An Evaluation of DCE-MRI Measures of Pulmonary Oedema and Vascular Permeability in Healthy Subjects and in Patients With Cardiac Failure: A Methods Validation Study for Evaluation of Novel Treatments Limiting Pulmonary Oedema in Cardiac Failure
Phase: PHASE1
Conditions: Heart Failure, Congestive
Sponsor: GlaxoSmithKline

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The GlaxoSmithKline group of companies
201137
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
An evaluation of DCE-MRI measures of pulmonary oedema and 
vascular permeability in healthy subjects and in patients with 
cardiac failure:  A methods validation study for evaluation of 
novel treatments limiting pulmonary oedema in cardiac failure
Compound Number:
GSK2798745
Development Phase:
I
Effective Date:
08-APR-2016
Protocol Amendment Number:  3
Author (s):
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD

2013N186309_03
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Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2013N186309_00
2014-FEB-04
Original
2013N186309_01
2014-APR-24
Amendment No.: 01
This protocol amendment clarifies the exercise protocol to be conducted, details measures 
for endpoints, defines the biomarker to be measured (NT-pro BNP), reduces total blood 
volume to be collected, updates study schematic, adds an interim review of the data, 
removes collection of AEs as there is no IP included in the study, alters physical exams to 
brief physical exams, and adds a dyspnea scale and the Borg Rating of Perceived 
Exertion.
2013N186309_02
2015-FEB-16
Amendment No.: 02
This protocol amendment changes modifies inclusion criteria, clarifies the exercise 
protocol, and corrects the footnote numbering in the time and events table.
2013N186309_03
2016-APR-08
Amendment No. 3
Amendment No. 3 adds an evaluation of an additional group of subjects who have been 
hospitalized for acute decompensated heart failure to determine whether DCE-MRI can 
detect changes in measures of pulmonary oedema with standard of care treatment. 

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SPONSOR/MEDICAL MONITOR INFORMATION PAGE
Medical Monitor and Sponsor Contact Information:
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
GSK Address
Primary 
Medical 
Monitor
 MD
GlaxoSmithKline
709 Swedeland Road, King 
of Prussia, PA 19406 USA
Secondary 
Medical 
Monitor
 MD
GlaxoSmithKline
709 Swedeland Road, King 
of Prussia, PA 19406 USA
Tertiary 
Medical 
Monitor
 MD
GlaxoSmithKline
709 Swedeland Road, King 
of Prussia, PA 19406 USA
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
PPD
PPD
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 201137
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date

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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS.............................................................................................9
1.
INTRODUCTION....................................................................................................11
1.1.
Study Rationale ..........................................................................................11
1.2.
Brief Background ........................................................................................12
2.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................12
3.
STUDY DESIGN ....................................................................................................14
3.1.
Study Schematic.........................................................................................14
3.2.
Study Design Detail ....................................................................................14
3.3.
Risk Management.......................................................................................15
4.
STUDY POPULATION...........................................................................................17
4.1.
Number of Subjects ....................................................................................17
4.2.
Eligibility Criteria .........................................................................................18
4.2.1.
Inclusion Criteria..........................................................................18
4.2.1.1.
Inclusion Criteria for Heart Failure Group 
(Group 2)....................................................................18
4.2.1.2.
Inclusion Criteria for Healthy Volunteer Group 
(Group 1)....................................................................18
4.2.1.3.
Inclusion Criteria for Both the Healthy 
Volunteer and Heart Failure Groups (Group 1 
and 2).........................................................................18
4.2.1.4.
Inclusion Criteria for Subjects with ADHF 
(Group 3)....................................................................18
4.2.2.
Exclusion Criteria.........................................................................19
4.2.2.1.
Exclusion Criteria for Heart Failure Group 
(Group 2)....................................................................19
4.2.2.2.
Exclusion Criteria for Both the Healthy 
Volunteer and Heart Failure Groups (Group 1 
and 2).........................................................................19
4.2.2.3.
Exclusion Criteria for Subjects with ADHF 
(Group 3)....................................................................20
4.3.
Lifestyle and/or Dietary Restrictions............................................................21
4.3.1.
Contraception Requirements .......................................................21
4.3.1.1.
Female Subjects.........................................................21
4.3.1.2.
Male Subjects.............................................................21
4.3.2.
Exercise.......................................................................................21
4.3.3.
Caffeine and Alcohol (Groups 1 and 2)........................................21
4.4.
Withdrawal Criteria and Procedures............................................................21
4.5.
Subject Completion.....................................................................................22
5.
STUDY TREATMENT ............................................................................................22
5.1.
Concomitant Medications and Non-Drug Therapies....................................22
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................23
6.1.
Time and Events Tables .............................................................................24

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6.1.1.
Time and Event Table for Healthy Volunteers and 
Subjects with HF (Groups 1 and 2) ..............................................24
6.1.2.
Time and Event Table for Subjects with ADHF (Group 3) ............26
6.2.
Demographic/Medical History Assessments ...............................................28
6.3.
Safety .........................................................................................................28
6.3.1.
Brief Physical Examinations.........................................................28
6.3.2.
Vital Signs....................................................................................28
6.3.3.
Electrocardiogram (ECG).............................................................29
6.3.4.
Clinical Laboratory Assessments and Urinalysis..........................29
6.3.4.1.
Pregnancy Testing......................................................30
6.4.
N-terminal pro-Brain-type Natriuretic Peptide (NT-pro-BNP).......................30
6.5.
Dyspnoea Scale Scoring.............................................................................30
6.6.
Respiratory Rate.........................................................................................30
6.7.
Chest X-rays...............................................................................................31
6.8.
Lung Ultrasound .........................................................................................31
6.9.
Magnetic Resonance Imaging.....................................................................31
6.9.1.
Subject Scanning Procedures......................................................31
6.9.2.
Phantom Scanning ......................................................................31
6.9.3.
Data Transfer...............................................................................32
6.9.4.
DCE-MRI Data Analysis...............................................................32
6.10.
Exercise Test..............................................................................................32
6.11.
DLco and DLno...........................................................................................33
6.12.
Serious Adverse Events (SAEs) .................................................................33
6.12.1.
Time Period for Collecting SAE Information.................................33
6.12.2.
Definition of Adverse Events........................................................33
6.12.3.
Definition of Serious Adverse Events...........................................34
6.12.4.
Death Events...............................................................................35
6.12.5.
Prompt Reporting of SAEs to GSK...............................................36
6.12.6.
Regulatory Reporting Requirements for SAEs .............................36
6.13.
Pregnancy ..................................................................................................36
6.13.1.
Time Period for Collecting Pregnancy information .......................36
6.13.2.
Action to be Taken if Pregnancy Occurs ......................................36
7.
DATA MANAGEMENT ...........................................................................................37
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................37
8.1.
Hypotheses Comparisons...........................................................................37
8.2.
Sample Size Considerations.......................................................................37
8.3.
Data Analysis Considerations .....................................................................37
8.3.1.
Interim Analysis ...........................................................................38
8.3.2.
Final Analyses .............................................................................38
8.3.2.1.
Safety Analyses..........................................................38
9.
STUDY GOVERNANCE CONSIDERATIONS........................................................39
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............39
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................39
9.2.1.
Urgent Safety Measures ..............................................................39
9.3.
Quality Control (Study Monitoring) ..............................................................39
9.4.
Quality Assurance.......................................................................................40
9.5.
Study and Site Closure ...............................................................................40
9.6.
Records Retention......................................................................................40

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9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................41
10. REFERENCES.......................................................................................................42
11. APPENDICES........................................................................................................44
11.1.
Appendix 1: Procedures for Detection, Evaluation, Follow-Up and 
Reporting of SAEs ......................................................................................44
11.2.
Appendix 2: Dyspnoea Scale......................................................................46
11.3.
Appendix 3: Borg Rating of Perceived Exertion (RPE) Scale ......................47
11.4.
Appendix 4:  Protocol Amendment Changes...............................................48

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LIST OF ABBREVIATIONS
3D SPGR
3D Spoiled Gradient Echo
ADHF
Acute Decompensated Heart Failure
AE
Adverse Event
AIF
Arterial Input Function
ALT
Alanine Transaminase
AST
Aspartate Transaminase
BMI
Body Mass Index
BNP
B-Type Natriuretic Peptide
BP
CXR
Blood Pressure
Chest X-Ray
CHF
Chronic Heart Failure
DCE
Dynamic Contrast Enhanced
DLCO
Diffusing Capacity of the Lung for Carbon Monoxide
DLNO
Diffusing Capacity of the Lung for Nitrous Oxide
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eGFR
Estimated Glomerular Filtration Rate
FDA
Food and Drug Administration
FENa
Fractional excretion of sodium
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
Gd
Gadolinium
GSK
GlaxoSmithKline
HF
Heart Failure
HV
Healthy Volunteers
IB
Investigator Brochure
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IEC
Institutional Ethics Committee
IRB
Institutional Review Board
Kg
Kilogram
Ktrans
Exchange Rate
LSLV
LUS
Last Subject’s Last Visit
Lung Ultrasound
MD
Medical Doctor
MedDRA
Medical Dictionary for Regulatory Activities
mL
Milliliter
MRI
Magnetic Resonance Imaging
mSv
Milli-sievert
NHS
National Health Service
NO
Nitric Oxide
NSF/NFD
Nephrogenic Systemic Fibrosis/Nephrogenic Fibrosing 
Dermopathy
NT-proBNP
N-terminal of pro-Brain-type Natriuretic Peptide
NYHA
New York Heart Association

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PACS
Picture Archiving and Communication System 
PE
Pulmonary Oedema
PIMS
Phase I Information Management System
RBC
Red Blood Cells
RER
Respiratory Exchange Ratio
RPE
Rating of Perceived Exertion
RIS
Radiology Information System
SAE
Serious Adverse Event
SaO2
Saturation of Oxygen
SPM
Sv
Study Procedures Manual
Sievert
TE
Constant Echo Time
TR
Repetition Time
TRPV4
Transient Receptor Potential Vanilloid 4
UK
United Kingdom
ULN
Upper Limit of Normal
VCO2
Carbon Dioxide Production [Volume of Carbon Dioxide]
Ve
Interstitial Volume
VE
Ventilation
VO2
Oxygen Consumption [Volume of Oxygen]
Vp
Plasma Volume
WBC
White Blood Cells
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
The Borg CR10 scale

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1.
INTRODUCTION
1.1.
Study Rationale
In cardiogenic pulmonary oedema, increased venous pressure causes fluid extravasation 
from the vascular to the pulmonary interstitial and alveolar spaces.  Reduced exercise 
tolerance, orthopnoea and paroxysmal nocturnal dyspnoea are all thought to be associated 
symptoms related to interference with gas exchange or up-regulation of baroreceptors 
activating a centrally mediated response (Redfield, 2003).  The therapeutic arsenal is 
limited, and many patients are found refractory to current therapies.  This is a substantial 
clinical problem, waiting for a novel therapeutic option such as a transient receptor 
potential vanilloid 4 (TRPV4) channel blocker.
TRPV4 channels are expressed at the pulmonary alveolar septal barrier, limiting the 
movement of intravascular fluid into the interstitial and alveolar air spaces.  TRPV4 is 
activated by increases in pulmonary vascular pressure, resulting in endothelial cell 
contraction and breakdown of the septal barrier.  The breakdown of the barrier results in 
the development of pulmonary oedema.
TRPV4 channel blockade may be promising in the treatment of pulmonary oedema and 
dyspnoea in heart failure patients by re-establishing the alveolar septal barrier.  Although 
these drugs are effective in animal models, pharmacological studies in humans are likely 
to be restricted by difficulty in accurately quantifying pulmonary oedema.
There is interest in the potential role of magnetic resonance imaging (MRI) in quantifying 
pulmonary oedema.  MRI has demonstrated increased lung water content in people with 
heart failure (Chow, 2009); however quantification remains problematic, and it is not 
possible to distinguish between intravascular and extravascular water using existing 
techniques.
Dynamic contrast enhanced (DCE) MRI is an established technique for assessing changes 
in vascular permeability and interstitial water volume. DCE-MRI measures the exchange 
of an extracellular MRI contrast agent as it travels between the intravascular space and 
the interstitial space.  DCE-MRI enables quantification of the plasma volume (vp), 
interstitial volume (ve), and exchange rate (ktrans), a parameter strongly dependent on 
vascular permeability.  DCE-MRI is routinely used within oncology studies (O’Connor,
2007), and is used increasingly in other indications such as renal disease (Buckley, 2006)
and rheumatoid arthritis (Hodgson, 2007).  DCE-MRI has been used to detect alterations 
in vascular permeability and interstitial water volume in the lungs of smokers relative to 
healthy controls (Naish, 2008). However, DCE-MRI has not yet been used in the context 
of heart failure (HF).
The primary objective of this study is to characterize the capability of MRI to detect 
increased interstitial lung fluid or altered vascular permeability.  First, the DCE-MRI
markers of vascular permeability and pulmonary oedema will be measured in healthy 
volunteers (HV) and subjects with HF at rest to determine whether there is a difference 
between the two populations.  Next, exercise-induced changes (relative to rest) in
interstitial volume and exchange rate will be evaluated in both HV and subjects with HF.  

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In patients with chronic HF, an abnormal alveolar-vascular interface leading to increased 
fluid flux at high pulmonary arterial pressures, as well as a tendency toward greater 
exercise-induced pulmonary vascular pressure, increases the chance for excess fluid 
under these conditions compared to what may be observed in normal subjects.
The secondary outcome measure will be the intrasubject variability in DCE-MRI 
measures of pulmonary physiology, determined by a same-subject comparison of two 
imaging sessions.
To correlate the potential clinical significance of MRI findings, exploratory endpoints 
will include comparison of DCE-MRI measures with a dyspnoea scale validated in acute 
pulmonary oedema (Mebazaa, 2010), disease severity, and pulmonary function (e.g., 
diffusing capacity of the lung for carbon monoxide (DLCO)).
Additionally, the capability of DCE-MRI to detect changes in interstitial lung fluid in 
patients with acute decompensated heart failure (ADHF) will be investigated.  DCE-MRI 
markers of pulmonary oedema will be assessed when patients are initially hospitalized 
with ADHF and subsequently after receiving standard of care treatment to determine 
whether differences can be detected by this methodology.  Lung ultrasound (LUS) may 
also be explored in patients with ADHF as a potential tool for assessment of extra-
vascular lung water through measurement of B-lines.
1.2.
Brief Background
Specific TRPV4 channel blockers limit the development of pulmonary oedema in animal 
models.  Target validation and dose-ranging studies in humans are likely to be restricted 
by a lack of sensitive and specific endpoints.  MRI can provide quantitative measures of 
vascular permeability and pulmonary oedema.  The aim of this study is to establish the 
potential utility of MRI as a novel endpoint for future dose-ranging and proof-of-
mechanism studies with TRPV4 blockers.
2.
OBJECTIVE(S) AND ENDPOINT(S)
The objectives and endpoints for the study are summarised in the table below:
Objectives
Endpoints
Primary

Establish whether DCE-MRI can 
detect differences in measures of 
pulmonary oedema or vascular 
permeability between HF and HV 
groups.

Explore the effect of exercise on DCE-
MRI measures of pulmonary oedema 
and vascular permeability in HF and 
HV groups.

Interstitial volume (ve) and 
exchange rate (ktrans) measured
using DCE-MRI in HF patients 
and HVs at baseline.

Change in interstitial volume (ve) 
and exchange rate (ktrans) measured 
using DCE-MRI in HF patients 
and HVs before and following 
exercise.

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Objectives
Endpoints

Explore the effect of standard of care 
treatment on DCE-MRI measures of 
pulmonary oedema and vascular 
permeability in patients with ADHF.

Change in interstitial volume (ve) 
and exchange rate (ktrans) measured 
using DCE-MRI in patients with 
ADHF during hospitalization and 
following the resolution of 
pulmonary oedema.
Secondary

Estimate the intrasubject variability of 
DCE-MRI measures of pulmonary 
oedema and vascular permeability.

