times on Day 7 of each treatment period: Predose, 0.5, 1, 
1.5, 2, 3, 5 and 10 hours.  On Day 2 of each treatment period, samples will be collected predose and at 12 hours post dose. On Days 3 through 6, 
PK samples will be collected predose.  On Days 8 and 9, samples will be collected at 24 and 48 hours, respectively, after thelast dose of study 
medication administered on Day 7. The time points may be modified based on emerging data.  Some of these timepoints may also be utilized to 
collect samples to determine concentrations of other medications (e.g., atorvastatin and/or simvastatin).  See the SRM for detailed information.
2. Digoxin concentrations will be monitored only in those subjects who are taking digoxin
3. Time and frequency domains assessed by ECG obtained on Day -1 and Day 7
4. Subjects will remain in the CRU for a minimum of 4 hours after each administration of study medication.  [Note: The first 6 subjects enrolled will 
remain in the CRU for 52 hours after the first dose of study medication in each period]
5. Only for subjects participating in the sub-study: At Day -1 of the first study period only, subjects will undergo an overnight sleep study.  Only 
those subjects who are participating in the sub-study with sleep disordered breathing will undergo additional sleep studies on Day 6 of both study 
Periods I and II.
6. Only for subjects participating in the sub-study: Urinary norepinephrine(NE) and epinephrine (E) concentrations will be determined from 8-hour 
collections obtained during the overnight sleep study; urinary creatinine will also be measured to normalize the NE and E concentrations.  A blood 
sample to determine plasma concentrations of NE and E will be obtained the morning after the sleep study between the hours of 9:00 am and 10:00 
am after the subject has been supine for 20 minutes in a quiet room.
7. The first 6 subjects enrolled will remain in the CRU for two days (Day 1 and Day2) after the first dose of study medication in each period.
8. Three meals per day will be provided by the dietary department either in the CRU or as a boxed meal(s) to take home.
9. ECGs to be performed in triplicate
10.On the days where exercise or the saline infusion is performed, DLco/DLno will be completed just prior to and after both exercise and the saline 
infusion.
11.Blood sample for analysis of Serum CTX must be collected when the subject is fasting.  See Section 7.4.9.1

2014N221874_02
CONFIDENTIAL
201881
150
12.Fecal Occult Blood Test (FOBT) cards will be provided to subjects at the end of the screening visit and must be completed and sent back to the 
laboratory prior to the baseline visit according to the laboratory’s standard collection procedures.  Similarly, subjects will be given FOBT cards at 
the end of the Day 7 visit of each study period with completion instructions.  See Section 7.4.9.2
13.Day -1 audiometry and sleep study assessments may be completed 7 days prior to Day -1.
14.Clinical laboratory assessments will be collected as a fasting sample.
REVISED TEXT
7.1.    Time and Events Table
Procedure
Screening 
Period
Treatment Periods I and II (Day)
Follow-up
Day -25  
to Day -1 
pr
ior to 
Per
iod I
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9
14 ± 4 days 
after 
last 
dose of 
study 
med
icat
ion
Informed consent
X
Inc
lus
ion and exc
lus
ion 
cr
iter
ia
X
Demography
X
Fu
l
l phys
ica
l exam
inat
ion
inc
lud
ing he
ight & we
ight
X
Br
ief phys
ica
l exam
inc
lud
ing we
ight
X
X
X
X
Med
ica
l 
h
istory/Med
icat
ion h
istory
X
Hepat
it
is B & C screen
X
Echocard
iogram
X
Ur
ine drug and a
lcoho
l
breathtest
X 
X
C
l
in
ica
l 
lab 
assessments
14
X 
X
X
X
X
NT-proBNP 
X
X
X
Serum CTX11
X
X

2014N221874_02
CONFIDENTIAL
201881
151
Procedure
Screening 
Period
Treatment Periods I and II (Day)
Follow-up
Day -25  
to Day -1 
pr
ior to 
Per
iod I
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9
14 ± 4 days 
after 
last 
dose of 
study 
med
icat
ion
Feca
l Occu
lt B
lood Test12
X
X
Pharmacok
inet
ic samp
le
1
X
X
X
X
X
X
X
X
X
X
D
igox
in samp
le2
X
X
X
X
X
X
X
X
X
Tropon
in
X
X
X
X
X
X
DLco/DLno10
X15
X
X
X
X
X
12-lead ECG/  
t
ime & frequency 
doma
ins
3
X9
X9
X
X
X
V
ita
l s
igns
X 
X 
X 
X 
X 
X 
X 
X 
X
X
We
ight
X 
X 
X
X 
X
Genet
ic samp
le 
For sub
jects who prov
ide consent, samp
le co
l
lected after start of treatment
Study treatment4
X
X
X
X
X
X
X
AE/SAE rev
iew
X
==============================================================
X
Concom
itant med rev
iew
X
==============================================================
X
Pu
lmonary funct
ion tests 
X
X
X
X
Step exerc
ise test/breath-
by-breath gas exchange 
X
X
X
Dyspneaassessment
X
X
X
X
Orthopnea
X
SF-36 Acute
X
X
X
Po
lysomnography 
inc
lud
ing ox
imetry (S
leep 
Apnea C
l
in
ic)5,13
      =========
      =========
P
lasma and 8-hour ur
ine 
catecho
lam
ines
6
X
X
Sa
l
ine 
infus
ion
X
Adm
iss
ion to CRUunit7
X

2014N221874_02
CONFIDENTIAL
201881
152
Procedure
Screening 
Period
Treatment Periods I and II (Day)
Follow-up
Day -25  
to Day -1 
pr
ior to 
Per
iod I
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9
14 ± 4 days 
after 
last 
dose of 
study 
med
icat
ion
D
ischarge from CRU
unit7
X
Mea
ls8
X
X
X
X
X
X
X
X
Appet
ite Assessment 
(SNAQ)
X
X
X
X
CSSRS (Su
ic
ida
l
ity) 
X
X
X
Aud
iometry
X13
X17
X
BodyGuard
ian Mon
itor 
(Prevent
ice)
============================Cont
inuous===================================
1. Pharmacokinetic samples to determine GSK2798745 and any metabolite(s) concentrations will be obtained at the following times on Day 1 of 
each treatment period:  Predose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours and at the following times on Day 7of each treatment period: Predose, 0.5, 
1, 1.5, 2, 3, 5 and 10 hours.  On Day 2 of each treatment period, samples will be collected predose and at 12 hours post dose. On Days 3 
through 6, PK samples will be collected predose.  On Days 8 and 9, samples will be collected at 24 and 48 hours, respectively, after the last 
dose of study medication administered on Day 7. The time points may be modified based on emerging data.  Some of these timepoints may 
willalso be utilized to collect samples to determine concentrations of other medications (e.g., atorvastatin and/or simvastatin).  See the SRM 
for detailed information.
2. Digoxin concentrations will be monitored only in those subjects who are taking digoxin
3. Time and frequency domains assessed by ECG obtained on Day -1 and Day 7
4. Subjects will remain in the CRUunitfor a minimum of 4 hours after each administration of study medication.  [Note: The first 6 subjects 
enrolled will remain in the CRUunitfor 52 hours after the first dose of study medication in each period]
5. Only for subjects participating in the sub-study: At Day -1 of the first study period only, subjects will undergo an overnight sleep study.  Only 
those subjects who are participating in the sub-study with sleep disordered breathing will undergo additional sleep studies on Day 6 of both 
study Periods I and II.
6. Only for subjects participating in the sub-study: Urinary norepinephrine (NE) and epinephrine (E) concentrations will be determined from 8-
hour collections obtained during the overnight sleep study; urinary creatinine will also be measured to normalize the NE and E concentrations.  
A blood sample to determine plasma concentrations of NE and E will be obtained the morning after the sleep study between the hours of 9:00 
am and 10:00 am after the subject has been supine for 20 minutes in a quiet room.