Estimation of the variability in 
the interstitial volume (ve) and
exchange rate (ktrans) between 2 
MRI visits approximately 1 
week apart.
Exploratory

Explore the relationship between 
DCE-MRI measures of pulmonary 
physiology and disease severity, 
symptoms, pulmonary function,  
volume status and renal function

Estimate differences in plasma volume 
and  MRI physical properties 
influenced by the tissue 
microenvironment relaxation rate, and 
proton density between HF and HV 
groups as measured using DCE-MRI

Explore the distribution of DCE-MRI 
measures of pulmonary physiology in 
HF and HV groups both before and 
after exercise

Explore the effect of standard of care 
treatment on plasma volume and MRI 
physical properties influenced by the 
tissue microenvironment relaxation 
rate, and proton density in patients 

Correlation of MRI measures with 
clinical and biochemical measures:
dyspnoea score, NYHA grade, 
respiratory rate, NT-proBNP , 
exercise capacity (including Borg 
RPE, heart rate, blood pressure, 
and gas exchange endpoints such 
as peak VO2, VE/VCO2 slope), 
DLCO, DLNO, body weight, urine 
specific gravity, fractional 
excretion of sodium (FENa), blood 
urea to creatinine ratio.

Plasma volume (vp), T1 relaxation 
rate, and proton density measured 
using MRI in HF patients and 
HVs.

Interstitial volume (ve) and 
exchange rate (ktrans), and other 
clinical and biochemical measures 
as listed above if data permit.

Change in Plasma volume (vp), T1
relaxation rate, and proton density 
measured using MRI in patients 
with ADHF during hospitalization 
and following the resolution of 

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Objectives
Endpoints
with ADHF.

Explore the effect of standard of care 
treatment on ultrasound measures of 
pulmonary oedema in patients with 
ADHF.

Explore the distribution of DCE-MRI 
measures of pulmonary physiology in 
ADHF patients both before and after 
standard of care treatment
pulmonary oedema

Change in B-lines measured using 
ultrasound in patients with ADHF 
during hospitalization and 
following the resolution of 
pulmonary oedema

Interstitial volume (ve) and 
exchange rate (ktrans), and other 
clinical and biochemical measures 
as listed above if data permit
3.
STUDY DESIGN
3.1.
Study Schematic
Protocol waivers or exemptions are not allowed. Therefore, adherence to the study 
design requirements, including those specified in the Time and Events Table, are 
essential. 
For healthy volunteers and subjects with HF (Groups 1 and 2, respectively), the study 
design schematic is shown below:
For subjects with ADHF (Group 3), the study design is shown below:
3.2.
Study Design Detail
For Groups 1 and 2, the study will consist of four sessions. The first visit will be a 
Screening Visit during which an appropriately trained study team member will describe 
the study, answer any questions the potential participant may have about the study seek 

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informed, written consent, and assess eligibility to enrol in the study.  Within 35 days, 
subjects will return for the first scanning session, where subjects will undergo the 
baseline procedure.  The second imaging session will occur approximately one week later 
to measure within-subject variability.  A third imaging session (which will be conducted 
in 2 visits) will incorporate a bicycle exercise challenge prior to the MRI scan, and this 
third scan will be performed approximately one to three days after the second imaging 
session.  
For subjects with ADHF (Group 3), Screening will occur during hospitalization to assess 
eligibility and enrolment in the study.  Session 1 will be conducted while the subject is 
still hospitalized with evidence of pulmonary oedema and receiving standard of care 
treatment.  Session 2 will be conducted within 4 weeks of the first scan, when the signs 
of pulmonary oedema are considered to be resolved as judged by the Investigator. If a 
subject’s pulmonary oedema has not resolved at Session 2, as judged by the Investigator 
using lung auscultation and/or chest x-ray, then the subject will be not be scanned by 
MRI at Session 2 and will be brought back for Session 3 up to 4 weeks after Session 2 for 
their second MRI. 
3.3.
Risk Management
Table 1
Summary of Key Issues, Their Impact and Strategy to Mitigate Risk
All inclusion criteria will be satisfied before patients undergo any procedures.
Potential risk
Summary of data
Impact- eligibility 
criteria
Strategy-monitoring/stopping 
criteria
Risk of 
exacerbation of 
dyspnoea in heart 
failure subjects 
when lying supine.
This is expected to be rapidly 
reversible on sitting upright, as the 
orthopnoea effect is dependent upon 
venous pressure
To minimize the 
risk, a trial of the 
supine position 
will be performed 
during the 
screening visit.
All procedures will be medically 
supervised. There is continuous 
monitoring of peripheral oxygen 
saturations and heart rate in the 
scanner control room, as well as 
direct vision down the magnet bore 
from the control room. The subject 
has a squeeze-bulb call bell to 
interrupt scanning. MRI 
compatible trolleys, wheel chairs 
and oxygen cylinders allow for 
removal from the scanner room 
into the foyer of the scanning suite 
where a full resuscitation trolley is 
available. All scanning staff 
members are trained in the 
emergency removal of subjects 
from the scanners.
In the event of significant 
dyspnoea, treatments available in 
the study area will include sitting 
upright and oxygen if required. If 
further therapies are required, best 
practice clinical management 
including transfer to hospital for 
further management will be 

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Potential risk
Summary of data
Impact- eligibility 
criteria
Strategy-monitoring/stopping 
criteria
undertaken.
Use of Gd in 
subjects with 
abnormal renal 
function may result 
in Nephrogenic 
Systemic 
Fibrosis/Nephroge
nic Fibrosing 
Dermopathy 
(NSF/NFD).
Gadobutrol (Gd) (Gadovist; Bayer) at 
a dose less than or equal to
0.1mmol/kg will be used in the MRI 
protocol. It is excreted in the urine 
with approximately 50% and 90% of 
the dose excreted by 2 and 12 hours, 
respectively, post-injection. 
Approximately 200 million patients 
have had contrast enhanced Gd MRI 
examinations since such scans were 
first introduced 20 years ago 
[Thomsen, 2006]. The contrast 
agents are widely used off label for 
MRI angiography and cardiac MRI 
due to their low side effect profile and 
low risk of nephrotoxicity.  From June 
2006 to 12 April 2007, more than 215 
individuals with NSF/NFD had been 
reported to the FDA [Cowper, 
ICNSFR Website, 2007].  All these 
individuals were exposed to Gd prior 
to developing NSF and all had 
moderate to end-stage renal disease 
prior to exposure to Gd: 
approximately 90% of the cases were 
dialysis dependent whilst the 
remaining 10% of subjects had 
chronic kidney disease or acute 
kidney injury [Perazella, 2007].  The 
incidence of NSF in dialysis and end-
stage renal disease patients when 
exposed to Gd is in the range 3-5% 
[Marckmann, 2006; Kuo, 2008;
However, there are no reports of NSF 
in subjects with normal renal function 
[Perazella, 2007; Deo, 2007; 
Chewning, 2007; Thomsen, 2006].  It 
is concluded that subjects dependent 
on dialysis and those with estimated 
glomerular filtration rate (eGFR) 
<30mL/min (chronic kidney disease 
stage 4/5) are at risk of developing 
NSF on exposure to Gd [Perazella, 
2007].
As a result of this 
recent evidence, 
subjects with 
creatinine 
clearance levels < 
60mL/min will be 
excluded from this 
study (Groups 1 
and 2) and < 
40mL/min in 
Group 3.
Gd contains unpaired electrons 
that interact with neighbouring 
water molecules and thereby 
generate MRI contrast.  Free 
unbound Gd is extremely toxic, but 
when chelated to a ligand, its 
safety profile is dramatically 
improved, assisted by a 500-fold 
increase in renal excretion 
[Kramer, 2007].
The elimination half-time in 
patients with normal renal function 
is approximately 1.5 hours,but in 
patients with severely reduced 
kidney function (GFRs between 2-
10), it is as long as 34 hours.  The 
decreased elimination time may 
allow Gd to dissociate from its 
chelating agent.  Free, unbound 
Gd may then deposit in tissue beds 
and incite a fibrotic process, 
perhaps via circulating fibrocytes. 
Patients with normal renal function 
appear to have negligible risk of 
developing NSF/NFD [Kramer, 
2007].
Side effects from 
bicycle testing
Side effects of bicycle testing can 
include shortness of breath, light-
headedness, drop in blood pressure, 
and abnormal heart rhythm. In rare 
cases, these side effects can be 
serious or life-threatening. Also 
possible are direct injuries such as 
Inclusion criteria.  
Medical history 
and PI discretion 
as to patient’s 
ability to 
participate in the 
exercise test.
Medical oversight during the test.

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Potential risk
Summary of data
Impact- eligibility 
criteria
Strategy-monitoring/stopping 
criteria
bruises, sprains, and strains and 
indirect problems such worsening of 
pain from arthritis.
Subject may not 
be able to enter 
the MRI machine
Certain interventions, prostheses, or 
foreign bodies might be incompatible 
with the MRI scanner.
Exclusion criteria 
and local MRI 
scanning facility 
criteria
All participants will be screened 
according to local hospital criteria 
and trial inclusion/exclusion before 
entering the MRI room to ensure 
they are able to have the MRI 
conducted.
Subject may not 
be able to 
complete MRI 
once started
MRI can be associated with 
claustrophobia. The radio fields used 
in MRI can cause mild nerve 
stimulation and tissue heating, both of 
which are strictly regulated by both
software and hardware controls 
implemented by the scanner 
manufacturer that cannot be 
bypassed.
Exclusion criteria 
and medical 
history.
All scans will be conducted by 
experienced radiographers and 
radiologists in the nominated 
scanning sites.  If a subject 
becomes claustrophobic, the 
subject will be withdrawn from the 
study if they are unable to tolerate 
it again.
Within group 3, 
exposure to 
ionizing radiation 
from chest x-ray.
The dose from a single chest X-ray 
should not exceed 20 micro-sievert 
(Sv) and this corresponds to a lifetime 
risk of a fatal malignancy of about 1 in 
1 million (ICRP 103). The study will 
minimize exposure by using x-rays 
acquired as part of clinical care 
whenever possible. It is expected that 
all subjects will require a single chest 
x-ray, but may have a maximum of 3 
chest x-rays (up to maximum 60 
micro-Sv within this study, lifetime risk 
of fatal malignancy of approximately 1 
in 333,333).
Females of 
reproductive 
potential and all
subjects under 50 
years of age will 
be excluded from
participation in 
group 3.
All procedures will be performed by 
a qualified technician.
4.
STUDY POPULATION
4.1.
Number of Subjects
With respect to Groups 1 and 2, this study plans to enrol a sufficient number of subjects 
to have at least 24 subjects (12 HV and 12 subjects with HF) with evaluable MRI data.  
For each subject, the MRI data must be of sufficient quality to enable DCE-MRI 
modelling from both Session 1 and Session 2.  Additionally, at least 6 HV and 6 subjects 
with HF are needed to complete the third scanning session with evaluable MRI data 
following exercise testing.
After 12 subjects (6 HV and 6 subjects with HF) have completed Sessions 1 and 2, an 
interim review will be performed.  Following the interim review, the study team will 
decide whether to (a) terminate the study if it is determined that the image quality is poor 
(e.g., due to excessive movement during scanning or related to specifics around lung 
tissue) or the procedures are not well tolerated in the HF group (e.g., inability to lie flat 

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for the duration of the imaging session), or (b) continue the study to enrol a sufficient 
number of additional subjects to meet the designated numbers required (see above).
The interim decision will be based on the expert opinion of the Investigator in 
consultation with the GSK Study Team.
For Group 3, it is planned that a sufficient number of subjects with ADHF will be 
enrolled so that at least 5 subjects complete two scanning Sessions (1 and 2 or 1 and 3).
4.2.
Eligibility Criteria
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is 
essential.
4.2.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply within each of the subject categories below: 
4.2.1.1.
Inclusion Criteria for Heart Failure Group (Group 2)
1. Established diagnosis of mild to moderate heart failure of any aetiology with 
symptoms defined as corresponding to the New York Heart Association 
(NYHA) class II or III
4.2.1.2.
Inclusion Criteria for Healthy Volunteer Group (Group 1)
1. Healthy as determined by a responsible and experienced physician, based on a 
medical evaluation including medical history, brief physical examination, 
clinical laboratory tests, and ECG
4.2.1.3.
Inclusion Criteria for Both the Healthy Volunteer and Heart Failure 
Groups (Group 1 and 2)
1. Males or females over 18 years of age at the time of signing the informed 
consent
2. Body weight 50kg and BMI within the range 18-40 kg/m2 (inclusive)
3. Able to understand and comply with protocol requirements, instructions and 
protocol-stated restrictions and is willing to take part in the imaging sessions
4. Capable of giving written informed consent, which includes compliance with 
the requirements and restrictions listed in the consent form
4.2.1.4.
Inclusion Criteria for Subjects with ADHF (Group 3)
1. Male subjects OR female subjects of non reproductive potential as defined as 
pre-menopausal females with a documented tubal ligation or hysterectomy, or 

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post-menopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) > 40 MIU/mL and oestradiol < 40pg/mL (< 140 pmol/L) is 
confirmatory. 
2. 50 years of age or over at the time of signing the informed consent
3. Hospitalized for the management of acute decompensated HF 
4. Presence of dyspnoea at rest or with minimal activity
5. Presence of at least one of the following signs:

Tachypnea with respiratory rate ≥20 breaths/min

Rales or crackles audible on auscultation
6. Chest x-ray with evidence of pulmonary congestion/oedema performed 
approximately within the last 48 hours (if not available – an additional 
research CXR may be requested)
7. Have received at least one treatment with an intravenous diuretic prior to the 
first MRI scan 
8. Body weight ≥ 50kg and BMI within the range 18-40 kg/m2 (inclusive)
9. Able to understand and comply with protocol requirements, instructions and 
protocol-stated restrictions and is willing to take part in the imaging sessions
10. Capable of giving written informed consent, which includes compliance with 
the requirements and restrictions listed in the consent form
4.2.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply within each of the subject categories below:
4.2.2.1.
Exclusion Criteria for Heart Failure Group (Group 2)
1.
History of known primary pulmonary disease requiring current medication or 
other therapy
2.
Orthopnoea of sufficient severity to preclude supine scanning as determined 
at screening
3.
Unstable angina within the past 3 months
4.
Uncontrolled hypertension (resting systolic BP > 160mmHg or resting 
diastolic BP > 100mmHg)
5.
Resting hypoxia while breathing room air (SaO2 <88%)
4.2.2.2.
Exclusion Criteria for Both the Healthy Volunteer and Heart Failure 
Groups (Group 1 and 2)
1.
Current smoker, defined as having smoked in the preceding 6 months

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2.
Contraindication for MRI scanning (as assessed by local MRI safety 
questionnaire), which includes but is not limited to:
a.
Intracranial aneurysm clips (except Sugita) or other metallic objects
b.
Intra- orbital metal fragments that have not been removed 
c.
Pacemakers or other implanted cardiac rhythm management devices and
non-MRI compatible heart valves
d.
Inner ear implants
e.
History of claustrophobia
3.
Pregnant females as determined by positive urine HCG test at screening or 
prior to any scanning session
4.
Positive test for drugs of abuse, not due to current prescription drugs as 
determined by the GSK Medical Monitor and PI, and alcohol screen
5.
Estimated creatinine clearance (Cockcroft-Gault) <60mL/minute
4.2.2.3.
Exclusion Criteria for Subjects with ADHF (Group 3)
1. End-stage heart failure defined as requiring left ventricular assist devices, 
intra-aortic balloon pump or any type of mechanical support
2. Chronic or intermittent renal support therapy (hemodialysis, ultrafiltration, or 
peritoneal dialysis)
3. Ongoing or planned intravenous diuretic treatment within 1 hour of MRI scan
appointment
4. History of known primary pulmonary disease requiring current medication or 
other therapy
5. Orthopnoea of sufficient severity to preclude supine scanning (as determined 
by a 15-minute test of lying supine with or without the use of oxygen)
6. Contraindication for MRI scanning (as assessed by local MRI safety 
questionnaire), which includes but is not limited to:
a. Intracranial aneurysm clips (except Sugita) or other metallic objects
b. Intra-orbital metal fragments that have not been removed
c. Pacemakers or other implanted cardiac rhythm management devices and 
non-MRI compatible heart valves
d. Inner ear implants
e. History of claustrophobia
7. Estimated creatinine clearance (Cockcroft-Gault) <40mL/minute
8. Contraindication to MRI contrast agents
9. Previous inclusion in a research and/or medical protocol involving nuclear 
medicine, PET or radiological investigations with significant radiation burden 
(a significant radiation burden being defined as 10 mSv in addition to natural 

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background radiation, in the previous 3 years including the dose from this 
study).
4.3.
Lifestyle and/or Dietary Restrictions
4.3.1.
Contraception Requirements
4.3.1.1.
Female Subjects
For subjects in Groups 1 and 2, no specific forms of contraception are required for female 
subjects of childbearing potential, though they will be informed that they will be 
withdrawn from the study if they become pregnant.  Female subjects under the age of 50 
years or of childbearing potential are not eligible for Group 3.
4.3.1.2.
Male Subjects
Male subjects with female partners of child-bearing potential do not require contraception 
in this study. 
4.3.2.
Exercise
In Groups 1 and 2, participants will be told to avoid strenuous exercise for 24 hours prior 
to each scanning session.
4.3.3.
Caffeine and Alcohol (Groups 1 and 2)
For 24 hours prior to screening and each scanning session, subjects will abstain from 
alcohol consumption.  Subjects with a positive alcohol breath test at any session will be 
excluded from the study.
On the day of each scanning session, subjects will refrain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate).
4.4.
Withdrawal Criteria and Procedures
A subject may withdraw 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.
For Groups 1 and 2, subjects who withdraw or do not have evaluable DCE-MRI data 
from Sessions 1 and 2 will be replaced in order to meet the designated number of subjects 
(see Section 4.1).  For subjects in group 3, who withdraw or do not have evaluable DCE-
MRI scans from either Session 1 and 2 or Session 1 and 3 will be replaced in order to 
meet the designated number of subjects.
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and re-schedule the missed visit as soon as possible. The site 
should also 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 based on previous non-compliance. In cases where the subject does not return for 
the rescheduled visit or cannot be reached to reschedule the missed visit, the site should 

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make every effort to regain contact with the subject so that they can be withdrawn 
appropriately from the study. 
4.5.
Subject Completion
A completed subject is defined as one who has completed all sessions of the study.
The end of the study is defined as the last subject’s last visit.
5.
STUDY TREATMENT
No treatment (investigational product) will be given in this study.
5.1.
Concomitant Medications and Non-Drug Therapies
Group 1: Subjects in the healthy group may take all regularly prescribed and over-the-
counter medication as planned throughout this study.
Group 2: Subjects in the heart failure group will take all regularly prescribed and over the 
counter medication as planned - except for loop diuretics, aldosterone antagonists, and 
thiazide diuretics on the day of imaging.  These subjects will take their dose of these 
medicines after imaging has completed on that day.
Group 3: Subjects who have been hospitalized for ADHF will receive standard of care 
treatment both during the hospitalization period and following discharge.   Within 1 hour 
of a planned MRI scan appointment, subjects should not have any ongoing or planned 
intravenous diuretic treatment (i.e., any treatment should be given after the planned scan 
appointment). Current diuretic dose will be recorded at each session.

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6.
STUDY ASSESSMENTS AND PROCEDURES
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Tables, Section 6.1.
For Groups 1 and 2, the procedures and assessments related to exercise testing in Session 
3, will be conducted on two separate visits as detailed in the Time and Events Table, 
Section 6.1.1.  The visits do not need to be on consecutive days.
Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECG, vital signs, 
blood draw.
The change in timing or addition of time points for any planned study assessments must 
be approved and documented by GSK, but this will not constitute a protocol amendment.  
The IRB/IEC will be informed of any safety issues that require alteration of the safety 
monitoring scheme.  No more than 50mL of blood will be collected over the duration of 
the study, including any extra assessments that may be required.

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6.1.
Time and Events Tables
6.1.1.
Time and Event Table for Healthy Volunteers and Subjects with HF (Groups 1 and 2)
Day:
Screening
Session 1
Session 2
Session 34
Visit Window
-35 to -1 days
Day 1
7±2 days after 
Session 1
Scan up to 3 days after 
Scan in Session 2
Visit 1
Visit 2
Informed Consent
X
Demography/Medical History/Concomitant 
Medications1
X
Brief Physical Examination
X
X
X
X
Orthopnoea Assessment2
X
Urinalysis, Pregnancy test3, 
Drugs of abuse screen, alcohol breath test
X
X
X
X
Electrocardiograph (ECG)
X
Vital Signs
X
X
X
X
X
Respiratory Rate6
X
X
X
X
Clinical Laboratory Assessments
X
X2
X2
X2
NT- pro BNP2
X
X5
X5
Dyspnoea Scoring6
X
X
X
X
Exercise Testing7
X
X
Magnetic Resonance Imaging 
with pulse oximetry monitoring
X
X
X
DLCO and DLNO8
X
X
X
Record any SAEs, and any AEs related to 
study procedures9
X
X
X
X
X
1.
For subjects with HF, additional history assessments are detailed in Section 6.2.
2.
HF subjects only, details in the SPM.
3.
Women of childbearing potential only.
4.
Session 3 will be conducted over two visits.  The two visits do not need to be on consecutive days.  
5.
In Session 3, a blood sample for NT-proBNP will be collected before and after the maximal exercise test, before the constant 
workload exercise test, and after the MRI scan.

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6.
The dyspnoea score will be obtained before and after the maximal exercise test, before the constant workload exercise test, and after 
the MRI scan. Respiratory rate will be measured at these same timepoints (and as indicated during the exercise testing).
7.
The exercise testing (maximal exercise to exhaustion and constant workload tests) may be conducted over a two-day (consecutive or 
non-consecutive) period.  The maximal exercise test will be conducted before the constant workload test.
8.
DLco and DLno measurements will be made after each MRI scan has been completed and prior to the constant workload exercise test 
in Session 3 (Visit 2).
9.
See Section 6.12.2 and Section 6.12.3.

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6.1.2.
Time and Event Table for Subjects with ADHF (Group 3)
PROCEDURE
SCREENING
SESSION 1
SESSION 24
SESSION 35
Following Hospital
Admission For ADHF
During Hospitalization
For ADHF
Up To 4 Weeks
After Session 1
Up To 4 Weeks
After Session 2
Informed Consent
X
Demography/Medical History/Concomitant 
Medications1
X
X8
X8
X8
Vital Signs including weight
X
X2
X
X
Lung Auscultation 
X
X2
X
X
Orthopnoea Assessment 
X
Chest X-Ray3
X2
X
X
Oximetry
X
X
X
X
Lung Ultrasound6
X7
X
X
Magnetic Resonance Imaging (DCE-MRI)
X
X
X
Dyspnoea Score (5-Point Likert Scale)
X
X
X
X
Respiratory Rate
X
X
X
X
Creatinine
X
X
X
X
Haematocrit9
X
X
X
X
FSH and Estradiol10
X
NT proBNP
X
X
X
Record Any SAEs and any AEs Related To 
Study Procedures
X
X
X

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1.
Information will be reviewed based on available hospital records
2.
Assessment does not need to be repeated if Session 1 is conducted within 48 hours of Screening
3.
At any designated visit, a chest X-ray need not be repeated if one has already been conducted as part of standard care
4.
Session 2 will only be conducted when the pulmonary oedema is considered resolved.  If pulmonary oedema is considered unresolved, 
only CXR and LUS may be collected.
5.
Session 3 only in subjects deemed to not have pulmonary oedema resolved at session 2 by the Investigator.  
6.
Where feasible, Ultrasound may be performed to assess pulmonary oedema in addition to lung auscultation and / or CXR.  The LUS 
may be completed at a separate visit (± 3 Days). Additional anatomic structures may be assessed during any ultrasound.
7.
Multiple ultrasounds may be performed during hospitalization period of Session 1 up to one daily with a maximum of 3.
8.
Sessions 1, 2 and 3 will include recording current diuretic dosage
9.
Haematocrit values that are no more than 1 week old may be used
10. In women of non child bearing potential only

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6.2.
Demographic/Medical History Assessments
The following demographic parameters will be recorded:

Year of birth

Gender

Race and ethnicity
For subjects with HF only, the following items pertaining to medical and medication 
history will be recorded/assessed at Screening (See eligibility criteria listed in Section 
4.2):  

Confirm heart failure class

Onset and type of symptoms

Years since diagnosis of HF

Degree of exercise intolerance:  distance/ stairs/time prior to breathlessness

Presence of orthopnoea and/or paroxysmal nocturnal dyspnoea

Peripheral oedema:  level above ankle, non-dependent limb

Significant past medical history including onset, aetiology, and results of any 
recent relevant investigations of heart failure, as applicable

Medication history
6.3.
Safety
Planned timepoints for all safety assessments are listed in the Time and Events Tables
(Section 6.1).  Additional time points for safety tests such as vital signs and physical 
examinations may be added during the course of the study based on newly available data 
to ensure appropriate safety monitoring.
6.3.1.
Brief Physical Examinations
A brief physical examination will be performed at each session for both groups of 
subjects  (Groups 1 and 2).  In subjects with HF (Group 2), peripheral oedema (level 
above ankle, non-dependent limb) should be monitored at all sessions.  Height will be 
measured only on the first visit (Screening), and weight will be measured at every 
session. Lung auscultation will be performed on patients with ADHF in Group3 at 
Screening, Sessions 1, 2, and 3 by investigator or medically trained designee.
6.3.2.
Vital Signs

Vital sign measurements will include systolic and diastolic blood pressure and heart
rate.

Vital signs will be collected with the subject semi-supine and after they have been 
resting for 5 minutes.

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For Groups 1 and 2, additional measurements of heart rate and blood pressure to be made 
during the exercise testing will be detailed in the SPM.
Group 3 will include a weight measurement at Sessions 1, 2 and 3 (if needed).
6.3.3.
Electrocardiogram (ECG)

For Groups 1 and 2, 12-lead ECGs will be obtained during the study using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and 
QTc intervals.

ECGs will be obtained in the semi-supine position after the subject has been resting 
for at least 5 minutes.
6.3.4.
Clinical Laboratory Assessments and Urinalysis
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed below for Groups 1 and 2.  Details for the preparation and shipment of samples will 
be provided by the local laboratory.
Haematology
Platelet Count
Automated WBC Differential:
RBC  Count
Neutrophils
WBC Count (absolute) 
Lymphocytes
Hemoglobin
Monocytes
Hematocrit
Eosinophils
Basophils
Clinical Chemistry
Urea
Calcium
Total and direct bilirubin 
Creatinine
Troponin
CrCl (estimated using Cockcroft-Gault)
Glucose
ALT (SGPT)
Sodium
AST (SGOT)
Potassium
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood and ketone by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Screening Tests
FSH and estradiol (as needed in women of non-child bearing potential only)
Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines)
Biomarkers
N-terminal pro-Brain-type Natriuretic Peptide (NT- pro BNP)

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If additional non-protocol specified laboratory assessments are performed at the site’s 
local laboratory, which result in a change in subject management or are considered 
clinical significant by the Investigator (for example, SAE), the results must be captured 
and sent to GSK along with other study data as defined in Appendix 1.
6.3.4.1.
Pregnancy Testing
For Groups 1 and 2, a standard urine pregnancy test will be performed at Screening and 
at every Session (first day of Session 3) in women of childbearing potential.  If the test is 
positive, the subject will be withdrawn from the study.  For Group 3, FSH and estradiol 
will be testing if needed to confirm non child bearing potential status.
6.4.
N-terminal pro-Brain-type Natriuretic Peptide (NT-pro-BNP)
For subjects in Group 2, blood samples for NT-proBNP determinations will be drawn at 
screening and in Session 3 before and after the maximal exercise test, before the constant
workload exercise test and after MRI scanning only in subjects with HF.  For subjects 
participating in Group 3, blood samples for NT proBNP levels will be drawn according to 
the time and events table. Record the date and time that each sample is collected.  Details 
of the processing, storage, and shipping of samples are located in the SPM.
6.5.
Dyspnoea Scale Scoring
After the MRI scan in Sessions 1 and 2, a standardised, validated dyspnoea 5-point Likert 
scale (Mebazaa, 2010) will be completed for Groups 1 and 2.  In Session 3 only, the score 
will be completed before and after the maximal exercise test, and before and after the 
constant workload exercise test (before scanning) and after MRI scanning.  
For Group 3, the dyspnoea 5-point Likert scale will be completed at Screening and before 
and after the MRI scan in Sessions 1, 2, and 3 (if needed).
Details of the scale and administration are located in Appendix 2 (Section 11.2) and the 
SPM.
6.6.
Respiratory Rate
Respiratory rate will be recorded over a 60-second period. 
For Groups 1 and 2, respiratory rate will be measured after the MRI scan in Sessions 1 
and 2.  In Session 3 only, respiratory rate will be measured immediately before and after 
the maximal exercise test, and before and after the constant workload exercise test 
(before scanning), and after MRI scanning.  Any additional measurements to be taken 
during the exercise testing procedure will be detailed in the SPM. 
For Group 3, the respiratory rate will be measured at Screening and before the MRI scan 
in Sessions 1, 2 and 3 (if needed).

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6.7.
Chest X-rays
For subjects with ADHF in Group 3, a clinically indicated chest X-ray (CXR) will be 
performed to assess cardiogenic pulmonary oedema.  CXRs used as part of standard 
clinical care may be used when a CXR is acquired within 48 hours of a scheduled CXR
per T&E Table Section 6.1.2. A maximum of 3 CXR scans will be performed as part of 
this study, each with a maximum of 20 microsievert. Additional details regarding the 
chest X-rays and the designation of resolution of pulmonary oedema may be found in the 
SPM.
6.8.
Lung Ultrasound
For subjects with ADHF in Group 3, lung ultrasound may be used to assess pulmonary 
oedema, where feasible, specifically through measurement of the number of B lines.
Additional anatomic structures may be assessed during any ultrasound. Additional details
regarding the ultrasounds will be included within the SPM.
6.9.
Magnetic Resonance Imaging
6.9.1.
Subject Scanning Procedures
Subjects will undergo MRI scanning at Addenbrookes Radiology Department using a 
1.5 T system.  On attendance at the Radiology Department, subjects will be placed supine 
in the scanner and will be prepared for intravenous contrast agent administration.
The scanning protocol will include routine localisers followed by T1 measurement 
sequences and a dynamic time series.  The T1 measurement sequences will consist of 3D 
spoiled gradient echo (3D-SPGR) with constant echo time (TE) and repetition time (TR) 
and varying flip angles.  The dynamic series will also consist of 3D-SPGR acquisitions 
with constant TE, TR and constant flip angle.  Contrast agent will be administered 
intravenously as a bolus using a power injector during the dynamic series.  Scanner gains 
will be controlled manually between all of the 3D-SPGR acquisitions to allow subsequent 
DCE-MRI parameter quantification.
Subjects within Group 3 may receive medical oxygen during the exam provided they
receive oxygen during all MRI sessions and delivery rate is kept constant during a 
scanning session and matched for both scanning sessions. Further details of scanning site 
training procedures and scanning protocols will be provided in a dedicated Imaging 
Manual.
All MRI scans will be reported (non-anonymised) for clinical abnormalities as per normal 
NHS Clinical Governance requirements for subject safety purposes.
6.9.2.
Phantom Scanning
In order to maximise image quality and data consistency throughout the study, regular 
scanning of a Eurospin TO5 phantom will be required.  The same scanning protocol as 
used in study subjects will be repeated using the phantom at intervals of no less than once 
every 6 weeks and immediately after any software or hardware upgrade or maintenance.

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6.9.3.
Data Transfer
All MRI data will be anonymised at site and transferred to Bioxydyn Limited.  Details for 
image transfer will be provided in the Imaging Manual.
6.9.4.
DCE-MRI Data Analysis
All DCE-MRI data analysis will take place at Bioxydyn Limited.  DCE-MRI data will be 
corrected for breathing motion using registration and the lungs will be segmented from 
the image volume.  An arterial input function (AIF) will be extracted from the pulmonary 
artery or right ventricle; if not available a population AIF will be substituted.  The 
‘extended Tofts’ tracer kinetic model will be applied to the data to provide measurements 
of ktrans (capillary transfer coefficient of contrast agent - /min), ve (leakage space -
fraction) and vp (plasma volume - fraction).  Median values of ktrans and ve will be 
provided from each lung (total lung, apical and basal) for subsequent statistical analysis.  
All values will be corrected for the individual’s haematocrit value. If not available, a 
typical haematocrit value will be assumed.
6.10.
Exercise Test
In Session 3, subjects in Groups 1 and 2 will perform two exercise tests.
Maximal Exercise Test Limited by Dyspnoea or Fatigue
Subjects will first be asked to perform a maximal exercise test limited by dyspnoea or 
fatigue on a cycle ergometer.  Baseline measurements (heart rate, blood pressure, 
respiratory rate, and breath-by-breath gas exchange measurements: oxygen consumption 
(VO2), ventilation/carbon dioxide production (VE/VCO2) slope, respiratory exchange 
ratio (RER), and VO2 and time at ventilator threshold) will be performed with subjects 
seated on the cycle ergometer for approximately 3 minutes.  Subjects will then be asked 
to commence cycling.  The workloads will be increased in a stepwise fashion until 
volitional fatigue.  Breath-by-breath gas measurements and heart rate will be recorded
throughout exercise.  At the end of each workload, Borg Rating of Perceived Exertion 
(RPE) (See Section 11.3 Appendix 3) and blood pressure will be obtained.  At peak 
exercise, heart rate, blood pressure, Borg RPE, and breath-by-breath gas exchange 
measurements including peak VO2 will be recorded.  Respiratory rate at the end of 
exercise will also be recorded.
Constant Workload Exercise Test
Subjects will be asked to perform cycle exercise for 10 minutes at a workload between
75% to 80% of the peak work rate achieved during the maximal exercise to exhaustion 
test described above.  Breath-by-breath gas measurements (VO2, RER, exercise time) and 
heart rate will be measured throughout the exercise period.  Blood pressure and 
respiratory rate will also be measured.
Full details of the exercise test protocols are included in the SPM.