2014N221874_02
CONFIDENTIAL
201881
153
7. The first 6 subjects enrolled will remain in the CRUunitfor two days (Day 1 and Day 2) after the first dose of study medication in each 
period.Subjects may remain in the unit for the duration of each of the 7 day treatment periods for convenience.  Housing should be 
consistent in both study periods.
8. Three meals per day will be provided by the dietary department either in the CRUunitor as a boxed meal(s) to take home.
9. ECGs to be performed in triplicate
10.On the days wherewhenexercise or the saline infusion is performed, DLco/DLno will be completed just prior to and after both exercise and 
the saline infusion.
11.Blood sample for analysis of Serum CTX must be collected when the subject is fasting.  See Section 7.4.9.1
12.Fecal Occult Blood Test (FOBT) cards will be provided to subjects at the end of the screening visit and must be completed andsent back to 
the laboratory prior to the baseline visit according to the laboratory’s standard collection procedures. Similarly, subjects will be given FOBT 
cards at the end of the Day 7 visit of each study period with completion instructions.  See Section 7.4.9.2
13.Day -1 audiometry and sleep study assessments may be completed 7 days prior to Day -1.
14.Clinical laboratory assessments will be collected as a fasting sample.
15.The screening visit will only collect %Predicted DLco (DLco single breath)
16.If a subject has had an echocardiogram completed within the last 6 months prior to screening, it does not need to be repeated
.
17.Day 7 Audiometry may be completed with a window of 2 day

2014N221874_02
CONFIDENTIAL
201881
154
PREVIOUS TEXT
7.2
Screening and Critical Baseline Assessments
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/alcohol/family history will be assessed as related to the 
inclusion/exclusion criteria listed in Section 5.  Cardiovascular medical history/risk 
factors will also be assessed at screening, including the following items pertaining to 
medical and medicationhistory:

Onset and type of symptoms
Years since diagnosis of HF
New York Heart Association (NYHA) class
LVEF (%)
Years since diagnosis of sleep apnea (if applicable)
Degree of exercise intolerance: distance/ stairs/time prior to breathlessness
Presence of orthopnea and/or paroxysmal nocturnal dyspnea

Peripheral edema: presence and height beyond ankle; recent weight gains, 
level of peripheral pitting edema

Significant past medical history including onset, etiology, and results of any 
recent relevant investigations of heart failure, as applicable

Medication history
Procedures conducted as part of the subject’s routine clinical management and obtained 
prior to signing of informed consent may be utilized for Screening or baseline purposes 
provided the procedure meets the protocol-defined criteria and has been performed in the 
timeframe of the study.
During the Screening Period prior to the first study period (Period I), subjects will have 
the following assessments performed to determine eligibility for enrollment:

NT-proBNP

DLco/DLno

Polysomnography (eligibility into sub-study)
REVISED TEXT
7.2
Screening and Critical Baseline Assessments
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.

2014N221874_02
CONFIDENTIAL
201881
155
Medical/medication/alcohol/family history will be assessed as related to the 
inclusion/exclusion criteria listed in Section 5.  Cardiovascular medical history/risk 
factors will also be assessed at screening, including the following items pertaining to 
medical and medicationhistory:

Onset and type of symptoms
Years since diagnosis of HF
New York Heart Association (NYHA) class
LVEF (%)
Years since diagnosis of sleep apnea (if applicable)
Degree of exercise intolerance: distance/ stairs/time prior to breathlessness
Presence of orthopnea and/or paroxysmal nocturnal dyspnea

Peripheral edema: presence and height beyond ankle; recent weight gains, 
level of peripheral pitting edema

Significant past medical history including onset, etiology, and results of any 
recent relevant investigations of heart failure, as applicable

Medication history
Procedures conducted as part of the subject’s routine clinical management and obtained 
prior to signing of informed consent may be utilized for Screening or baseline purposes 
provided the procedure meets the protocol-defined criteria and has been performed in the 
timeframe of the study.
During the Screening Period prior to the first study period (Period I), subjects will have 
the following assessments performed to determine eligibility for enrollment:
NT-proBNP

DLco/DLno % Predicted DLco

Polysomnography (eligibility into sub-study)
PREVIOUS TEXT
7.3.1.
DLco and DLno
The diffusing capacity of the lung to carbon monoxide (DLco) or nitric oxide (DLno) is a 
measure of the ability of a gas to transfer from the alveoli across the alveolar epithelium 
and the capillary endothelium to the red blood cells.  Changes in DLco and DLno reflect 
the alveolar-capillary membrane conductance (D
M).  Since nitric oxide has a greater 
affinity for hemoglobin, the diffusion of nitric oxide is mainly limited by the transfer of 
gas across the alveolar capillary membrane.  Measurements are made simultaneously. 
Acute pulmonary congestion causes a reduction in DLco.  In patients with heart failure, 
DLco is decreased and serves as a predictor of disease progression.  An impairment in the 

2014N221874_02
CONFIDENTIAL
201881
156
diffusing capacity of the lung may be related to the symptoms and exercise intolerance 
associated with heart failure.  
DLco will be measured during the Screening Period to determine eligibility for 
enrollment into the study.  Subjects must have a % Predicted DLco <80%. 
During each study period, DLco and DLno will be measured just prior to and after the 3-
minute step test on Days -1, and 7 and at the Follow-up Visit.  Measurements will also be 
made just prior to and after an intravenous saline infusion on Day 6.  
Details of the pulmonary testing methodology including diffusing capacity and measured 
components are included in the SRM.  Refer to the instruction manual(s) for the 
equipment for further details.
REVISED TEXT
7.3.1.
DLcoand DLno
The diffusing capacity of the lung to carbon monoxide (DLco) or nitric oxide (DLno) is a 
measure of the ability of a gas to transfer from the alveoli across the alveolar epithelium 
and the capillary endothelium to the red blood cells.  Changes in DLco and DLno reflect 
the alveolar-capillary membrane conductance (D
M).  Since nitric oxide has a greater 
affinity for hemoglobin, the diffusion of nitric oxide is mainly limited by the transfer of 
gas across the alveolar capillary membrane.  Measurements are made simultaneously. 
Acute pulmonary congestion causes a reduction in DLco.  In patients with heart failure, 
DLco is decreased and serves as a predictor of disease progression.  An impairment in the 
diffusing capacity of the lung may be related to the symptoms and exercise intolerance 
associated with heart failure.  
DLco will be measured during the Screening Period to determine eligibility for 
enrollment into the study.  Subjects must have a % Predicted DLco <80%. 
During each study period, DLco andDLno will be measured just prior to and after the 3-
minute step test on Days -1, and 7 and at the Follow-up Visit.  Measurements will also be 
made just prior to and after an intravenous saline infusion on Day 65.  
Details of the pulmonary testing methodology including diffusing capacity and measured 
components are included in the SRM.  Refer to the instruction manual(s) for the 
equipment for further details.
PREVIOUS TEXT
7.3.2.
Submaximal Exercise Test
Blockade of the TRPV4 channel with GSK2798745 may decrease pulmonary edema 
resulting in an increase in exercise capacity and/or oxygen uptake.  
Subjects will be asked to participate in a submaximal exercise test that consists of 3 parts: 
a 2-minute resting baseline, a 3-minute step exercise, and a 1-minute recovery period 