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6.11.
DLco and DLno
Pulmonary diffusion is impaired at rest in patients with chronic heart failure (HF) and has 
been implicated in the generation of symptoms and exercise intolerance. It is 
hypothesized that exercise increases pulmonary vascular pressures, thereby mediating a 
further lessening of the integrity of the vascular: alveolar membrane.  This results in 
enhanced interstitial fluid, thereby altering membrane gas exchange as measured by 
DLco.  This is based on the alveolar: vascular membrane conductance as well as the 
affinity for hemoglobin.  To better characterize the membrane conductance alone, 
nitrogen oxide (NO) absorption will also be tested, as it is mostly dependent on the 
membrane itself.  This is due to its profound affinity for hemoglobin well beyond that of 
CO.  A correlation between DLco and DLno and the change in MRI imaging will be 
evaluated.
For Groups 1 and 2, DLco and DLno measurements will be made after each MRI 
scan has been completed and prior to the constant workload exercise test in Session 
3, Visit 2.  
Details of the pulmonary testing methodology including diffusing capacity and 
measured components are included in the SPM.
6.12.
Serious Adverse Events (SAEs)
The Investigator (or designated site staff) is responsible for detecting, documenting and 
reporting events that meet the definition of an SAE.
6.12.1.
Time Period for Collecting SAE Information
Any SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) will be recorded from the time a subject 
consents to participate in the study up to and including the last visit.  All SAEs will be 
recorded and reported to GSK within 24 hours, as indicated in Appendix 1.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the Investigator learns of any SAE, including a death, at any time after a 
subject has been discharged from the study, and he/she considers the event reasonably 
related to study participation, the Investigator would promptly notify GSK.
NOTE: The method of, recording, evaluating and follow-up of SAEs plus procedures for 
completing and transmitting SAE reports to GSK are provided in Appendix 1.
6.12.2.
Definition of Adverse Events
An AE is any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.  An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a medicinal product.

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Since no investigational product will be administered in this study, information regarding 
the occurrence of adverse events will not be routinely collected.   Medical occurrences 
(non-serious events) and non-serious events related to study procedures that begin during 
the study will be recorded in the medical notes.  
Events meeting the definition of an AE include:

Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the Investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of 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.).
Events that do not meet the definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the subject’s condition.

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.
6.12.3.
Definition of Serious Adverse Events
If an event is not an AE per Section 6.12.2, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
An SAE is any untoward medical occurrence that, at any dose:
a.
Results in death

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b.
Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization.
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity, or
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect.
f.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
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.
6.12.4.
Death Events
In addition, all deaths, whether or not they are considered SAEs, will require a specific 
death data collection tool to be completed.  The death data collection tool includes 
questions regarding cardiovascular (including sudden cardiac death) and 
noncardiovascular death.
This information should be recorded in the specific death form within one week of when 
the death is first reported.

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6.12.5.
Prompt Reporting of SAEs to GSK
Once the Investigator determines that an event meets the protocol definition of an SAE, 
the SAE will be reported to GSK within 24 hours.  Any follow-up information on a 
previously reported SAE will also be reported to GSK within 24 hours.
If the Investigator does not have all information regarding an SAE, he/she will not wait to 
receive additional information before notifying GSK of the event and completing the 
appropriate data collection tool.  The Investigator will always provide an assessment of 
causality at the time of the initial report as described in Appendix 1.
6.12.6.
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the Investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
GSK will comply with country specific regulatory requirements relating to safety 
reporting to regulatory authorities, IRBs/IECs and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.  An investigator who receives an investigator safety report 
describing an SAE(s) or other specific safety information (e.g., summary or listing of 
SAEs) from GSK will notify the IRB/IEC, if appropriate according to local requirements.
6.13.
Pregnancy
If a woman in the study becomes pregnant, she will be withdrawn from the study.
6.13.1.
Time Period for Collecting Pregnancy information
Any pregnancies occurring after the first session and up to and including the last visit 
should be reported.
6.13.2.
Action to be Taken if Pregnancy Occurs
The Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study.  The Investigator will record pregnancy 
information on the appropriate form and submit it to GSK within 2 weeks of learning of a 
subject's pregnancy.  The subject 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 premature termination of the pregnancy will be reported.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE.
A spontaneous abortion is always considered to be an SAE and will be reported as such.  
Furthermore, any SAE occurring as a result of a post-study pregnancy will be reported to 

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GSK as described in Section 6.12.5. While the Investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
7.
DATA MANAGEMENT
The MRI data will be transferred to a separate analysis company in an anonymised 
fashion.  Instructions on MRI data transfer will provided to the scanning site.
For this study, subject data will be entered into an electronic Phase I Information 
Management System (PIMS), transmitted electronically to GSK, and combined with data 
provided from other sources in a validated data system.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Serious adverse events and concomitant 
medications terms will be coded using MedDRA (Medical Dictionary for Regulatory 
Activities) and an internal validated medication dictionary, GSKDrug eCRFs (including 
queries and audit trails) will be retained by GSK, and copies will be sent to the 
Investigator to maintain as the investigator copy.  Subject initials will be collected in 
PIMS and remain as a site record; subject initials will not be transmitted to GSK 
according to GSK policy.
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypotheses Comparisons
Estimation approach will be used for the comparison of interests.  No formal hypothesis 
testing will be performed.  There are two comparisons of interest in this study to be 
performed between Group 1 and Group 2.  The first is to estimate the feasibility of 
whether DCE-MRI can detect differences in DCE-MRI measures of pulmonary oedema 
or vascular permeability between HF and HV groups.  The second comparison is to 
determine whether a burst of exercise activity can enhance the interstitial lung fluid 
(and/or exchange rate) from baseline.
8.2.
Sample Size Considerations
Sample size is based on feasibility. A similarly sized study using DCE-MRI was able to 
detect statistically significant differences in the lungs of smokers compared to HVs 
(Naish, 2008).
8.3.
Data Analysis Considerations
Anonymised data may be transferred within GSK or to external sites.  In some cases, we 
may use pooled or anonymised individual image data to support scientific reports.
All imaging data will be anonymised and stored on a Picture Archiving and 
Communication System (PACS) and RIS.

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8.3.1.
Interim Analysis
Interim analysis will be conducted as described in Section 3.1
8.3.2.
Final Analyses
The formal statistical analysis described below will be performed for Groups 1 and 2.  
For the primary endpoints, contrast agent interstitial volume (ve) and exchange rate (ktrans)
data will be fitted separately using a mixed effect model with subject treated as a random 
effect, patient population (HF or HV) and scanning session as a fixed effect.  Point 
estimates and associated 95% confidence intervals (CI) will be constructed to provide a 
plausible range of values for the true comparisons of interest such as the mean difference 
DCE-MRI measures of interests between HF and HV groups for the different scanning 
sessions of interest.  If model assumptions of normality appear grossly violated, 
alternative methods (e.g., use of raw data with log transformation or non-parametric 
methods) will be considered.
For the secondary endpoint, the estimation of the within subject variability of DCE-MRI 
measures of pulmonary oedema and vascular permeability between study visits will be 
calculated based on the mixed model above using data from baseline scans by group.
For the exploratory analysis on the differences in plasma volume, relaxation rate, and 
proton density between HF and HV groups as measured using DCE-MRI, the similar 
analysis will be provided as above if data permit. The correlations of  MRI measures 
with clinical and biochemical measures:  dyspnoea score, NYHA grade, respiratory rate, 
NT-proBNP, exercise capacity, DLco, DLno, body weight, urine specific gravity, 
fractional excretion of sodium (FENa), blood urea to creatinine ratio and others will also 
be explored as data permit.
The distribution of DCE-MRI measures of pulmonary physiology (interstitial volume 
(ve), exchange rate (ktrans) and others) in HF and HV groups both before and after exercise 
will be explored using empirical cdf/pdf and/or scatter plots for each subgroup of interest 
to help visualize the univariate distribution and the change.
For Group 3, DCE-MRI measures, lung ultrasound (B Line count), NT proBNP,
dyspnoea score, and respiratory rate will be summarized by visit/session.  Individual line 
plots will be provided for each endpoint of interest to visualize the change in these 
measurements during hospitalization and after standard treatment. For subjects in Group 
3 who withdrew after Session 1, the DCE-MRI measures from this scan may be included 
in the analyses.
8.3.2.1.
Safety Analyses
Safety data will be presented in tabular and/or graphical format and summarised 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.

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9.
STUDY GOVERNANCE CONSIDERATIONS
9.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
9.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study 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.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and, the guiding principles of the 2008 
Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favourable opinion/approval to conduct the study and of any 
subsequent relevant amended documents

Written informed consent (and any amendments) to be obtained for each subject 
before participation in the study

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)
Written informed consent must be obtained from each subject prior to participation in the 
study.
9.2.1.
Urgent Safety Measures
If an event occurs that is related to the conduct of the study, and this new event is likely 
to affect the safety of subjects, the sponsor and the Investigator will take appropriate 
urgent safety measures to protect subjects against any immediate hazard.
The sponsor will work with the Investigator to ensure the IEC/IRB is notified.
9.3.
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 PIMS 
record will serve as the source document.

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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.
9.4.
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.
9.5.
Study and Site Closure
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the Investigator or site staff, as appropriate, in accordance with 
applicable regulations including GCP, and GSK procedures.
In addition, GSK reserves the right to temporarily suspend or prematurely discontinue 
this study at any time for reasons including, but not limited to, safety or ethical issues or 
severe non-compliance. For multicenter studies, this can occur at one or more or at all 
sites.  If GSK determines such action is needed, GSK will discuss this with the 
Investigator or the head of the medical institution (where applicable), including the 
reasons for taking such action.  When feasible, GSK will provide advance notification to 
the Investigator or the head of the medical institution, where applicable, of the impending 
action prior to it taking effect.
If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform investigators or the head of the medical institution (where applicable) 
and the regulatory authorities of the suspension or premature discontinuation of the study 
and the reason(s) for the action.  If required by applicable regulations, the Investigator or 
the head of the medical institution (where applicable) must inform the IRB/IEC promptly 
and provide the reason for the suspension or premature discontinuation.
9.6.
Records Retention
Following closure of the study, the Investigator or the head of the medical institution 
(where applicable) must maintain all site study records, except for those required by local 
regulations to be maintained by someone else, in a safe and secure location.  The records 

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must be maintained to allow easy and timely retrieval, when needed (e.g., audit or 
inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and staff.  Where 
permitted by local laws/regulations or institutional policy, some or all of these records 
can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken.  The 
Investigator must assure that all reproductions are legible and are a true and accurate 
copy of the original, and meet accessibility and retrieval standards, including re-
generating a hard copy, if required.  Furthermore, the Investigator must ensure there is an 
acceptable back-up of these reproductions and that an acceptable quality control process 
exists for making these reproductions.
GSK will inform the Investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements.  The minimum retention time will meet the 
strictest standard applicable to that site for the study, as dictated by any institutional 
requirements or local laws or regulations, or GSK standards/procedures; otherwise, the 
retention period will default to 15 years.
The Investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership of the 
records in the event the Investigator leaves the site.
9.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The Investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the Investigator with the full summary of the study results.  The 
Investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The results summary will be posted to the Clinical Study Register no later than eight 
months after the final primary completion date, the date that the final subject was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome. In addition, a manuscript will be submitted to a peer reviewed journal 
for publication no later than 18 months after the last subject’s last visit (LSLV).  When 
manuscript publication in a peer reviewed journal is not feasible, a statement will be 
added to the public register to explain the reason for not publishing.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.

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10.
REFERENCES
Borg GA.  Borg's Rating of Perceived Exertion and Pain Scales. 1 ed. Champagne IL: 
Human Kinetics; 1998.
Borg GA.  Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 
1982;14:377-81. 
Buckley DL, Shurrab AE, Cheung CM, Jones AP, Mamtora H, Kalra PA. Measurement 
of single kidney function using dynamic contrast-enhanced MRI: comparison of two 
models in human subjects. J Magn Reson Imaging. 2006 Nov;24(5):1117–23.
Chewning RH, Murphy KJ. Gadolinium-based contrast media and the development of 
nephrogenic systemic fibrosis in patients with renal insufficiency. J Vasc Interv Radiol. 
2007 Mar;18(3):331–3.
Chow K, Toma M, Esch B, et al.  Comparison of MRI-derived pulmonary oedema 
measures with LVEDP and serum BNP. J Cardiovasc Magn Reson 2009. 11(Suppl 
1):P41.
Cowper SE.  Nephrogenic Systemic Fibrosis [ICNSFR Website]. 2001-2013. Available 
at http://www.icnsfr.org.
Deo A, Fogel M, Cowper SE. Nephrogenic systemic fibrosis: a population study 
examining the relationship of disease development to gadolinium exposure. Clin J Am 
Soc Nephrol 2007 Mar;2(2):264–7.
ESCAPE Investigators and ESCAPE Study Coordinators.  Evaluation Study of 
Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness: The 
ESCAPE Trial. JAMA 2005;294:1625-33.
Hodgson RJ, Connolly S, Barnes T, Eyes B, Campbell RSD, Moots R. Pharmacokinetic 
modeling of dynamic contrast-enhanced MRI of the hand and wrist in rheumatoid 
arthritis and the response to anti-tumor necrosis factor-alpha therapy. Magn Reson Med
2007 Sep;58(3):482–9.
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; 37:1779-84.
Kramer H, Michaely HJ, Requardt M, Rohrer M, Reeder S, Reiser MF, et al. Effects of 
injection rate and dose on image quality in time-resolved magnetic resonance
angiography (MRA) by using 1.0M contrast agents. Eur Radiol 2007 Jun;17(6):1394–
402.
Kuo PH. NSF-active and NSF-inert species of gadolinium: mechanistic and clinical 
implications. Am J Roentgenol 2008 Dec;191(6):1861–3.

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Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of hepatitis delta virus RNA in serum by consensus real-time PCR indicates different 
patterns of virological response to interferon therapy in chronically infected patients.  J 
Clin Microbiol 2005;43(5):2363–9.
Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG, et al. Nephrogenic 
systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced 
magnetic resonance imaging. J Am Soc Nephrol 2006 Sep;17(9):2359–62.
Matthay M, Folkesson H, and Clerici C.  Lung epithelial fluid transport and the 
resolution of pulmonary edema Phys Rev July 2002;82(3):569-600.
Mebazaa A, Pang P, Tavares, M, et al.  The impact of early standard therapy on dyspnoea 
in patients with acute heart failure: the URGENT-dyspnoea study. Eur Heart J
2010;31:832-41.
Monnet X, Rienzo M, Osman D, et al.  Passive leg raising predicts fluid responsiveness 
in the critically ill. Crit Care Med 2006;34(5):1402.
Naish JH, McGrath DM, Hutchinson CE, et al.  Increased pulmonary capillary 
permeability in smokers as measured by DCE-MRI. Proc Int Soc Magn Reson Med
2008;16:401.
O’Connor JPB, Jackson a, Parker GJM, Jayson GC. DCE-MRI biomarkers in the clinical 
evaluation of antiangiogenic and vascular disrupting agents. Br J Cancer 2007 Jan 
29;96(2):189–95.
Perazella M a. Nephrogenic systemic fibrosis, kidney disease, and gadolinium: is there a 
link? Clin J Am Soc Nephrol 2007;Mar;2(2):200–2.
Redfield M, Jacobsen S, Burnett, Jr J., et al.  Burden of systolic and diastolic ventricular 
dysfunction in the community: appreciating the scope of the heart failure epidemic. 
JAMA 2003;289(2):194.
Thomsen HS. Nephrogenic systemic fibrosis: A serious late adverse reaction to 
gadodiamide. Eur Radiol 2006 Dec;16(12):2619–21.