2014N221874_02
CONFIDENTIAL
201881
157
[Woods, 2011].  Throughout the test, breathing pattern, gas exchange, and heart rate will 
be monitored using a simplified gas analysis system (SHAPE Medical Systems, Inc).  
Respiratory exchange ratio (RER) and the Borg Rating of Perceived Exertion (RPE) 
measures will be utilized to ensure subjects perform progressive exercise while 
maintaining a submaximal level throughout the exercise period.  Minute ventilation, 
breath frequency, tidal volume, oxygen consumption, carbon dioxide production, RER 
and end tidal CO
2will be obtained from the breath-by-breath gas measurements.  The 
ventilation/carbon dioxide production (VE/VCO2) slope and other variables will be 
derived from this data.  
The exercise protocol will be completed on Day -1 and Day 7 of each study period.  
DLco/DLno measurements will be obtained before and after the exercise challenge.  
Additional details of the exercise protocol for the 3-minute step test are provided in the 
SRM. 
REVISED TEXT
7.3.2.
Submaximal Exercise Test
Blockade of the TRPV4 channel with GSK2798745 may decrease pulmonary edema 
resulting in an increase in exercise capacity and/or oxygen uptake.  
Subjects will be asked to participate in a submaximal exercise test that consists of 3 parts: 
a 2-minute resting baseline, a 3-minute step exercise, and a 1-minute recovery period 
[Woods, 2011].  Throughout the test, breathing pattern, gas exchange, and heart rate will 
be monitored using a simplified gas analysis system (i.e.SHAPE Medical Systems, Inc).  
Respiratory exchange ratio (RER) and the Borg Rating of Perceived Exertion (RPE) 
measures will be utilized to ensure subjects perform progressive exercise while 
maintaining a submaximal level throughout the exercise period.  Minute ventilation, 
breath frequency, tidal volume, oxygen consumption, carbon dioxide production, RER 
and end tidal CO
2will be obtained from the breath-by-breath gas measurements.  The 
ventilation/carbon dioxide production (VE/VCO2) slope and other variables will be 
derived from this data.  
The exercise protocol will be completed on Day -1 and Day 7 of each study period.  
DLco/DLno measurements will be obtained before and after the exercise challenge.  
Additional details of the exercise protocol for the 3-minute step test are provided in the 
SRM. 
PREVIOUS TEXT
7.3.3.
Intravenous Saline Infusion
In patients with chronic HF, intravenously infused saline elicited a reduction of D
M [Puri, 
1999] suggesting that the abnormal pulmonary diffusion in this population may have a 
variable component that could be amenable to therapeutic intervention.  Similarly, an 
infusion of saline into the pulmonary artery significantly reduced both DLco and D
M in 
patients with chronic HF but not in control subjects [Guazzi, 1999]; the changes in DM 
were inversely related to VE/VCO2 [Guazzi,2001].  The hemodynamic effects of volume

2014N221874_02
CONFIDENTIAL
201881
158
expansionwith saline loading has been shown to be associated with increases in left and 
right heart filling pressures and pulmonary artery pressures in patients with HF 
[Andersen, 2015].  In thislatter study, no patient developed dyspnea or any evidence of 
pulmonary congestion despite increase in cardiac filling pressures. 
All subjects will undergo an intravenous 0.9% NaCl infusion on Day 5 of both study 
periods in the presence of a cardiologist specializing in heart failure. The procedure will 
be conducted only if the subject is without any signs of obvious congestion as determined 
by the Investigator. Subjects will be carefully monitored both during and after the 
infusion and will be provided intravenous diuretics if necessary. Details of this procedure 
are described in Appendix 9.
DLco and DLno measurements will be obtained prior to the initiation of the infusion and 
after the completion of the infusion.
REVISED TEXT
7.3.3.
Intravenous Saline Infusion
In patients with chronic HF, intravenously infused saline elicited a reduction of D
M [Puri, 
1999] suggesting that the abnormal pulmonary diffusion in this population may have a 
variable component that could be amenable to therapeutic intervention.  Similarly, an 
infusion of saline into the pulmonary artery significantly reduced both DLco and D
M in 
patients with chronic HF but not in control subjects [Guazzi, 1999]; the changes in DM 
were inversely related to VE/VCO2 [Guazzi, 2001].  The hemodynamic effects of 
volumeexpansionwith saline loading has been shown to be associated with increases in 
left and right heart filling pressures and pulmonary artery pressures in patients with HF 
[Andersen, 2015].  In this latter study, no patient developed dyspnea or any evidence of 
pulmonary congestion despite increase in cardiac filling pressures. 
All subjects will undergo an intravenous 0.9% NaCl infusion on Day 5 of both study 
periods in the presence of a cardiologist specializing in heart failure. The procedure will 
be conducted only if the subject is without any signs of obvious congestion as determined 
by the Investigator. Subjects will be carefully monitored both during and after the 
infusion and will be provided intravenous diuretics if necessary. Details of this procedure 
are described in Appendix 9.
DLco and DLno measurements will be obtained prior to the initiation of the infusion and 
after the completion of the infusion.  Additional details are included in the SRM.
PREVIOUS TEXT
7.3.4.
Pulmonary Function Tests
Measures of pulmonary function have been shown to predict prognosis in patients with 
HF [Olson, 2013].

2014N221874_02
CONFIDENTIAL
201881
159
Sprirometry measures will include forced vital capacity (FVC) and forced expiratory 
volume in 1 second (FEV1) as well as forced expiratory flows, FEF
25-75FEF50, and FEF
75 
Functional residual capacity (FRC) and end-expiratory lung volume (EELV) measured by 
body plethysmography.
REVISED TEXT
7.3.4.
Pulmonary Function Tests
Measures of pulmonary function have been shown to predict prognosis in patients with 
HF [Olson, 2013].
Sprirometry measures will include forced vital capacity (FVC) and forced expiratory 
volume in 1 second (FEV1) as well as forced expiratory flows, FEF
25-75FEF50, and FEF
75 
Functional residual capacity (FRC) and end-expiratory lung volume (EELV) will be
measured by body plethysmography.
PREVIOUS TEXT
7.3.6.
Polysomnography
Subjects only participating in the sleep apnea substudy will undergo overnight 
polysomnography during the Screening Period.  Consenting subjects who meet all the 
eligibility criteria for the main study and have an apnea/hypopnea index (AHI) ≥5 
events/hour based on polysomnography will participate in subsequent sleep studies on 
Day 6 of both study periods. 
Multiple recordings will be monitored including electroencephlogram (EEG), 
electrooculogram (EOG), electromyogram (EMG), electrocardiogram (ECG), and 
oximetry.  Sleep stages and arousals, respiratory rate, and O
2saturation will be measured.  
Disordered breathing events will be classified as apneas or hypopneas and as either 
obstructive or central.
Additional details outlining the polysomnography procedure are detailed in the SRM.  
REVISED TEXT
7.3.6.
Polysomnography
Only Ssubjectsonlyparticipating in the sleep apnea substudy will undergo overnight 
polysomnography during the Screening Period.  Consenting subjects who meet all the 
eligibility criteria for the main study and have an apnea/hypopnea index (AHI) ≥5 
events/hour based on polysomnography will participate in subsequent sleep studies on 
Day 6 of both study periods. 
Multiple recordings will be monitored including electroencephlogram (EEG), 
electrooculogram (EOG), electromyogram (EMG), electrocardiogram (ECG), and 
oximetry.  Sleep stages and arousals, respiratory rate, and O
2saturation will be measured.  