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11.
APPENDICES
11.1.
Appendix 1: Procedures for Detection, Evaluation, Follow-
Up and Reporting of SAEs
When an 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 SAE 
in the appropriate data collection tool.
It is not acceptable for the Investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK SAE data collection tool.  However, 
there may be instances when copies of medical records for certain cases are requested by 
GSK.  In this instance, all subject identifiers, with the exception of the subject number, 
will be blinded on the copies of the medical records prior to submission of to GSK.
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the SAE and not the individual signs/symptoms.
Evaluating SAEs
Assessment of Intensity
The Investigator will make an assessment of intensity for each 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 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 

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the Investigator Brochure (IB) and/or Product Information, for marketed products, in the 
determination of his/her assessment.
For each SAE the Investigator must document in the medical notes that he/she has 
reviewed the SAE and has provided an assessment of causality.
There may be situations when an SAE has occurred and the Investigator has minimal 
information to include in the initial report to GSK.  However, it is very important that the 
Investigator always make an assessment of causality for every event prior to the initial 
transmission of the SAE data to GSK.  The Investigator may change his/her opinion of 
causality in light of follow-up information, amending the SAE data collection tool 
accordingly.  The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.
Follow-up of SAEs
After the initial SAE report, the Investigator is required to proactively follow each subject 
at subsequent visits/contacts.  All SAEs will be followed until resolution, until the 
condition stabilizes, until the event is otherwise explained, or until the subject is lost to 
follow-up.
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the 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 data collection 
tool.  The Investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
Reporting of SAEs to GSK
Facsimile transmission of the SAE data collection tool is the preferred method to transmit 
this information to the project contact for SAE receipt. In rare circumstances and in the 
absence of facsimile equipment, notification by telephone is acceptable, with a copy of 
the SAE data collection tool sent by overnight mail. Initial notification via the telephone 
does not replace the need for the Investigator to complete and sign the SAE data 
collection tool within the designated reporting time frames.
GSK contacts for SAE receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.

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11.2.
Appendix 2: Dyspnoea Scale
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.

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11.3.
Appendix 3: Borg Rating of Perceived Exertion (RPE) Scale
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.

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11.4.
Appendix 4:  Protocol Amendment Changes
AMENDMENT 1
Where the Amendment Applies
This amendment applies to all sites (single site study).
Summary of Amendment Changes with Rationale
This protocol amendment clarifies the exercise protocol to be conducted, details measures 
for endpoints, defines the biomarker to be measured (NT-pro BNP), reduces total blood 
volume to be collected, updates study schematic, adds an interim review of the data, 
removes collection of AEs as there is no IP included in the study, alters physical exams to 
brief physical exams, and adds a dyspnea scale and the Borg Rating of Perceived 
Exertion.
List of Specific Changes
Trademark Information
REVISED TEXT
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
The Borg CR10 scale NONE
Section 1.1 Study Rationale
PREVIOUS TEXT
The primary objective of this study is to characterize the capability of MRI to detect 
increased interstitial lung fluid or altered vascular permeability.  First, the DCE-MRI 
markers of vascular permeability and pulmonary oedema will be measured in healthy 
volunteers (HV) and HF patients at rest to determine whether there is a difference 
between the two populations.  Next, exercise-induced changes relative to rest in 
interstitial volume and exchange rate will be evaluated in both HV and HF patients.
REVISED TEXT
The primary objective of this study is to characterize the capability of MRI to detect 
increased interstitial lung fluid or altered vascular permeability.  First, the DCE-MRI
markers of vascular permeability and pulmonary oedema will be measured in healthy 
volunteers (HV) and HF subjects patients with HF at rest to determine whether there is 
a difference between the two populations.  Next, exercise-induced changes (relative to 
rest) in interstitial volume and exchange rate will be evaluated in both HV and subjects 
with HF patients.  In patients with chronic HF, an abnormal alveolar-vascular 

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interface leading to increased fluid flux at high pulmonary arterial pressures, as 
well as a tendency toward greater exercise-induced pulmonary vascular pressure, 
increases the chance for excess fluid under these conditions compared to what may 
be observed in normal subjects.
Exercise increases pulmonary pressure, which may result in increased vascular 
permeability and pulmonary oedema in HF patients compared to HVs.
Section 2 Objectives and Endpoints
DELETED TEXT
Primary Endpoint:  Explore the effect of exercise on DCE-MRI measures of pulmonary 
oedema and vascular permeability in a subset of the HF and HV groups.
DELETED TEXT
Secondary Endpoints

Estimate the intrasubject variability of 
DCE-MRI measures of pulmonary 
oedema and vascular permeability
between study visits.

Estimation of the variability in the 
interstitial volume (ve) and
exchange rate (ktrans) within HF 
patients between 2 MRI visits 
approximately 1 week apart.
PREVIOUS TEXT
Correlation of MRI measures with clinical and biochemical measures: dyspnoea score, 
NYHA grade, respiratory rate, BNP , exercise capacity DLCO, DLNO, body weight, urine 
specific gravity, fractional excretion of sodium (FENa), blood urea to creatinine ratio
REVISED TEXT
Correlation of MRI measures with clinical and biochemical measures: dyspnoea score, 
NYHA grade, respiratory rate, NT-proBNP , exercise capacity (including Borg RER, 
heart rate, blood pressure, and gas exchange endpoints such as peak VO2, VE/VCO2
slope),  DLCO, DLNO, body weight, urine specific gravity, fractional excretion of sodium 
(FENa), blood urea to creatinine ratio.
Section 3.1 Study Schematic
PREVIOUS TEXT

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REVISED TEXT
Section 3.2 Study Design Detail
PREVIOUS TEXT
The study consists of five visits. The first visit will be a Screening Visit during which an 
appropriately trained study team member will describe the study, answer any questions 
the potential participant may have about the study and seek informed, written consent to 
enrol in the study. Subjects will be assessed for their tolerance of lying flat.  Within 35 
days, subjects will return for the first scanning session, where subjects will undergo the 
baseline procedure.  The second imaging session will occur approximately one week later 
to measure within-subject variability.  A third imaging visit will incorporate a bicycle 
exercise challenge prior to imaging and will occur approximately one to three days after 
the second imaging session.  The final contact will be a follow-up phone call, which will 
take place up to 1 week after the last scanning session.
REVISED TEXT
The study consists of four sessions ive visits.  The first visit will be a Screening Visit 
during which an appropriately trained study team member will describe the study, answer 
any questions the potential participant may have about the study and seek informed, 
written consent, and assess eligibility to enrol in the study.  Subjects will be assessed 
for their tolerance of lying flat.  Within 35 days, subjects will return for the first 
scanning session, where subjects will undergo the baseline procedure.  The second 
imaging session will occur approximately one week later to measure within-subject 
variability.  A third imaging session visit (which will be conducted in 2 visits) will 
incorporate a bicycle exercise challenge prior to the MRI scan, imaging and this third 
scan will be performed occur approximately one to three days after the second imaging 
session.  The final contact will be a follow-up phone call, which will take place up to 
1 week after the last scanning session.
Section 4.1. Number of Subjects
PREVIOUS TEXT
This study will enrol a sufficient number of subjects to have up to 24 evaluable subjects 
(up to 12 HV and up to 12 HF patients).  An evaluable subject is defined as a subject that 
has MRI data of sufficient quality to enable DCE-MRI modelling both Scan Visit 1 and 
Scan Visit 2.

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REVISED TEXT
This study plans to will enrol a sufficient number of subjects to have at least up to 24 
evaluable subjects (up to 12 HV and up to 12 subjects with HF patients) with
evaluable MRI data.  An evaluable subject is defined For each subject, the as a 
subject that has MRI data must be of sufficient quality to enable DCE-MRI modelling 
from both Session 1 and Session can Visit 2.  Additionally, at least 6 HV and 6 
subjects with HF are needed to complete the third scanning session with evaluable 
MRI data following exercise testing.
After 12 subjects (6 HV and 6 subjects with HF) have completed Sessions 1 and 2, 
an interim review will be performed.  Following the interim review, the study team 
will decide whether to (a) terminate the study if it is determined that the image 
quality is poor (e.g., due to excessive movement during scanning or related to 
specifics around lung tissue) or the procedures are not well tolerated in the HF 
group (e.g., inability to lie flat for the duration of the imaging session), or (b) 
continue the study to enrol a sufficient number of additional subjects to meet the 
designated numbers required (see above).
The interim decision will be based on the expert opinion of the Investigator in 
consultation with the GSK Study Team.
Section 4.2.1.2 Inclusion Criteria for Healthy Volunteer Group
ADDED TEXT
1.
Healthy as determined by a responsible and experienced physician, based on a 
medical evaluation including medical history, brief physical examination, clinical 
laboratory tests, and ECG
Section 4.2.1.3 Inclusion Criteria for Both the Healthy Volunteer and Heart 
Failure Groups
ADDED TEXT
2. Body weight 50kg and BMI within the range 18.5-32.0 kg/m2 (inclusive)

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Section 4.2.2 Exclusion Criteria
PREVIOUS TEXT
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply within each of the subject categories below:
REVISED TEXT
A subject will not be eligible for inclusion in this study only if any ll of the following 
criteria apply within each of the subject categories below:
Section 4.2.2.2 Exclusion Criteria for Both the Healthy Volunteer and Heart 
Failure Groups
DELETED TEXT
2.
Contraindication for MRI scanning (as assessed by local MRI safety 
questionnaire), which includes but is not limited to:
a.
Intracranial aneurysm clips (except Sugita) or other metallic objects
b.
I History of intra- orbital metal fragments that have not been removed 
by an MD
Section 4.3.2 Exercise [ADDED SECTION]
Participants will be told to avoid strenuous exercise for 24 hours prior to each 
scanning session.
Section 4.3.3 Caffeine and Alcohol
PREVIOUS TEXT

Prior to each No alcohol or.  People who have smoked within the previous 6 months
will be excluded in accordance with study inclusion and exclusion criteria. 
Subjects with a positive alcohol breath test at any session will be excluded from the 
study.  Subjects will abstain from alcohol consumption during each scanning session.
During each scanning session, subjects will refrain from ingesting caffeine- or xanthine-
containing products (e.g., coffee, tea, cola drinks, and chocolate) on the day of scan.
REVISED TEXT
For 24 hours prior to screening and each scanning session, subjects will abstain from No
alcohol consumption.  People who have smoked within the previous 6 months will be 
excluded in accordance with study inclusion and exclusion criteria
Subjects with a positive alcohol breath test at any session will be excluded from the 
study.  Subjects will abstain from alcohol consumption during each scanning session.

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On the day of During each scanning session, subjects will refrain from ingesting 
caffeine- or xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate)on 
the day of scan.
Section 4.4 Withdrawal Criteria and Procedures
PREVIOUS TEXT
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.
Subjects who withdraw or do not have evaluable DCE-MRI data from Scan Visit 1 and 
Scan Visit 2 will be replaced (see Section 4.4).
REVISED TEXT
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.
Subjects who withdraw or do not have evaluable DCE-MRI data from Sessions can Visit 
1 and Scan Visit 2 will be replaced in order to meet the designated number of subjects 
(see Section 4.1).
Section 5 Study Treatment
ADDED TEXT
No treatment (investigational product) will be given in this study.
Section 6 Study Assessments and Procedures
ADDED TEXT
In Session 3, the procedures and assessments related to exercise testing  be 
conducted on two separate visits as detailed in the Time and Events Table.  The 
visits do not need to be on consecutive days.
DELETED TEXT
The change in timing or addition of time points for any planned study assessments must 
be approved and documented by GSK, but this will not constitute a protocol amendment.  
The IRB/IEC will be informed of any safety issues that require alteration of the safety 
monitoring scheme.  No more than 500mL of blood will be collected over the duration of 
the study, including any extra assessments that may be required.

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Section 6.1. Time and Events Table
PREVIOUS TEXT
Day:
Screening
Scan VisSessionit 1
Scan Session 2
Scan Session 3
Visit Window
-35 to -1 days
Day 1
7±2 days after 
Session 1
Up to 3 days after 
Session 2
Informed Consent
X
Medical History / con Meds
X
Physical examination
X
Urinalysis, pregnancy test1, drugs of abuse 
screen
X
X
X
X
Electrocardiograph (ECG)
X
Vital signs and respiratory rate
X
X
X
X
Clinical Laboratory Assessments
X
X2
X2
X2
B-Type Natriuretic Peptide (NT- pro BNP)2
X
X
X
X
Dyspnoea Scoring
X
X
X
Exercise Test4
X
Magnetic resonance imaging with pulse 
oximetry monitoring
X
X
X
DLCO and DLNO53
X
X
Adverse Events
X
X
X
X
X
1.
Women of childbearing potential only
2.
HF subjects only 
3.
The maximal exercise test will be conducted before the constant workload test.
4.
DLCO and DLNO will be measured after the MRI scan

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REVISED TEXT
Day:
Screening
Scan VisSession it
1
Scan Session 2
Scan Session 34
Visit Window
-35 to -1 days
Day 1
7±2 days after 
Session 1
Scan uUp to 3 days 
after Scan in 
Session 2
Visit 1
Visit 2
Informed Consent
X
Demography/Medical History/Concomitant 
Medications1
X
Brief Physical Examination
X
X
X
X
Orthopnoea Assessment2
X
Urinalysis, Pregnancy test3, 
Drugs of abuse screen, alcohol breath test
X
X
X
X
Electrocardiograph (ECG)
X
Vital Signsand respiratory rate
X
X
X
X
X
Respiratory Rate6
X
X
X
X
Clinical Laboratory Assessments
X
X2
X2
X2
B-Type Natriuretic Peptide NT- pro BNP2
X
X
X
X5
X5
Dyspnoea Scoring6
X
X
X
X
Exercise Testing7
X
X
Magnetic Resonance Imaging
with pulse oximetry monitoring
X
X
X
DLCO and DLNO8
X
X
X
Record any SAEs, and anyAEs related to 
study procedures9
X
X
X
X
X
1.
For subjects with HF, additional history assessments are detailed in Section 6.2.
2.
Women of childbearing potential only
2.
HF subjects only, details in the SPM.
3.
Women of childbearing potential only

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4.
Session 3 will be conducted over two visits.  The two visits do not need to be on consecutive days.In Session 3, a blood sample 
for NT-proBNP will be collected before and after the maximal exercise test, before the constant workload exercise test, and 
after the MRI scan.
5.
The dyspnoea score will be obtained before and after the maximal exercise test, before the constant workload exercise test, 
and after the MRI scan.  Respiratory rate will be measured at these same timepoints (and as indicated during the exercise 
testing).
6.
The exercise testing (maximal exercise to exhaustion and constant workload tests) may be conducted over a two-day 
(consecutive or non-consecutive) period.  The maximal exercise test will be conducted before the constant workload test.
7.
DLco and DLno measurements will be made after each MRI scan has been completed and prior to the constant workload 
exercise test in Session 3 (Visit 2).
8.
See Section 6.10.2 and Section 6.10.3.

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Section 6.2 Demographic/Medical History Assessments
PREVIOUS TEXT
Medical and medication history will be assessed as related to the eligibility criteria listed 
in Section 4.2.  Specific areas covered will include: 

Confirm heart failure class

Onset of symptoms—when and type
REVISED TEXT
For subjects with HF only, the following items pertaining to medical and medication 
history will be recorded/assessed at Screening as related (See eligibility criteria listed 
in Section 4.2):  Specific areas covered will include:

Confirm heart failure class

Onset and type of symptoms
Section 6.3.1. Brief Physical Examinations [RENAMED SECTION]
PREVIOUS TEXT
A physical examination will be performed by a study physician at each study visit in both 
groups and will include an assessment of the skin, lungs, cardiovascular system, 
abdomen, and legs with particular focus on fluid balance in addition to the medical 
history (Section 6.2).  Height will be measured only on the first visit, and weight will be 
measured at every visit.
REVISED TEXT
A brief physical examination will be performed by a study physician at each session in 
both groups of subjects.  In subjects with HF, peripheral oedema (level above ankle, 
non-dependent limb) should be monitored at all sessions.  and will include an 
assessment of the skin, lungs, cardiovascular system, abdomen, and legs with 
particular focus on fluid balance in addition to the medical history (Section 6.2).  
Height will be measured only on the first visit (Screening), and weight will be measured 
at every session.
Section 6.3.2 Vital Signs Respiratory Rate [RENAMED SECTION]
PREVIOUS TEXT

Vital sign measurements will include systolic and diastolic blood pressure and heart
rate.

Vital signs will be collected with the subject semi-supine and after they have been 
resting for 5 minutes.

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
Respiratory rate should be recorded as a 60-second average at all time points along 
with vital signs.  In addition immediately before exercise (Scan Visit 3 only), before 
scanning, and after scanning.
REVISED TEXT

Vital sign measurements will include systolic and diastolic blood pressure and heart
rate.

Vital signs will be collected with the subject semi-supine and after they have been 
resting for 5 minutes.
Additional measurements of heart rate and blood pressure to be made during the 
exercise testing will be detailed in the SPM.

Respiratory rate should be recorded as a 60-second average at all time points 
along with vital signs.  In addition immediately before exercise (Scan Visit 3
only), before scanning, and after scanning.
Section 5.3.4 Clinical Laboratory Assessments and Urinalysis
PREVIOUS TEXT
Platelet Count
Automated WBC Differential:
Neutrophils
WBC Count (absolute) 
Lymphocytes
Hemoglobin
Monocytes
Hematocrit
Eosinophils
Basophils
Urea
Calcium
Bilirubin (isolated bilirubin >1.5xULN is 
acceptable if bilirubin is fractionated and direct 
bilirubin <35%)
Creatinine
Troponin
eGFR (estimated Glomerular Filtration Rate)
Glucose, fasting
ALT (SGPT)
Sodium
AST (SGOT)
Potassium CPK
Biomarkers
(NT- pro BNP

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REVISED TEXT
Haematology
Platelet Count
Automated WBC Differential:
RBC  Count
Neutrophils
WBC Count (absolute) 
Lymphocytes
Hemoglobin
Monocytes
Hematocrit
Eosinophils
Basophils
Clinical Chemistry
Urea
Calcium
Total and direct bilirubin (isolated bilirubin 
>1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%)
Creatinine
Troponin
eGFR (estimated Glomerular Filtration Rate)
Glucosefasting
ALT (SGPT)
Sodium
AST (SGOT)
Potassium CPK
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood and ketone by dipstick
Microscopic examination (if blood or protein is abnormal)
Biomarkers
N-terminal pro-Brain-type Natriuretic Peptide (NT- pro BNP)
Section 6.4 N-terminal pro-Brain-type Natriuretic Peptide (NT-pro-BNP) 
[RENAMED SECTION]
PREVIOUS TEXT
Blood samples for NT-Pro BNP will be drawn at the timepoints in \  Collect each serial 
whole blood biomarker sample as close as possible to the planned time relative to 
dosing. Collect whole blood into a properly labeled 2.5mL SST blood collection tube 
(supplied by GSK). Record the date and exact time that each sample is collected.
Immediately after collection, gently invert (DO NOT SHAKE) the evacuated blood
collection tube 5 times to mix and place upright at room temperature for 30 – 120 
minutes (or at 2 – 8 °C for 12 -16 hours) to clot. Centrifuge the tube (1200 – 1400 x g for 
10 minutes at room temperature) and collect 3 x 500ul of supernatant into correctly 
labeled vials. Transfer serum to storage in a -80 °C freezer within 30 minutes of 
collection.

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REVISED TEXT
At Screening and in Session 3 only, blood samples for NT-Pro BNP determinations
will be drawnat the timepoints in Section 6.1 before and after the maximal exercise 
test, before the constant workload exercise test and after MRI scanning only in 
subjects with HF.  Collect each serial whole blood biomarker sample as close as 
possible to the planned time relative to dosing. Collect whole blood into a properly 
labeled 2.5mL SST blood collection tube (supplied by GSK). Record the date 
andexact time that each sample is collected.  Details of the processing, storage, and 
shipping of samples are located in the SPM.
Immediately after collection, gently invert (DO NOT SHAKE) the evacuated blood 
collection tube 5 times to mix and place upright at room temperature for 30 – 120 
minutes (or at 2 – 8 °C for 12 -16 hours) to clot. Centrifuge the tube (1200 – 1400 x 
g for 10 minutes at room temperature) and collect 3 x 500ul of supernatant into 
correctly labeled vials.  Transfer serum to storage in a -80 °C freezer within 30 
minutes of collection.
Section 6.5. Dyspnoea Scale Scoring
PREVIOUS TEXT
A standardised, validated dyspnoea 5-point Likert scale and a visual analog scale 
(Mebazaa 2010) will be used immediately before exercise (Session 3 only), before 
scanning, and after scanning to provide a clinical correlate of changes of MRI measures 
of pulmonary physiology as measured by DCE-MRI.  The data will be correlated to 
respiratory rate measured in the same time points.
Details for the scales are located in the SPM (Section 11.2).
REVISED TEXT
After the MRI scan in Sessions 1 and 2, a standardised, validated dyspnoea 5-point 
Likert scale and a visual analog scale (Mebazaa 2010) will be completed.  In Session 3 
only, the score will be completed used immediately before and after the maximal
exercise test, and before and after the constant workload exercise (Session 3 only),
test (before scanning) and after MRI scanning before scanning, and after scanning 
to provide a clinical correlate of changes of MR measures of pulmonary physiology 
as measured by DCE-MRI.  The data will be correlated to respiratory rate 
measured in the same time points.
Details of the scale and administration are located in Appendix 2 (Section 11.2) and 
the SPM.
Section 6.6 Respiratory Rate [ADDED SECTION]
Respiratory rate will be recorded over a 60-second period.  Respiratory rate will be 
measured after the MRI scan in Sessions 1 and 2.  In Session 3 only, respiratory rate 
will be measured immediately before and after the maximal exercise test, and before 

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and after the constant workload exercise test (before scanning), and after MRI
scanning.  Any additional measurements to be taken during the exercise testing 
procedure will be detailed in the SPM. 
Section 6.7.1 Subject Scanning Procedures
DELETED TEXT
All subjects will be scanned using this scanner.
Section 6.7.4 DCE-MRI Data Analysis
ADDED TEXT
...Median values of ktrans and ve will be provided from each lung (total lung, apical and 
basal) for subsequent statistical analysis.  All values will be corrected for the individual’s 
haematocrit value. If not available, a typical haematocrit value will be assumed.
Section 6.8 Exercise Test
PREVIOUS TEXT
On Scan Visit 3, subjects will perform a maximal exercise test limited by dysponea or 
fatigue on a cycle ergometer.  After a rest period, the workloads will be increased in a 
step wise fashion by 25 watts every 3 minutes.  Breath by breath gas exchange and heart 
rate will be measured throughout exercise.  During each 3 minute workload, Borg RPE 
and blood pressure will be obtained including same at peak exercise.  Gas exchange 
endpoints included peak VO2, Ve/VCO2 slope, RER, exercise time, and VO2 and time at 
ventilator threshold will also be recorded.  Details of the exercise test protocol are located 
in the SPM.
REVISED TEXT
In Session 3, subjects will perform two exercise tests.
Maximal Exercise Test Limited by Dyspnoea or Fatigue
Subjects will first be asked to perform a maximal exercise test limited by dyspnoea or 
fatigue on a cycle ergometer.  Baseline measurements (heart rate, blood pressure, 
respiratory rate, and breath-by-breath gas exchange measurements: oxygen 
consumption (VO2), ventilation/carbon dioxide production (VE/VCO2) slope, 
respiratory exchange ratio (RER), and VO2 and time at ventilator threshold) will be 
performed with subjects seated on the cycle ergometer for approximately 3 minutes.  
Subjects will then be asked to commence cycling at 20 watts for 3 minutes.  The 
workloads will be increased in a stepwise fashion by 20 watts every 3 minutes until 
volitional fatigue.  Breath-by-breath gas measurements and heart rate will be recorded
throughout exercise.  At the end of each 3-minute workload, Borg Rating of Perceived 
Exertion (RPE) (See Section 11.3 Appendix 3) and blood pressure will be obtained.  At
peak exercise, heart rate, blood pressure, Borg RPE, and breath-by-breath gas 
exchange measurements including peak VO2 will be recorded.  Respiratory rate at 
the end of exercise will also be recorded.

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Constant Workload Exercise Test
Subjects will be asked to perform cycle exercise for 10 minutes at a workload 
between 75% to 80% of the peak work rate achieved during the maximal exercise to 
exhaustion test described above.  Breath-by-breath gas measurements (VO2, RER, 
exercise time) and heart rate will be measured throughout the exercise period.  
Blood pressure and respiratory rate will also be measured.
Full details of the exercise test protocols are included in the SPM.
Section 6.9 DLCO and DLNO
PREVIOUS TEXT
Details of test are located in the SPM.
REVISED TEXT
DLco and DLno measurements will be made after each MRI scan has been 
completed and prior to the constant workload exercise test in Session 3, Visit 2.
Details of the pulmonary testing methodology including diffusing capacity and 
measured components are included in the SPM.  Details of test are located in the 
SPM.
Section 6.10 Adverse Events (AE) and Serious Adverse Events (SAEs) 
[RENAMED SECTION]
DELETED TEXT
The Investigator (or designated site staff) is responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
Section 6.10.1 Time Period for Collecting AE and SAE Information
PREVIOUS TEXT
AEs will be collected from the start of the study (Visit 1) and until the discharge from the 
last visit.  Medical occurrences that begin prior to the start of study (Visit 1) but after 
obtaining informed consent may be recorded on the Medical History/Current Medical 
Conditions eCRF.
SAEs will be collected over the same time period as stated above for AEs.  However, any 
SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) will be recorded from the time a subject 
consents to participate in the study up to and including any follow-up contact...
NOTE: The method of, recording, evaluating and follow-up of AEs and SAEs plus 
procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 1.

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REVISED TEXT
AEs will be collected from the start of the study (Visit 1) and until the discharge 
from the last visit.  Medical occurrences that begin prior to the start of study (Visit 
1) but after obtaining informed consent may be recorded on the Medical 
History/Current Medical Conditions eCRF.
SAEs will be collected over the same time period as stated above for AEs.  However, 
Any SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) will be recorded from the time a subject 
consents to participate in the study up to and including the last visit any follow-up 
contact...
NOTE: The method of, recording, evaluating and follow-up of AEs and SAEs plus 
procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 1.
Section 6.10.2 Method of Detecting AEs and SAEs [DELETED SECTION]
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-
ended and non-leading verbal questioning of the subject is the preferred method to 
inquire about AE occurrence.  Appropriate questions include:

How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, since your last visit/contact?”
Section 6.10.2 Definition of Adverse Events
ADDED TEXT
Since no investigational product will be administered in this study, information 
regarding the occurrence of adverse events will not be routinely collected.   Medical 
occurrences (non-serious events) that begin during the study may be recorded under 
Medical History/Current Medical Conditions.  Non-serious events related to study 
procedures may also be recorded.
Section 6.10.4 Death Events
PREVIOUS TEXT
This information should be recorded in the specific death eCRF within one week of when 
the death is first reported.
REVISED TEXT
This information should be recorded in the specific death form eCRF within one week of 
when the death is first reported.

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Section 6.10.6 Regulatory Reporting Requirements for SAEs
DELETED TEXT
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 regulatory authorities, IRBs/IECs and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.  An investigator who receives an investigator safety report 
describing an SAE(s) or other specific safety information (e.g., summary or listing of 
SAEs) from GSK will file it with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
Section 7. Data Management
PREVIOUS TEXT
For this study, subject data will be entered into GSK-defined electronic case report forms 
(eCRFs), transmitted electronically to GSK and combined with data provided from other 
sources in a validated data system.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using MedDRA (Medical Dictionary for Regulatory Activities) and 
an internal validated medication dictionary, GSKDrug eCRFs (including queries and 
audit trails) will be retained by GSK, and copies will be sent to the Investigator to 
maintain as the investigator copy.  Subject initials will not be collected or transmitted to 
GSK according to GSK policy.
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 Regulatory Activities) and 
an internal validated medication dictionary, GSKDrug.  eCRFs will be retained by GSK, 
and the Investigator will retain a copy.  Subject initials will not be collected or 
transmitted to GSK according to GSK policy.
REVISED TEXT
For this study, subject data will be entered into an GSK-defined electronic Phase I 
Information Management System case report forms (PIMS eCRFs), transmitted 
electronically to GSK, and combined with data provided from other sources in a validated 
data system.

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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.  Serious adverse events and concomitant 
medications terms will be coded using MedDRA (Medical Dictionary for Regulatory 
Activities) and an internal validated medication dictionary, GSKDrug eCRFs (including 
queries and audit trails) will be retained by GSK, and copies will be sent to the 
Investigator to maintain as the investigator copy.  Subject initials will be collected in 
PIMS and remain as a site record; subject initials will not be collected or transmitted to 
GSK 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 Regulatory 
Activities) and an internal validated medication dictionary, GSKDrug.  eCRFs will 
be retained by GSK, and the Investigator will retain a copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.
Section 8.1 Hypotheses and Treatment Comparisons [RENAMED SECTION]
Section 8.4.2 Final Analyses
ADDED TEXT
The correlations of  MRI measures with clinical and biochemical measures:  dyspnoea 
score, NYHA grade, respiratory rate, NT-proBNP, exercise capacity, DLco, DLno,
body weight, urine specific gravity, fractional excretion of sodium (FENa), blood urea to 
creatinine ratio and others will also be explored as data permit.
Section 11.3 Appendix 2: Dsyspnoea Scale [ADDED APPENDIX]
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.

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Source:  Mebazaa A et al.  The impact of early standard therapy on dyspnoea in 
patients with acute heart failure: the URGENT-dyspnea study.  Eur. Heart J 2010; 
31:832-841.
Section 11.5 Appendix 3:  Borg Rating of Perceived Exertion (RPE) Scale 
[ADDED APPENDIX]
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.

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AMENDMENT 2
Where the Amendment Applies
This amendment applies to all sites (single site study).
Summary of Amendment Changes with Rationale
This protocol amendment changes modifies inclusion criteria, clarifies the exercise 
protocol, and corrects the footnote numbering in the time and events table.
List of Specific Changes
Section 4.2.1  Inclusion Criteria
PREVIOUS TEXT
4.2.1.1 Inclusion Criteria for Heart Failure Group
1. Established diagnosis of mild to moderate heart failure of any aetiology with 
symptoms defined as corresponding to the New York Heart Association (NYHA) 
class II or III
2. Capable in participating in the exercise assessments
4.2.1.2 Inclusion Criteria for Healthy Volunteer Group
1. Healthy as determined by a responsible and experienced physician, based on a 
medical evaluation including medical history, brief physical examination, clinical 
laboratory tests, and ECG
4.2.1.3 Inclusion Criteria for Both the Healthy Volunteer and Heart Failure Groups
1. Male or females over 18 years of age at the time of signing the informed consent
2. Body weight 50kg and BMI within the range 18.5-32.0 kg/m2 (inclusive)
3. Able to understand and comply with protocol requirements, instructions and 
protocol-stated restrictions and is willing to take part in the imaging sessions
4. Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form

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REVISED TEXT
4.2.1.1 Inclusion Criteria for Heart Failure Group
1. Established diagnosis of mild to moderate heart failure of any aetiology with 
symptoms defined as corresponding to the New York Heart Association (NYHA) 
class II or III
2. Capable of participating in the exercise assessments
4.2.1.2 Inclusion Criteria for Healthy Volunteer Group
1. Healthy as determined by a responsible and experienced physician, based on a 
medical evaluation including medical history, brief physical examination, clinical 
laboratory tests, and ECG
4.2.1.3 Inclusion Criteria for Both the Healthy Volunteer and Heart Failure Groups
1. Males or females over 18 years of age at the time of signing the informed consent
2. Body weight 50kg and BMI within the range 18.5-32.040 kg/m2 (inclusive)
3. Able to understand and comply with protocol requirements, instructions and 
protocol-stated restrictions and is willing to take part in the imaging sessions
4. Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form

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Section 6.1 Time and Events Table
PREVIOUS TEXT
Day:
Screening
Session 1
Session 2
Session 34
Visit Window
-35 to -1 days
Day 1
7±2 days after 
Session 1
Scan up to 3 days after 
Scan in Session 2
Visit 1
Visit 2
Informed Consent
X
Demography/Medical History/Concomitant 
Medications1
X
Brief Physical Examination
X
X
X
X
Orthopnoea Assessment2
X
Urinalysis, Pregnancy test3, 
Drugs of abuse screen, alcohol breath test
X
X
X
X
Electrocardiograph (ECG)
X
Vital Signs
X
X
X
X
X
Respiratory Rate6
X
X
X
X
Clinical Laboratory Assessments
X
X2
X2
X2
NT- pro BNP2
X
X5
X5
Dyspnoea Scoring6
X
X
X
X
Exercise Testing7
X
X
Magnetic Resonance Imaging 
with pulse oximetry monitoring
X
X
X
DLCO and DLNO8
X
X
X
Record any SAEs, and any AEs related to 
study procedures9
X
X
X
X
X
1.
For subjects with HF, additional history assessments are detailed in Section 6.2.
2.
HF subjects only, details in the SPM.
3.
Women of childbearing potential only.
4.
Session 3 will be conducted over two visits.  The two visits do not need to be on consecutive days.  In Session 3, a blood sample for 
NT-proBNP will be collected before and after the maximal exercise test, before the constant workload exercise test, and after the MRI 
scan.