2014N221874_02
CONFIDENTIAL
201881
160
Disordered breathing events will be classified as apneas or hypopneas and as either 
obstructive or central.
Additional details outlining the polysomnography procedure are detailed in the SRM.  
PREVIOUS TEXT
7.4.5.
Electrocardiogram (ECG)
Triplicate 12-Lead ECGs will be obtained during the Screening Period and at 
baseline and single 12-lead ECGs will be obtained on Days -1, 4 and 7 and the 
Follow-up Visit using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTcF or QTcB intervals.  
Refer to Section 5.5.2for QTc withdrawal criteria and additional QTc readings that 
may be necessary.

Resting and stationary measures will also be collected to determine heart rate 
variability and time domains
REVISED TEXT
7.4.5.
Electrocardiogram (ECG)
Triplicate 12-Lead ECGs will be obtained during the Screening Period and at 
baseline(Day -1)and single 12-lead ECGs will be obtained on Days -1, 4 and 7 and 
the Follow-up Visit using an ECG machine that automatically calculates the heart 
rate and measures PR, QRS, QT, and QTcF or QTcB intervals.  
Refer to Section 5.5.2for QTc withdrawal criteria and additional QTc readings that 
may be necessary.
Resting and stationary measures will also be collected to determine heart rate 
variability and time domains
PREVIOUS TEXT
7.4.6.
Echocardiogram
A transthoracic echocardiogram will be performed during the Screening Period.  Images 
will be obtained in standard views (e.g., long axis parasternal, short axis parasternal, and 
apical 2, 3, 4 and 5 chamber).  The time to acquire images should not exceed 30minutes.
REVISED TEXT
7.4.6.
Echocardiogram
A transthoracic echocardiogram will be performed during the Screening Period, unless 
the subject has had an echocardiogram completed withinthe 6 monthsprior to 
screening.  Images will be obtained in standard views (e.g., long axis parasternal, short 
axis parasternal, and apical 2, 3, 4 and 5 chamber).  The time to acquire images should 
not exceed 30minutes.

2014N221874_02
CONFIDENTIAL
201881
161
PREVIOUS TEXT
Table 3
Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
P
late
let Count
RBC Ind
ices: WBC count w
ith D
ifferent
ia
l:
RBC Count
MCV
Neutroph
i
ls
Hemog
lob
in
MCH
Lymphocytes
Hematocr
it
MCHC
Monocytes
WBC Count (abso
lute)
Eos
inoph
i
ls
Ret
icu
locytecount
Basoph
i
ls
Clinical 
Chemistry 
BUN
Potass
ium AST (SGOT)
Tota
l and d
irect 
b
i
l
irub
in
Creat
in
ine
Sod
ium
ALT (SGPT)
Tota
l Prote
in
G
lucose, 
fast
ing
Ca
lc
ium
A
lka
l
ine phosphat
ise
A
lbum
in
CPK
Ur
ic Ac
id
GGT
Tropon
in
Ch
lor
ide
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Urinary norepinephrine and epinephrine (during sleep study)
Other 
Screening 
Tests
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody)
Digoxin concentrations (only in subjects treated with Digoxin)
Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)
HMG CoA Reductase Inhibitor concentration (only in subjects 
taking medication)
Biomarker(s)/ 
Other 
Assessments
N-terminal pro-B-type Natriuretic Peptide (NT-proBNP)
Norepinephrine and Epinephrine
Serum Collagen Type I C-Telopeptide (CTX), fasting
Fecal Occult Blood Test (FOBT)
NOTES :
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 5.5.1and 
Appendix 2

2014N221874_02
CONFIDENTIAL
201881
162
REVISED TEXT
Table 3
Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
P
late
let Count
RBC Ind
ices: WBC count w
ith D
ifferent
ia
l:
RBC Count
MCV
Neutroph
i
ls
Hemog
lob
in
MCH
Lymphocytes
Hematocr
it
MCHC
Monocytes
WBC Count (abso
lute)
Eos
inoph
i
ls
Ret
icu
locyte count
Basoph
i
ls
Clinical 
Chemistry 
BUN
Potass
ium AST (SGOT)
Tota
l and direct 
b
i
l
irub
in
Creat
in
ine
Sod
ium
ALT (SGPT)
Tota
l Prote
in
G
lucose, 
fast
ing
Ca
lc
ium
A
lka
l
ine phosphat
ise
A
lbum
in
CPK
Ur
ic Ac
id
GGT
Troponin
Ch
lor
ide
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Urinary norepinephrine and epinephrine (during sleep study)
Other 
Screening 
Tests
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody)
Digoxin concentrations (only in subjects treated with Digoxin)
Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)
HMG CoA Reductase Inhibitor concentration (only in subjects 
taking medication)
Biomarker(s)/ 
Other 
Assessments
N-terminal pro-B-type Natriuretic Peptide (NT-proBNP)
Norepinephrine and Epinephrine(substudy only)
Serum Collagen Type I C-Telopeptide (CTX), fasting
Fecal Occult Blood Test (FOBT)
Troponin
NOTES :
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 5.5.1 and 
Appendix 2

2014N221874_02
CONFIDENTIAL
201881
163
PREVIOUS TEXT
7.4.9.2 Fecal Occult Blood Test (FOBT)
Based on the gastric erosions found in a preclinical model (dogs at ≥3 mg/kg), FOBT will 
be performed to assess any possible drug-related GI blood loss.  Due to concomitant anti-
platelet therapy that many patients with heart failure receive, along with thecommon 
incidence of intestinal mucosal edema and associated diarrhea,findings of fecal blood 
would not be unexpected in this population.  Subjects will be tested for the presence of 
fecal occult blood prior to the start of studyperiod I (between Screening and Baseline) 
and after each of the two study periods.  
Once subjects have signed the consent form and have been enrolled into the study based 
on meeting the eligibility criteria, they will be provided 3 FOBT cards at the end of the 
screening visit.  Study staff will provide the subjects with instructions for completing the 
tests and subsequent shipment of the tests back to the laboratory.  This assessment will be 
completed between Screening and Baseline (Day -1).  Additionally, subjects will be 
provided 3 FOBT cards on Day 7 of each study period with the same instructions for 
completion and shipment for laboratory analysis.
REVISED TEXT
7.4.9.2 Fecal Occult Blood Test (FOBT)
Based on the gastric erosions found in a preclinical model (dogs at ≥3 mg/kg), FOBT will 
be performed to assess any possible drug-related GI blood loss.  Due to concomitant anti-
platelet therapy that many patients with heart failure receive, along with thecommon 
incidence of intestinal mucosal edema and associated diarrhea,findings of fecal blood 
would not be unexpected in this population.  Subjects will be tested for the presence of 
fecal occult blood prior to the start of studytreatmentperiod I (between Screening and 
Baseline) and after each of the two studytreatmentperiods.  
Once subjects have signed the consent form and have been enrolled into the study based 
on meeting the eligibility criteria, they will be provided 3 FOBT cards at the end of the
screening visit.  Study staff will provide the subjects with instructions for completing the 
tests and subsequent shipment of the tests back to the laboratory.  This assessment will be 
completed between Screening and Baseline (Day -1).  Additionally, subjects will be 
provided 3 FOBT cards on Day 7 of each study treatment period with the same 
instructions for completion and shipment for laboratory analysis.
PREVIOUS TEXT
7.5.1.
Blood Sample Collection
Blood samples for pharmacokinetic analysis of GSK2798745 will be collected at the time 
points indicated in Section 7.1 Time and Events Table.
Approximately 2 mL of blood will be collected in 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 

2014N221874_02
CONFIDENTIAL
201881
164
adequate PK monitoring of GSK2798745 and, if possible, any relevant GSK2798745 
metabolites. 
Where possible, PK monitoring of relevant co-administered drugs and their metabolites 
may also be undertaken (e.g. atorvastatin and/orsimvastatin).  Approximately 2 mL of 
blood will be collected into sodium heparin tubes.  The actual date and time of each 
blood sample collection will be recorded.  The volume of such samples may be altered 
and additional time points may be added to ensure adequate statin PK monitoring.
Additional collection, processing, storage and shipping procedures are provided in the 
Study Reference Manual (SRM).
REVISED TEXT
7.5.1.
Blood Sample Collection
Blood samples for pharmacokinetic analysis of GSK2798745 will be collected at the time 
points indicated in Section 7.1Time and Events Table.
Approximately 2 mL of blood will be collected in 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. 
Where possible, PK monitoring of relevant co-administered drugs and their metabolites 
maywill also be undertaken (e.g.atorvastatin and/orsimvastatin).  Approximately 2 mL 
of blood will be collected into sodium heparin tubes.  The actual date and time of each 
blood sample collection will be recorded.  The volume of such samples may be altered 
and additional time points may be added to ensure adequate statin PK monitoring.
Additional collection, processing, storage and shipping procedures are provided in the 
Study Reference Manual (SRM).
PREVIOUS TEXT
7.5.2.
Sample Analysis
Plasma analysis will be performed under the control of Platform Technologies and 
Science-Drug Metabolism and Pharmacokinetics (PTS-DMPK)/ GlaxoSmithKline, the 
details of which will be included in theStudy Reference Manual (SRM).Concentrations 
of GSK2798745, and co-administered statins and corresponding metabolites(e.g., 
atorvastatin and metabolites, or simvastatin and metabolites) will be determined in 
plasma samples 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 metabolite M1 dependent upon the availability of an 
assay.  Until this time, GSK will store the remaining plasma from the PK plasma samples 
for future possible metabolite analysis.  

2014N221874_02
CONFIDENTIAL
201881
165
REVISED TEXT
7.5.2.
Sample Analysis
Plasma analysis will be performed under the control of Platform Technologies and 
Science-Drug Metabolism and Pharmacokinetics (PTS-DMPK)/ GlaxoSmithKline,the 
details of which will be included in the Study Reference Manual (SRM).Concentrations 
of GSK2798745, and co-administered statins and corresponding metabolites (e.g.,
atorvastatin and metabolites, orandsimvastatin and metabolites)will be determined in 
plasma samples 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 metabolite M1 dependent upon the availability of an 
assay.  Until this time, GSK will store the remaining plasma from the PK plasma samples 
for future possible metabolite analysis.  
PREVIOUS TEXT
9.3.1 Analysis Populations
All Subjects Population
The ‘All Subjects Population’ is defined as all randomized subjects who receive at least 
one dose of study medication.  
Per Protocol Population
The ‘Per Protocol Population’ is defined as subjects in the ‘All Subjects’ population 
having baseline and post-baseline assessments of the endpoint of interest for both 
periods.
REVISED TEXT
9.3.1.Analysis Populations
All Subjects Population
The ‘All Subjects Population’ is defined as all randomized subjects who receive at least 
one dose of study medication.  
Per Protocol Population
The ‘Per Protocol Population’ is defined as subjects in the ‘All Subjects’ population 
having baseline and post-baseline assessments of the endpoint of interest for both 
periods.  The ‘Per Protocol Population’ will consist of any Analysis Population 
subjects who are compliant with protocol-specific criteria. Subjects with specified 
protocol deviations will be excluded.

2014N221874_02
CONFIDENTIAL
201881
166
PREVIOUS TEXT
9.4.1.
Primary Analyses
Profiles for DLco will be summarized and presented graphically by treatment group as 
appropriate for the data.The change from baseline in DLco at Day 4, Day 6 and Day 7 
will be calculated and summarized in tabular format and/or graphically by treatment.For 
the change from baseline in DLco, a statistical analysis will be performed using a mixed 
effect model with repeated measures with a fixed effect term for treatment, period and 
day,with a random effect forsubject,day in the repeated statement with subject being 
subject by period, and baseline as a covariate, if data permit.Point estimates and 
associated 95% confidence intervals will be constructed forthe differences between the 
active treatment and placebo.
Full details of analysis will be specified in the RAP.
REVISED TEXT
9.4.1.
Primary Analyses
Profiles for DLco will be summarized and presented graphically by treatment group as 
appropriate for the data.The change from baseline in DLco at Day 4, Day 6 5and Day 7 
will be calculated and summarized in tabular format and/or graphically by treatment.For 
the change from baseline in DLco, a statistical analysis will be performed using a mixed 
effect model with repeated measures with a fixed effect term for treatment, period and 
day,with a random effect forsubject,day in the repeated statement with subject being 
subject by period, and baseline as a covariate, if data permit.Point estimates and 
associated 95% confidence intervals will be constructed for the differences between the 
active treatment and placebo.
Full details of analysis will be specified in the RAP.
PREVIOUS TEXT
9.4.2.
Secondary Analyses
For other diffusing capacitypharmacodynamic(PD) endpoints such as DLno, D
M and 
Vc, similar analyses as in Section 9.4.1will be provided, as data permit.  For these PD 
endpoints, which may be log
etransformed prior to analysis to satisfy model assumptions, 
point estimates and their associated 95% confidence intervals will be back-transformed to 
provide point estimates and 95% confidence intervals for the ratios.
For pulmonary function measurement endpoints such as FVC, FEV1, FEF25-75FEF50, and 
FEF75, FRC and EELV, similar analysis as in Section 9.4.1will be provided, as data 
permit.  For these PD endpoints, which may be log
etransformed prior to analysis to 
satisfy model assumptions, point estimates and their associated 95% confidence intervals 
will be back-transformed to provide point estimates and 95% confidence intervals for the 
ratios.
For respiratory rate measurement and dyspnea score,similar analysis as in Section 9.4.1
will be provided, as data permit.  