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5.
The dyspnoea score will be obtained before and after the maximal exercise test, before the constant workload exercise test, and after 
the MRI scan. Respiratory rate will be measured at these same timepoints (and as indicated during the exercise testing).
6.
The exercise testing (maximal exercise to exhaustion and constant workload tests) may be conducted over a two-day (consecutive or 
non-consecutive) period.  The maximal exercise test will be conducted before the constant workload test.
7.
DLco and DLno measurements will be made after each MRI scan has been completed and prior to the constant workload exercise test 
in Session 3 (Visit 2).
8.
See Section 6.10.2 and Section 6.10.3.
REVISED TEXT
6.1
Time and Events Table
Day:
Screening
Session 1
Session 2
Session 34
Visit Window
-35 to -1 days
Day 1
7±2 days after 
Session 1
Scan up to 3 days after 
Scan in Session 2
Visit 1
Visit 2
Informed Consent
X
Demography/Medical History/Concomitant 
Medications1
X
Brief Physical Examination
X
X
X
X
Orthopnoea Assessment2
X
Urinalysis, Pregnancy test3, 
Drugs of abuse screen, alcohol breath test
X
X
X
X
Electrocardiograph (ECG)
X
Vital Signs
X
X
X
X
X
Respiratory Rate6
X
X
X
X
Clinical Laboratory Assessments
X
X2
X2
X2
NT- pro BNP2
X
X5
X5
Dyspnoea Scoring6
X
X
X
X
Exercise Testing7
X
X
Magnetic Resonance Imaging 
with pulse oximetry monitoring
X
X
X
DLCO and DLNO8
X
X
X

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Day:
Screening
Session 1
Session 2
Session 34
Record any SAEs, and any AEs related to 
study procedures9
X
X
X
X
X
1.
For subjects with HF, additional history assessments are detailed in Section 6.2.
2.
HF subjects only, details in the SPM.
3.
Women of childbearing potential only.
4.
Session 3 will be conducted over two visits.  The two visits do not need to be on consecutive days.  
5.
In Session 3, a blood sample for NT-proBNP will be collected before and after the maximal exercise test, before the constant 
workload exercise test, and after the MRI scan.
6.
The dyspnoea score will be obtained before and after the maximal exercise test, before the constant workload exercise test, and after 
the MRI scan. Respiratory rate will be measured at these same timepoints (and as indicated during the exercise testing).
7.
The exercise testing (maximal exercise to exhaustion and constant workload tests) may be conducted over a two-day (consecutive or 
non-consecutive) period.  The maximal exercise test will be conducted before the constant workload test.
8.
DLco and DLno measurements will be made after each MRI scan has been completed and prior to the constant workload exercise test 
in Session 3 (Visit 2).
9.
See Section 6.10.2 and Section 6.10.3.

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Section 6.8 Exercise
PREVIOUS TEXT
In Session 3, subjects will perform two exercise tests.
Maximal Exercise Test Limited by Dyspnoea or Fatigue
Subjects will first be asked to perform a maximal exercise test limited by dyspnoea or 
fatigue on a cycle ergometer.  Baseline measurements (heart rate, blood pressure, 
respiratory rate, and breath-by-breath gas exchange measurements: oxygen consumption 
(VO2), ventilation/carbon dioxide production (VE/VCO2) slope, respiratory exchange 
ratio (RER), and VO2 and time at ventilator threshold) will be performed with subjects 
seated on the cycle ergometer for approximately 3 minutes.  Subjects will then be asked 
to commence cycling at 20 watts for 3 minutes.  The workloads will be increased in a 
stepwise fashion by 20 watts every 3 minutes until volitional fatigue.  Breath-by-breath 
gas measurements and heart rate will be recorded throughout exercise.  At the end of each 
3-minute workload, Borg Rating of Perceived Exertion (RPE) (See Section 11.3 
Appendix 3) and blood pressure will be obtained.  At peak exercise, heart rate, blood 
pressure, Borg RPE, and breath-by-breath gas exchange measurements including peak 
VO2 will be recorded.  Respiratory rate at the end of exercise will also be recorded.
DELETED TEXT
In Session 3, subjects will perform two exercise tests.
Maximal Exercise Test Limited by Dyspnoea or Fatigue
Subjects will first be asked to perform a maximal exercise test limited by dyspnoea or 
fatigue on a cycle ergometer.  Baseline measurements (heart rate, blood pressure, 
respiratory rate, and breath-by-breath gas exchange measurements: oxygen consumption 
(VO2), ventilation/carbon dioxide production (VE/VCO2) slope, respiratory exchange 
ratio (RER), and VO2 and time at ventilator threshold) will be performed with subjects 
seated on the cycle ergometer for approximately 3 minutes.  Subjects will then be asked 
to commence cycling at 20 watts for 3 minutes.  The workloads will be increased in a 
stepwise fashion by 20 watts every 3 minutes until volitional fatigue.  Breath-by-breath 
gas measurements and heart rate will be recorded throughout exercise.  At the end of each 
3-minute workload, Borg Rating of Perceived Exertion (RPE) (See Section 11.3 
Appendix 3) and blood pressure will be obtained.  At peak exercise, heart rate, blood 
pressure, Borg RPE, and breath-by-breath gas exchange measurements including peak 
VO2 will be recorded.  Respiratory rate at the end of exercise will also be recorded.

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AMENDMENT 3
WHERE THIS AMENDMENT APPLIES
This amendment applies to all sites (single site study).Amendment 3
SUMMARY OF CHANGES WITH RATIONALE
Amendment No. 3 adds an evaluation of an additional group of subjects who have been 
hospitalized for acute decompensated heart failure to determine whether DCE-MRI can 
detect changes in measures of pulmonary oedema with standard of care treatment.
List of Changes
LIST OF ABBREVIATIONS
ADDED TEXT
ADHF
Acute Decompensated Heart Failure
CXR
Chest X-Ray
LUS
Lung Ultrasound
mSv
Milli-Sievert
PE
Pulmonary Oedema
Sv
Sievert
Section 1.1 Study Rationale
ADDED TEXT
Additionally, the capability of DCE-MRI to detect changes in interstitial lung fluid 
in patients with acute decompensated heart failure (ADHF) will be investigated.  
DCE-MRI markers of pulmonary oedema will be assessed when patients are 
initially hospitalized with ADHF and subsequently after receiving standard of care 
treatment to determine whether differences can be detected by this methodology.  
Lung ultrasound (LUS) may also be explored in patients with ADHF as a potential 
tool for assessment of extra-vascular lung water through measurement of B-lines.

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Section 2 Objectives and Endpoints
ADDED TEXT
Objectives
Endpoints
Primary

Explore the effect of standard of 
care treatment on DCE-MRI 
measures of pulmonary oedema and 
vascular permeability in patients 
with ADHF.

Change in interstitial volume (ve) 
and exchange rate (ktrans) 
measured using DCE-MRI in 
patients with ADHF during 
hospitalization and following the 
resolution of pulmonary oedema.
Exploratory

Explore the effect of standard of care 
treatment on plasma volume and 
MRI physical properties influenced 
by the tissue microenvironment 
relaxation rate, and proton density in 
patients with ADHF.

Explore the effect of standard of care 
treatment on ultrasound measures of 
pulmonary oedema in patients with 
ADHF.

Explore the distribution of DCE-
MRI measures of pulmonary 
physiology in ADHF patients both 
before and after standard of care 
treatment

Change in Plasma volume (vp), 
T1 relaxation rate, and proton 
density measured using MRI in 
patients with ADHF during 
hospitalization and following the 
resolution of pulmonary oedema

Change in B-lines measured 
using ultrasound in patients with 
ADHF during hospitalization 
and following the resolution of 
pulmonary oedema

Interstitial volume (ve) and 
exchange rate (ktrans), and other 
clinical and biochemical 
measures as listed above if data 
permit
Section 3.1 Study Schematic
PREVIOUS TEXT
Protocol waivers or exemptions are not allowed.  Therefore, adherence to the study 
design requirements, including those specified in the Time and Events Table, are 
essential.  
The study design schematic is shown below:

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REVISED TEXT
Protocol waivers or exemptions are not allowed.  Therefore, adherence to the study 
design requirements, including those specified in the Time and Events Table, are 
essential.  
For healthy volunteers and subjects with HF (Groups 1 and 2, respectively), tThe 
study design schematic is shown below:
For subjects with ADHF (Group 3), the study design is shown below:
Section 3.2 Study Design Detail
PREVIOUS TEXT
The study consists of four sessions.  The first visit will be a Screening Visit during which 
an appropriately trained study team member will describe the study, answer any 
questions the potential participant may have about the study seek informed, written 
consent, and assess eligibility to enrol in the study.  Within 35 days, subjects will return 
for the first scanning session, where subjects will undergo the baseline procedure.  The 
second imaging session will occur approximately one week later to measure within-
subject variability.  A third imaging session (which will be conducted in 2 visits) will 
incorporate a bicycle exercise challenge prior to the MRI scan, and this third scan will be 
performed approximately one to three days after the second imaging session.

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REVISED TEXT
For Groups 1 and 2, tThe study will consists of four sessions.  The first visit will be a 
Screening Visit during which an appropriately trained study team member will describe 
the study, answer any questions the potential participant may have about the study seek 
informed, written consent, and assess eligibility to enrol in the study.  Within 35 days, 
subjects will return for the first scanning session, where subjects will undergo the 
baseline procedure.  The second imaging session will occur approximately one week later 
to measure within-subject variability.  A third imaging session (which will be conducted 
in 2 visits) will incorporate a bicycle exercise challenge prior to the MRI scan, and this 
third scan will be performed approximately one to three days after the second imaging 
session.  
For subjects with ADHF (Group 3), Screening will occur during hospitalization to 
assess eligibility and enrolment in the study.  Session 1 will be conducted while the 
subject is still hospitalized with evidence of pulmonary oedema and receiving 
standard of care treatment.   Session 2 will be conducted within 4 weeks of the first 
scan, when the signs of pulmonary oedema are considered to be resolved as judged 
by the Investigator.  If a subject’s pulmonary oedema has not resolved at Session 2, 
as judged by the Investigator using lung auscultation and/or chest x-ray, then the 
subject will be not be scanned by MRI at Session 2 and will be brought back for 
Session 3 up to 4 weeks after Session 2 for their second MRI.
Section 3.3 Risk Management
PREVIOUS TEXT
Table 1
Summary of Key Issues, Their Impact and Strategy to Mitigate Risk
All inclusion criteria will be satisfied before patients undergo any procedures.
Potential risk
Summary of data
Impact- eligibility 
criteria
Strategy-monitoring/stopping 
criteria
Risk of 
exacerbation of 
dyspnoea in heart 
failure subjects 
when lying supine.
This is expected to be rapidly 
reversible on sitting upright, as the 
orthopnoea effect is dependent upon 
venous pressure
To minimize the 
risk, only patients 
with clinically 
stable heart failure 
(as defined in 
Section 4.2 will be 
recruited, and a 
trial of the supine 
position will be 
performed during 
the screening 
visit.
All procedures will be medically 
supervised.  There is continuous 
monitoring of peripheral oxygen 
saturations and heart rate in the 
scanner control room, as well as 
direct vision down the magnet bore 
from the control room.  The subject 
has a squeeze-bulb call bell to 
interrupt scanning.  MRI 
compatible trolleys, wheel chairs 
and oxygen cylinders allow for 
removal from the scanner room 
into the foyer of the scanning suite 
where a full resuscitation trolley is 
available.  All scanning staff 
members are trained in the 
emergency removal of subjects 
from the scanners.

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Potential risk
Summary of data
Impact- eligibility 
criteria
Strategy-monitoring/stopping 
criteria
In the event of significant 
dyspnoea, treatments available in 
the study area will include sitting 
upright and oxygen if required.  If 
further therapies are required, best 
practice clinical management 
including transfer to hospital for 
further management will be 
undertaken.
Use of Gd in 
subjects with 
abnormal renal 
function may result 
in Nephrogenic 
Systemic 
Fibrosis/Nephroge
nic Fibrosing 
Dermopathy 
(NSF/NFD).
Gadobutrol (Gd) (Gadovist; Bayer) at 
a dose less than or equal to 
0.1mmol/kg will be used in the MRI 
protocol.  It is excreted in the urine 
with approximately 50% and 90% of 
the dose excreted by 2 and 12 hours, 
respectively, post-injection. 
Approximately 200 million patients 
have had contrast enhanced Gd MRI 
examinations since such scans were 
first introduced 20 years ago 
[Thomsen, 2006].  The contrast 
agents are widely used off label for 
MRI angiography and cardiac MRI 
due to their low side effect profile and 
low risk of nephrotoxicity.  From June 
2006 to 12 April 2007, more than 215 
individuals with NSF/NFD had been 
reported to the FDA [Cowper, 
ICNSFR Website, 2007].  All these 
individuals were exposed to Gd prior
to developing NSF and all had 
moderate to end-stage renal disease 
prior to exposure to Gd:  
approximately 90% of the cases were 
dialysis dependent whilst the 
remaining 10% of subjects had 
chronic kidney disease or acute 
kidney injury [Perazella, 2007].  The 
incidence of NSF in dialysis and end-
stage renal disease patients when 
exposed to Gd is in the range 3-5% 
[Marckmann, 2006; Kuo, 2008;  
However, there are no reports of NSF 
in subjects with normal renal function 
[Perazella, 2007; Deo, 2007;  
Chewning, 2007;Thomsen, 2006].  It 
is concluded that subjects dependent 
on dialysis and those with estimated 
glomerular filtration rate (eGFR) 
<30mL/min (chronic kidney disease 
stage 4/5) are at risk of developing 
NSF on exposure to Gd [Perazella, 
2007].
As a result of this 
recent evidence, 
subjects with 
creatinine 
clearance levels < 
60mL/min will be 
excluded from this 
study.
Gd contains unpaired electrons 
that interact with neighbouring 
water molecules and thereby 
generate MRI contrast.  Free 
unbound Gd is extremely toxic, but 
when chelated to a ligand, its 
safety profile is dramatically 
improved, assisted by a 500-fold 
increase in renal excretion 
[Kramer, 2007].
The elimination half-time in 
patients with normal renal function 
is approximately 1.5 hours,but in 
patients with severely reduced 
kidney function (GFRs between 2-
10), it is as long as 34 hours.  The 
decreased elimination time may 
allow Gd to dissociate from its 
chelating agent.  Free, unbound 
Gd may then deposit in tissue beds 
and incite a fibrotic process, 
perhaps via circulating fibrocytes. 
Patients with normal renal function 
appear to have negligible risk of 
developing NSF/NFD [Kramer, 
2007].
Side effects from 
Side effects of bicycle testing can 
Inclusion criteria.  
Medical oversight during the test.

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Potential risk
Summary of data
Impact- eligibility 
criteria
Strategy-monitoring/stopping 
criteria
bicycle testing
include shortness of breath, light-
headedness, drop in blood pressure, 
and abnormal heart rhythm.  In rare 
cases, these side effects can be 
serious or life-threatening.  Also 
possible are direct injuries such as 
bruises, sprains, and strains and 
indirect problems such worsening of 
pain from arthritis.
Medical history 
and PI discretion 
as to patient’s 
ability to 
participate in the 
exercise test.
Subject may not 
be able to enter 
the MRI machine
Certain interventions, prostheses, or 
foreign bodies might be incompatible 
with the MRI scanner.
Exclusion criteria 
and local MRI 
scanning facility 
criteria
All participants will be screened 
according to local hospital criteria 
and trial inclusion/exclusion before 
entering the MRI room to ensure 
they are able to have the MRI 
conducted.
Subject may not 
be able to 
complete MRI 
once started
MRI can be associated with 
claustrophobia.  The radio fields used 
in MRI can cause mild nerve 
stimulation and tissue heating, both of 
which are strictly regulated by both 
software and hardware controls 
implemented by the scanner 
manufacturer that cannot be 
bypassed.
Exclusion criteria 
and medical 
history.
All scans will be conducted by 
experienced radiographers and 
radiologists in the nominated 
scanning sites.  If a subject 
becomes claustrophobic, the 
subject will be withdrawn from the 
study if they are unable to tolerate 
it again.
REVISED TEXT
Table 1
Summary of Key Issues, Their Impact and Strategy to Mitigate Risk
All inclusion criteria will be satisfied before patients undergo any procedures.
Potential risk
Summary of data
Impact- eligibility 
criteria
Strategy-monitoring/stopping 
criteria
Risk of 
exacerbation of 
dyspnoea in heart 
failure subjects 
when lying supine.
This is expected to be rapidly 
reversible on sitting upright, as the 
orthopnoea effect is dependent upon 
venous pressure
To minimize the 
risk, only 
patients with 
clinically stable 
heart failure (as 
defined in 
Section 4.2 will 
be recruited, and 
a trial of the 
supine position 
will be performed 
during the 
screening visit.
All procedures will be medically 
supervised.  There is continuous 
monitoring of peripheral oxygen 
saturations and heart rate in the 
scanner control room, as well as 
direct vision down the magnet bore 
from the control room.  The subject 
has a squeeze-bulb call bell to 
interrupt scanning.  MRI 
compatible trolleys, wheel chairs 
and oxygen cylinders allow for 
removal from the scanner room 
into the foyer of the scanning suite 
where a full resuscitation trolley is 
available.  All scanning staff 
members are trained in the 
emergency removal of subjects 
from the scanners.