2014N221874_02
CONFIDENTIAL
201881
167
In terms of DLco and DLno changes from baseline after saline challenge on Day 6and 
after exercise on Day 7, the change from baseline for the challenge (after-before) will be 
calculated and summarized in tabular format by treatment.  Astatistical analysis will be 
performed using a mixed effect model with a fixed effect term for treatment, period and 
sequence, random effect term for subject-within-sequence, and baseline as a covariate, if 
data permit.  Point estimates and associated 95% confidence intervals will be constructed 
for the differences between the active treatment and placebo.  
Interms of ventilatory efficiency, scatter plots for Ve/VCO2 at Baseline and Day 7 will 
be performed and the slope or correlation of Ve/VO2 provided.  Summary statistics for 
Ve and VCO2 and change from baseline measurement will be provided. 
Details on the analysis of other endpoints will be provided in RAP.
Pharmacokinetic analyses will be the responsibility of the Clinical Pharmacology 
Modeling & Simulation Department within GlaxoSmithKline.  Plasma GSK2798745 
concentration-time data will be analyzed by non-compartmental methods with the latest 
available version of WinNonlin software.  Calculations will be based on the actual 
sampling times recorded during the study.  From the plasma concentration-time data, the 
pharmacokinetic parameters such as Cmax and AUC may be determined, as data permit.
The details of the PK analysis will be listed in the RAP.
REVISED TEXT
9.4.2.
Secondary Analyses
For other diffusing capacitypharmacodynamic (PD) endpoints such as DLno, DM and 
Vc, similar analyses as in Section 9.4.1will be provided, as data permit.  For these PD 
endpoints, which may be log
etransformed prior to analysis to satisfy model assumptions, 
point estimates and their associated 95% confidence intervals will be back-transformed to 
provide point estimates and 95% confidence intervals for the ratios.
For pulmonary function measurement endpoints such as FVC, FEV1, FEF25-75FEF50, and 
FEF75, FRC and EELV, similar analysis as in Section 9.4.1will be provided, as data 
permit.  For these PD endpoints, which may be log
etransformed prior to analysis to 
satisfy model assumptions, point estimates and their associated 95% confidence intervals 
will be back-transformed to provide point estimates and 95% confidence intervals for the 
ratios.
For respiratory rate measurement and dyspnea score,similar analysis as in Section 9.4.1 
will be provided, as data permit.  
In terms of DLco and DLno changes from baseline after saline challenge on Day 65and 
after exercise on Day 7, the change from baseline for the challenge (after-before) will be 
calculated and summarized in tabular format by treatment.  Astatistical analysis will be 
performed using a mixed effect model with a fixed effect term for treatment, period and 
sequence, random effect term for subject-within-sequence, and baseline as a covariate, if 

2014N221874_02
CONFIDENTIAL
201881
168
data permit.  Point estimates and associated 95% confidence intervals will be constructed 
for the differences between the active treatment and placebo.  
In terms of ventilatory efficiency, scatter plots for Ve/VCO2 at Baseline and Day 7 will 
be performed and the slope or correlation of Ve/VO2 provided.  Summary statistics for 
Ve and VCO2 and change from baseline measurement will be provided. 
Details on the analysis of other endpoints will be provided in RAP.
Pharmacokinetic analyses will be the responsibility of the Clinical Pharmacology 
Modeling & Simulation Department within GlaxoSmithKline.  Plasma GSK2798745 
concentration-time data will be analyzed by non-compartmental methods with the latest 
available version of WinNonlin software.  Calculations will be based on the actual 
sampling times recorded during the study.  From the plasma concentration-time data, the 
pharmacokinetic parameters such as Cmax and AUC may be determined, as data permit.
The details of the PK analysis will be listed in the RAP.
PREVIOUS TEXT
9.4.4.
Exploratory Analyses
Pharmacokinetic analyses will be the responsibility of the Clinical Pharmacokinetics 
Modeling & Simulation Department within GlaxoSmithKline.  Calculations will be based 
on the actual sampling times recorded during the study.  The systemic concentrations of 
any HMG-CoA reductase inhibitors(e.g., simvastatin, atorvastatin) and their metabolites 
will be summarized, as data permit.  The details of the PK analysis will be listed in the 
RAP.
Data from the polysomnography sub-study will be presented in tablular and/or graphical 
format and summarized descriptively.
REVISED TEXT
9.4.4.
Exploratory Analyses
Pharmacokinetic analyses for the statins and any statin metabolites will be the 
responsibility of the Clinical Pharmacokinetics Modeling & Simulation Department 
within GlaxoSmithKline.  Calculations will be based on the actual sampling times 
recorded during the study.  The systemic concentrations of any HMG-CoA reductase 
inhibitors(e.g., simvastatin, atorvastatin) and their metabolites will be summarized, as 
data permit.  The details of the PK analysis will be listed in the RAP.
Data from the polysomnography sub-study will be presented in tablular and/or graphical 
format and summarized descriptively.

2014N221874_02
CONFIDENTIAL
201881
169
PREVIOUS TEXT
Appendix 1:  Abbreviations and Trademarks
Abbreviations
ADHF
Acute decompensated heart failure
AE
Adverse Event
AHI
Apnea-hypopnea index
ALT
Alanine transaminase
AST
Aspartate aminotransferase
AUC
Area under the curve
BMI
Body mass index
Ca2+
Calcium
C-CASA
Columbia Classification Algorithm for Suicide Assessment
CHF
Chronic heart failure
CI
Confidence intervals
Cmax
Maximum concentration
CMT2C
Charcot-Marie-Tooth disease Type 2C 
CNS
Central nervous system
CO2
Carbon dioxide
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic obstructive pulmonary disease
CPK
Creatine phosphokinase
CRF
Case report form
CRU
Clinical research unit
CSA
Central sleep apnea
CSR
Cheyne-Strokes respiration
C-SSRS
Columbia Suicide Severity Rating Scale
cTn
Troponin (cardiac)
CTX
Collagen Type I Telopeptide
CV
Cardiovacsular
CYP
Cytochrome P450 enzyme
DLco
Diffusing capacity of the lung for carbon monoxide
DLno
Diffusing capacity of the lung for nitric oxide
DM
Alveolar-caplillary membrane conductance
DMPK
Drug Metabolism and Pharmacokinetics
DNA
Deoxyribonucleic acid
DPD
Deoxypyridinoline
E
Epinephrine
ECG
Electrocardiogram
EEG
Electroencephalography
EELV
End expiratory lung volume
EMG
Electromyogram
EOG
Electrooculogram
ER
Emergency Room
FDA
Food and Drug Administration

2014N221874_02
CONFIDENTIAL
201881
170
FEF
Forced expiratory flows
FEV1
Forced expiratory volume in 1 second
FOBT
Fecal Occult Blood Test
FRC
Forced residual capacity
FSH
Follicle stimulating hormone
FVC
Forced vital capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilence
GSK
GlaxoSmithKline
HBcAb
Hepatitis B core antibody
HbsAg
Hepatitis B surface antigen
HEK
Human embryonic kidney cells
HF
Heart failure
HR
Heart rate
HRT
Hormone Replacement Therapy
IDSL
Integrated Data Standards Library
IEC
Independent ethics committee
IgM
Immunoglobulin
INR
International normalized ratio
IP
Investigational Product
IRB
Institutional review board
IVRS
Interactive voice response system
Kg
Kilogram
KO
Knockout
LDH
Lactate dehydrogenase
LFT
Liver function tests
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mL
Milliliter
MSDS
Material Safety Data Sheet
Na
Sodium
NaCl
Sodium chloride
NE
Norepinephrine
nM
Nanomolar
NO
Nitric oxide
NOAEL
No observed adverse event level 
NYHA
New York Heart Association
O2
Oxygen
OSA
Obstructive sleep apnea
P1NP
Procollagen type 1 amino-terminal propeptide
PD
Pharmacodynamic
PFT
Pulmonary function tests
P-gp
P-glycoprotein
PGx
Pharmacogenomics
PK
Pharmacokinetics
PTH
Parathyroid hormone

2014N221874_02
CONFIDENTIAL
201881
171
PTS-DMPK
Platform Technologies and Sciences-Drug Metabolism and 
Pharmacokinetics
QTc
QT interval corrected
QTcB
QT interval corrected according to Bazett’s formula
QTcF
QT interval corrected accordingto Fridericia’s formular
RAP
Reporting and analysis plan
RER
Respiratory exchange ratio 
RPE
Rating of perceived exertion
SAE
Serious Adverse Event
SDw
Within-subject variability
SOP
Standard Operating Procedure
SRM
Study reference manual
t½
Half-life 
tmax
Time to maximum observed plasma concentration
TRPV4
Transient receptor potential vanilloid 4
µg
Micrograms
ULN
Upper limit of normal
VCO2
Volume of carbon dioxide production
Vc
Capillary blood volume
VE
Ventilation
VO2
Volume of oxygen
WBC
White blood cells
REVISED TEXT
Appendix 1:  Abbreviations and Trademarks
Abbreviations
ADHF
Acute decompensated heart failure
AE
Adverse Event
AHI
Apnea-hypopnea index
ALT
Alanine transaminase
AST
Aspartate aminotransferase
AUC
Area under the curve
BMI
Body mass index
Ca2+
Calcium
C-CASA
Columbia Classification Algorithm for Suicide Assessment
CHF
Chronic heart failure
CI
Confidence intervals
Cmax
Maximum concentration
CMT2C
Charcot-Marie-Tooth disease Type 2C 
CNS
Central nervous system
CO2
Carbon dioxide
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic obstructive pulmonary disease

2014N221874_02
CONFIDENTIAL
201881
172
CPK
Creatine phosphokinase
CRF
Case report form
CRU
Clinical research unit
CSA
Central sleep apnea
CSR
Cheyne-Strokes respiration
C-SSRS
Columbia Suicide Severity Rating Scale
cTn
Troponin (cardiac)
CTX
Collagen Type I Telopeptide
CV
Cardiovacsular
CYP
Cytochrome P450 enzyme
DLco
Diffusing capacity of the lung for carbon monoxide
DLno
Diffusing capacity of the lung for nitric oxide
DM
Alveolar-caplillary membrane conductance
DMPK
Drug Metabolism and Pharmacokinetics
DNA
Deoxyribonucleic acid
DPD
Deoxypyridinoline
E
Epinephrine
ECG
Electrocardiogram
EEG
Electroencephalography
EELV
End expiratory lung volume
EMG
Electromyogram
EOG
Electrooculogram
ER
Emergency Room
FDA
Food and Drug Administration
FEF
Forced expiratory flows
FEV1
Forced expiratory volume in 1 second
FOBT
Fecal Occult Blood Test
FRC
Forced residual capacity
FSH
Follicle stimulating hormone
FVC
Forced vital capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilence
GSK
GlaxoSmithKline
HBcAb
Hepatitis B core antibody
HbsAg
Hepatitis B surface antigen
HEK
Human embryonic kidney cells
HF
Heart failure
HR
Heart rate
HRT
Hormone Replacement Therapy
IDSL
Integrated Data Standards Library
IEC
Independent ethics committee
IgM
Immunoglobulin
INR
International normalized ratio
IP
Investigational Product
IRB
Institutional review board
IVWRS
Interactive voicewebresponse system

2014N221874_02
CONFIDENTIAL
201881
173
Kg
Kilogram
KO
Knockout
LDH
Lactate dehydrogenase
LFT
Liver function tests
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mL
Milliliter
MSDS
Material Safety Data Sheet
Na
Sodium
NaCl
Sodium chloride
NE
Norepinephrine
nM
Nanomolar
NO
Nitric oxide
NOAEL
No observed adverse event level 
NYHA
New York Heart Association
O2
Oxygen
OSA
Obstructive sleep apnea
P1NP
Procollagen type 1 amino-terminal propeptide
PD
Pharmacodynamic
PFT
Pulmonary function tests
P-gp
P-glycoprotein
PGx
Pharmacogenomics
PK
Pharmacokinetics
PTH
Parathyroid hormone
PTS-DMPK
Platform Technologies and Sciences-Drug Metabolism and 
Pharmacokinetics
QTc
QT interval corrected
QTcB
QT interval corrected according to Bazett’s formula
QTcF
QT interval corrected according to Fridericia’s formular
RAP
Reporting and analysis plan
RER
Respiratory exchange ratio 
RPE
Rating of perceived exertion
SAE
Serious Adverse Event
SDw
Within-subject variability
SOP
Standard Operating Procedure
SRM
Study reference manual
t½
Half-life 
tmax
Time to maximum observed plasma concentration
TRPV4
Transient receptor potential vanilloid 4
µg
Micrograms
ULN
Upper limit of normal
VCO2
Volume of carbon dioxide production
Vc
Capillary blood volume
VE
Ventilation
VO2
Volume of oxygen
WBC
White blood cells

2014N221874_02
CONFIDENTIAL
201881
174
PREVIOUS TEXT
Appendix 9: Intravenous Saline Infusion
Rapid intravenous saline infusion has been employed to elicit fluid extravasation from the 
vasculature to the pulmonary interstitium.  This methodology has been previously utilized 
in studies with healthy volunteers [Synder, 2006] and patients with heart failure 
[Fujimoto, 2013;Robbins, 2014;Andersen, 2015].
Subject Evaluation Prior to Infusion
On Day 5 of both study periods, the subject will be admitted to the clinical research unit 
(CRU) and undergo routine weight measurement and vital sign assessments including 
temperature, systolic and diastolic blood pressures, heart rate, respiratory rate, and pulse 
oximetry to assess O
2saturation.  The subject will also undergo a pulmonary 
examination.  
While in a sitting position, a dyspnea assessment, utilizing a standardized 5-point Likert 
scale, will be obtained to document the subject’s current status.  A subject, who is not 
severely or very severely short of breath, will undergo an orthopnea test (placed supine 
with head ≤ 20 degrees relative to horizontal).  After an equilibration period of 2 minutes, 
the 5-point scale will be repeated.  A subject who reports a worse dyspnea score when 
supine compared to sitting will be categorized as having orthopnea.  Subjects categorized 
with having orthopnea will not be eligible to participate in the saline infusion. 
Study treatment will be administered after all planned pre-dose assessments for Day 5 are 
completed.  
Saline Infusion Procedure
A subject, who is judged by the Investigator to be in a stable condition and without 
obvious congestion, will then undergo the intravenous saline infusion procedure.  This 
procedure will be conducted in the clinical research unit, which is adjacent to the 
catheterization laboratory, in the presence of a cardiologist and monitoring personnel.  A 
crash cart will be accessible, and intravenous diuretic will be available, if necessary.  
An 18-gauge venous catheter will be inserted into a prominent antecubital vein while the 
subject is semi-recumbent (approximately 45°).  The subject will remain in a semi-
recumbent position throughout the procedure.
DLco and DLno measurements and simple spirometry assessments will be obtained prior
to the initiation of the infusion.
Prewarmed 0.9% normal saline will be infused intravenously at a rate of 150 mL/min to a 
total volume of 500 mL.  During the saline infusion, blood pressure, heart rate, 
respiratory rate, and O
2saturation, will be continuously monitored, and any physical 
symptoms recorded.  

2014N221874_02
CONFIDENTIAL
201881
175
DLco and DLno measurements and spirometry assessments will be obtained after the 
completion of the infusion.
Post-infusion Monitoring
Following the completion of the saline infusion procedure, the subject will remain in the 
clinical research unit for the next 4 hours.  Blood pressure, heart rate, respiratory rate, and 
O2saturation, will be continuously monitored, and any physical symptoms recorded.  The 
subject will also be assessed for dyspnea and orthopnea, as described above, at hourly 
intervals.
After the 4-hour period, the subject will be eligible to leave the CRU if heart rate and 
respiratory rate are within 20% of the baseline value, O
2saturation is within 2% of the 
baseline value, and if the dyspnea score is the same as the baseline score.  
The subject will continue to be monitored by the Preventice BodyGuardian Remote 
Monitoring System as described in Section 7.4.7of the protocol; ECG, heart rate, 
respiratory rate and activity level will be measured continuously.  
Any worsening of heart failure that requires treatment in the 48 hours subsequent to the 
saline infusion will be reported as a serious adverse event.
Individual Stopping Criteria During the Saline Infusion Procedure
If the subject demonstrates oneof the following changes during the saline infusion, the 
infusion should be discontinued:
Decrease in O2 saturation of >4% compared to baseline 
Increase in respiratory rate of >20% compared to baseline
Any increase in dyspnea perceived bythe patient 
If the subject has met one of these criteria during or immediately after the infusion, the 
subject should be carefully monitored and given intravenous diuretic treatment, 
intravenous or sublingual nitrates, or other treatment as required.  
The subject may continue in the study.  However, if this response occurred in the first 
study period, the subject should not undergo a second saline infusion in the subsequent 
study period.
Discontinuation of Saline Infusion Procedure
If during the conduct of the study, twosubjects meet the individual stopping criteria 
during the infusion or demonstrate a worsening of heart failure in the 48 hours after 
completion of the infusion, this challenge procedure will be removed from the study 
design.  No other subjects will undergo this assessment. 

2014N221874_02
CONFIDENTIAL
201881
176
Reporting of Adverse Outcomes Associated with the Saline Infusion
Any of the following outcomes must be reported to the sponsor as a serious adverse 
event:
Treatment with intravenous diuretic subsequent to the saline infusion
Need for continued monitoring in the CRU beyond the 4-hour mandated 
observation period 
Any worsening of heart failure that requires treatment during the 48-hour 
monitoring period after the saline infusion procedure
These events will be reported by the investigator as serious adverse events in the InForm 
electronic data collection tool.  They will be reported by the sponsor to the FDA as an 
Expedited Report via electronic submission in eCTD format to the IND, as a 7-day or 15-
day IND safety report,as applicable per timeframe specified in 21 CFR 312.32(c)(1).  
The completed report will also be provided to the IRB.
REVISED TEXT
Appendix 9: Intravenous Saline Infusion
Rapid intravenous saline infusion has been employed to elicit fluid extravasation from the 
vasculature to the pulmonary interstitium.  This methodology has been previously utilized 
in studies with healthy volunteers [Synder, 2006] and patients with heart failure 
[Fujimoto, 2013;Robbins, 2014;Anderson, 2015].
Subject Evaluation Prior to Infusion
On Day 5 of both study periods, the subject will be admitted to the clinical researchunit 
(CRU)and undergo routine weight measurement and vital sign assessments including 
temperature, systolic and diastolic blood pressures, heart rate, respiratory rate, and pulse 
oximetry to assess O
2saturation.  The subject will also undergo a pulmonary 
examination.  
While in a sitting position, a dyspnea assessment, utilizing a standardized 5-point Likert 
scale, will be obtained to document the subject’s current status.  A subject,who is not 
severely or very severely short of breath,will undergo an orthopnea test (placed supine 
with head ≤ 20 degrees relative to horizontal).  After an equilibration period of 2 minutes, 
the 5-point scale will be repeated.  A subject who reports a worse dyspnea score when 
supine compared to sitting will be categorized as having orthopnea.  Subjects categorized 
withashaving orthopnea will not be eligible to participate in the saline infusion. 
Study treatment will be administered after all planned pre-dose assessments for Day 5 are 
completed.  
SalineInfusion Procedure
A subject,who is judged by the Investigator to be in a stable condition and without 
obvious congestion,will then undergo the intravenous saline infusion procedure.  This 

2014N221874_02
CONFIDENTIAL
201881
177
procedure will be conducted in the clinical researchunit, whichis adjacent to the 
catheterization laboratory, in the presence of a cardiologist and monitoring personnel.  
A crash cart will be accessible, and intravenous diuretic will be available, if necessary.  
An 18-gauge venous catheter will be inserted into a prominent antecubital veinwhile 
the subject is semi-recumbent (approximately 45°).  The subject will remain in a semi-
recumbent position throughout the procedure.
DLco and DLno measurements and simple spirometry assessments will be obtained prior 
to the initiation of the infusion.  
Prewarmed0.9% normal saline will be infused intravenously at a rate of approximately
150 mL/min to a total volume of 500 mL.  During the saline infusion, blood pressure, 
heart rate, respiratory rate, and O
2saturation,will be continuously monitored, and any 
physical symptoms recorded.  
DLco and DLno measurements and spirometry assessments will be obtained after the 
completion of the infusion.  Additional details are provided in the SRM.
Post-infusion Monitoring
Following the completion of the saline infusion procedure, the subject will remain in the 
clinical researchunit for the next 4 hours.  Blood pressure, heart rate, respiratory rate, 
and O
2saturation,will be continuously monitored, and any physical symptoms recorded.  
The subject will also be assessed for dyspnea and orthopnea, as described above, at 
hourly intervals.
After the 4-hour period, the subject will be eligible to leave the CRUunitif heart rate 
and respiratory rate are within 20% of the baseline value, O
2saturation is within 2% of 
the baseline value, and if the dyspnea score is the same as the baseline score.  
The subject will continue to be monitored by the Preventice BodyGuardian Remote 
Monitoring System as described in Section 7.4.7of the protocol; ECG, heart rate, 
respiratory rate and activity level will be measured continuously.  
Any worsening of heart failure that requires treatment in the 48 hours subsequent to the 
saline infusion will be reported as a serious adverse event.
Individual Stopping Criteria During the Saline Infusion Procedure
If the subject demonstrates oneof the following changes during the saline infusion, the 
infusion should be discontinued:
Decrease in O2 saturation of >4% compared to baseline 
Increase in respiratory rate of >20% compared to baseline
Any increase in dyspnea perceived by the patient 

2014N221874_02
CONFIDENTIAL
201881
178
If the subject has met one of these criteria during or immediately after the infusion, the 
subject should be carefully monitored and given intravenous diuretic treatment, 
intravenous or sublingual nitrates, or other treatment as required.  
The subject may continue in the study.  However, if this response occurred in the first 
study period, the subject should not undergo a second saline infusion in the subsequent 
study period.
Discontinuation of Saline Infusion Procedure
If during the conduct of the study, twosubjects meet the individual stopping criteria 
during the infusion or demonstrate a worsening of heart failure in the 48 hours after 
completion of the infusion, this challenge procedure will be removed from the study 
design.  No other subjects will undergo this assessment. 
Reporting of Adverse Outcomes Associated with the Saline Infusion
Any of the following outcomes must be reported to the sponsor as a serious adverse 
event:
Treatment with intravenous diuretic subsequent to the saline infusion
Need for continued monitoring in the CRUunitbeyond the 4-hour mandated 
observation period 
Any worsening of heart failure that requires treatment during the 48-hour 
monitoring period after thesaline infusion procedure
These events will be reported by the investigator as serious adverse events in the InForm 
electronic data collection tool.  They will be reported by the sponsor to the FDA as an 
Expedited Report via electronic submission in eCTD format to the IND, as a 7-day or 15-
day IND safety report, as applicable per timeframe specified in 21 CFR 312.32(c)(1).  
The completed report will also be provided to the IRB.

2014N221874_02
CONFIDENTIAL
201881
179
12.11.
Appendix 11: Country Specific Requirements
No country-specific requirements exist.