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Potential risk
Summary of data
Impact- eligibility 
criteria
Strategy-monitoring/stopping 
criteria
In the event of significant 
dyspnoea, treatments available in 
the study area will include sitting 
upright and oxygen if required.  If 
further therapies are required, best 
practice clinical management 
including transfer to hospital for 
further management will be 
undertaken.
Use of Gd in 
subjects with 
abnormal renal 
function may result 
in Nephrogenic 
Systemic 
Fibrosis/Nephroge
nic Fibrosing 
Dermopathy 
(NSF/NFD).
Gadobutrol (Gd) (Gadovist; Bayer) at 
a dose less than or equal to 
0.1mmol/kg will be used in the MRI 
protocol.  It is excreted in the urine 
with approximately 50% and 90% of 
the dose excreted by 2 and 12 hours, 
respectively, post-injection. 
Approximately 200 million patients 
have had contrast enhanced Gd MRI 
examinations since such scans were 
first introduced 20 years ago 
[Thomsen, 2006].  The contrast 
agents are widely used off label for 
MRI angiography and cardiac MRI 
due to their low side effect profile and 
low risk of nephrotoxicity.  From June 
2006 to 12 April 2007, more than 215 
individuals with NSF/NFD had been 
reported to the FDA [Cowper, 
ICNSFR Website, 2007].  All these 
individuals were exposed to Gd prior 
to developing NSF and all had 
moderate to end-stage renal disease 
prior to exposure to Gd:  
approximately 90% of the cases were 
dialysis dependent whilst the 
remaining 10% of subjects had 
chronic kidney disease or acute 
kidney injury [Perazella, 2007].  The 
incidence of NSF in dialysis and end-
stage renal disease patients when
exposed to Gd is in the range 3-5% 
[Marckmann, 2006; Kuo, 2008;  
However, there are no reports of NSF 
in subjects with normal renal function 
[Perazella, 2007; Deo, 2007; 
Chewning, 2007;Thomsen, 2006].  It 
is concluded that subjects dependent 
on dialysis and those with estimated 
glomerular filtration rate (eGFR) 
<30mL/min (chronic kidney disease 
stage 4/5) are at risk of developing 
NSF on exposure to Gd [Perazella, 
2007].
As a result of this 
recent evidence, 
subjects with 
creatinine 
clearance levels < 
60mL/min will be 
excluded from this 
study (Groups 1 
and 2) and < 
40mL/min in 
Group 3.
Gd contains unpaired electrons 
that interact with neighbouring 
water molecules and thereby 
generate MRI contrast.  Free 
unbound Gd is extremely toxic, but 
when chelated to a ligand, its 
safety profile is dramatically 
improved, assisted by a 500-fold 
increase in renal excretion 
[Kramer, 2007].
The elimination half-time in 
patients with normal renal function 
is approximately 1.5 hours,but in 
patients with severely reduced 
kidney function (GFRs between 2-
10), it is as long as 34 hours.  The 
decreased elimination time may 
allow Gd to dissociate from its 
chelating agent.  Free, unbound 
Gd may then deposit in tissue beds 
and incite a fibrotic process, 
perhaps via circulating fibrocytes. 
Patients with normal renal function 
appear to have negligible risk of 
developing NSF/NFD [Kramer, 
2007].
Side effects from 
bicycle testing
Side effects of bicycle testing can 
include shortness of breath, light-
Inclusion criteria.  
Medical history 
Medical oversight during the test.

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Potential risk
Summary of data
Impact- eligibility 
criteria
Strategy-monitoring/stopping 
criteria
headedness, drop in blood pressure, 
and abnormal heart rhythm.  In rare 
cases, these side effects can be 
serious or life-threatening.  Also 
possible are direct injuries such as 
bruises, sprains, and strains and 
indirect problems such worsening of 
pain from arthritis.
and PI discretion 
as to patient’s 
ability to 
participate in the 
exercise test.
Subject may not 
be able to enter 
the MRI machine
Certain interventions, prostheses, or 
foreign bodies might be incompatible 
with the MRI scanner.
Exclusion criteria 
and local MRI 
scanning facility 
criteria
All participants will be screened 
according to local hospital criteria 
and trial inclusion/exclusion before 
entering the MRI room to ensure 
they are able to have the MRI 
conducted.
Subject may not 
be able to 
complete MRI 
once started
MRI can be associated with 
claustrophobia.  The radio fields used 
in MRI can cause mild nerve 
stimulation and tissue heating, both of 
which are strictly regulated by both 
software and hardware controls 
implemented by the scanner 
manufacturer that cannot be 
bypassed.
Exclusion criteria 
and medical 
history.
All scans will be conducted by 
experienced radiographers and 
radiologists in the nominated 
scanning sites.  If a subject 
becomes claustrophobic, the 
subject will be withdrawn from the 
study if they are unable to tolerate 
it again.
Within group 3, 
exposure to 
ionizing radiation 
from chest x-ray.
The dose from a single chest X-ray 
should not exceed 20 micro-sievert 
(Sv) and this corresponds to a 
lifetime risk of a fatal malignancy 
of about 1 in 1 million (ICRP 103). 
The study will minimize exposure 
by using x-rays acquired as part of 
clinical care whenever possible. It 
is expected that all subjects will 
require a single chest x-ray, but 
may have a maximum of 3 chest x-
rays (up to maximum 60 micro-Sv 
within this study, lifetime risk of 
fatal malignancy of approximately 
1 in 333,333).
Females of 
reproductive 
potential and all 
subjects under 
50 years of age 
will be excluded 
from 
participation in 
group 3.
All procedures will be performed 
by a qualified technician.
Section 4.1 Number of Subjects
PREVIOUS TEXT
This study plans to enrol a sufficient number of subjects to have at least 24 subjects (12 
HV and 12 subjects with HF) with evaluable MRI data.  For each subject, the MRI data 
must be of sufficient quality to enable DCE-MRI modelling from both Session 1 and 
Session 2.  Additionally, at least 6 HV and 6 subjects with HF are needed to complete the 
third scanning session with evaluable MRI data following exercise testing.
After 12 subjects (6 HV and 6 subjects with HF) have completed Sessions 1 and 2, an 
interim review will be performed.  Following the interim review, the study team will 

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decide whether to (a) terminate the study if it is determined that the image quality is poor 
(e.g., due to excessive movement during scanning or related to specifics around lung 
tissue) or the procedures are not well tolerated in the HF group (e.g., inability to lie flat 
for the duration of the imaging session), or (b) continue the study to enrol a sufficient 
number of additional subjects to meet the designated numbers required (see above).
The interim decision will be based on the expert opinion of the Investigator in 
consultation with the GSK Study Team.
REVISED TEXT
With respect to Groups 1 and 2, tThis study plans to enrol a sufficient number of 
subjects to have at least 24 subjects (12 HV and 12 subjects with HF) with evaluable MRI 
data.  For each subject, the MRI data must be of sufficient quality to enable DCE-MRI 
modelling from both Session 1 and Session 2.  Additionally, at least 6 HV and 6 subjects 
with HF are needed to complete the third scanning session with evaluable MRI data 
following exercise testing.
After 12 subjects (6 HV and 6 subjects with HF) have completed Sessions 1 and 2, an 
interim review will be performed.  Following the interim review, the study team will 
decide whether to (a) terminate the study if it is determined that the image quality is poor 
(e.g., due to excessive movement during scanning or related to specifics around lung 
tissue) or the procedures are not well tolerated in the HF group (e.g., inability to lie flat 
for the duration of the imaging session), or (b) continue the study to enrol a sufficient 
number of additional subjects to meet the designated numbers required (see above).
The interim decision will be based on the expert opinion of the Investigator in 
consultation with the GSK Study Team.
For Group 3, it is planned that a sufficient number of subjects with ADHF will be 
enrolled so that at least 5 subjects complete two scanning Sessions (1 and 2 or 1 and 
3).
Section 4.2 Eligibility Criteria
PREVIOUS TEXT
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety.  Therefore, adherence to the criteria as specified in the protocol is 
essential.
4.2.1 Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply within each of the subject categories below: 

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4.2.1.1 Inclusion Criteria for Heart Failure Group
3. Established diagnosis of mild to moderate heart failure of any aetiology with 
symptoms defined as corresponding to the New York Heart Association 
(NYHA) class II or III
4.2.1.2 Inclusion Criteria for Healthy Volunteer Group
4.
Healthy as determined by a responsible and experienced physician, based on 
a medical evaluation including medical history, brief physical examination, 
clinical laboratory tests, and ECG
4.2.1.3 Inclusion Criteria for Both the Healthy Volunteer and Heart Failure Groups
5. Males or females over 18 years of age at the time of signing the informed 
consent
6. Body weight 50kg and BMI within the range 18-40 kg/m2 (inclusive)
7. Able to understand and comply with protocol requirements, instructions and 
protocol-stated restrictions and is willing to take part in the imaging sessions
8. Capable of giving written informed consent, which includes compliance with 
the requirements and restrictions listed in the consent form
4.2.2 Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply within each of the subject categories below:
4.2.2.1 Exclusion Criteria for Heart Failure Group
5.
History of known primary pulmonary disease requiring current medication or 
other therapy
6.
Orthopnoea of sufficient severity to preclude supine scanning as determined 
at screening
7.
Unstable angina within the past 3 months
8.
Uncontrolled hypertension (resting systolic BP > 160mmHg or resting 
diastolic BP > 100mmHg)
9.
Resting hypoxia while breathing room air (SaO2 <88%)
4.2.2.2 Exclusion Criteria for Both the Healthy Volunteer and Heart Failure Groups
10. Current smoker, defined as having smoked in the preceding 6 months
11. Contraindication for MRI scanning (as assessed by local MRI safety 
questionnaire), which includes but is not limited to:
c.
Intracranial aneurysm clips (except Sugita) or other metallic objects
d.
Intra- orbital metal fragments that have not been removed 

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e.
Pacemakers or other implanted cardiac rhythm management devices and 
non-MRI compatible heart valves
f.
Inner ear implants
g.
History of claustrophobia
12. Pregnant females as determined by positive urine HCG test at screening or 
prior to any scanning session
13. Positive test for drugs of abuse, not due to current prescription drugs as 
determined by the GSK Medical Monitor and PI, and alcohol screen
14. Estimated creatinine clearance (Cockcroft-Gault) <60mL/minute
REVISED TEXT
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety.  Therefore, adherence to the criteria as specified in the protocol is 
essential.
4.2.1 Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply within each of the subject categories below: 
4.2.1.1 Inclusion Criteria for Heart Failure Group (Group 2)
1. Established diagnosis of mild to moderate heart failure of any aetiology with 
symptoms defined as corresponding to the New York Heart Association 
(NYHA) class II or III
4.2.1.2 Inclusion Criteria for Healthy Volunteer Group (Group 1)
2.
Healthy as determined by a responsible and experienced physician, based on 
a medical evaluation including medical history, brief physical examination, 
clinical laboratory tests, and ECG
4.2.1.3 Inclusion Criteria for Both the Healthy Volunteer and Heart Failure Groups 
(Group 1 and 2)
1. Males or females over 18 years of age at the time of signing the informed consent
2. Body weight 50kg and BMI within the range 18-40 kg/m2 (inclusive)
3. Able to understand and comply with protocol requirements, instructions and 
protocol-stated restrictions and is willing to take part in the imaging sessions
4. Capable of giving written informed consent, which includes compliance with 
the requirements and restrictions listed in the consent form
4.2.1.4 Inclusion Criteria for Subjects with ADHF (Group 3)
1. Male subjects OR female subjects of non reproductive potential as defined as 
pre-menopausal females with a documented tubal ligation or hysterectomy, 
or post-menopausal defined as 12 months of spontaneous amenorrhea [in 

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questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) > 40 MIU/mL and oestradiol < 40pg/mL (< 140 pmol/L) is 
confirmatory. 
2. 50 years of age or over at the time of signing the informed consent
3. Hospitalized for the management of acute decompensated HF 
4. Presence of dyspnoea at rest or with minimal activity
5. Presence of at least one of the following signs:

Tachypnea with respiratory rate ≥20 breaths/min 

Rales or crackles audible on auscultation
6. Chest x-ray with evidence of pulmonary congestion/oedema performed 
approximately within the last 48 hours (if not available – an additional 
research CXR may be requested)
7. Have received at least one treatment with an intravenous diuretic prior to the 
first MRI scan 
8. Body weight ≥ 50kg and BMI within the range 18-40 kg/m2 (inclusive)
9. Able to understand and comply with protocol requirements, instructions and 
protocol-stated restrictions and is willing to take part in the imaging sessions
10. Capable of giving written informed consent, which includes compliance with 
the requirements and restrictions listed in the consent form
4.2.2 Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply within each of the subject categories below:
4.2.2.1 Exclusion Criteria for Heart Failure Group (Group 2)
1.
History of known primary pulmonary disease requiring current medication or 
other therapy
2.
Orthopnoea of sufficient severity to preclude supine scanning as determined 
at screening
3.
Unstable angina within the past 3 months
4.
Uncontrolled hypertension (resting systolic BP > 160mmHg or resting 
diastolic BP > 100mmHg)
5.
Resting hypoxia while breathing room air (SaO2 <88%)

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4.2.2.2 Exclusion Criteria for Both the Healthy Volunteer and Heart Failure Groups 
(Group 1 and 2)
6.
Current smoker, defined as having smoked in the preceding 6 months
7.
Contraindication for MRI scanning (as assessed by local MRI safety 
questionnaire), which includes but is not limited to:
h.
Intracranial aneurysm clips (except Sugita) or other metallic objects
i.
Intra- orbital metal fragments that have not been removed 
j.
Pacemakers or other implanted cardiac rhythm management devices and 
non-MRI compatible heart valves
k.
Inner ear implants
l.
History of claustrophobia
8.
Pregnant females as determined by positive urine HCG test at screening or 
prior to any scanning session
9.
Positive test for drugs of abuse, not due to current prescription drugs as 
determined by the GSK Medical Monitor and PI, and alcohol screen
10. Estimated creatinine clearance (Cockcroft-Gault) <60mL/minute
4.2.2.3 Exclusion Criteria for Subjects with ADHF (Group 3)
1.
End-stage heart failure defined as requiring left ventricular assist devices, 
intra-aortic balloon pump or any type of mechanical support
2.
Chronic or intermittent renal support therapy (hemodialysis, ultrafiltration, or 
peritoneal dialysis)
3.
Ongoing or planned intravenous diuretic treatment within 1 hour of MRI scan 
appointment
4.
History of known primary pulmonary disease requiring current medication or 
other therapy
5.
Orthopnoea of sufficient severity to preclude supine scanning (as determined 
by a 15-minute test of lying supine with or without the use of oxygen)
6.
Contraindication for MRI scanning (as assessed by local MRI safety 
questionnaire), which includes but is not limited to:
a. Intracranial aneurysm clips (except Sugita) or other metallic objects
b. Intra-orbital metal fragments that have not been removed
c. Pacemakers or other implanted cardiac rhythm management devices and 
non-MRI compatible heart valves
d. Inner ear implants
e. History of claustrophobia
7.
Estimated creatinine clearance (Cockcroft-Gault) <40mL/minute
8.
Contraindication to MRI contrast agents
9.
Previous inclusion in a research and/or medical protocol involving nuclear 
medicine, PET or radiological investigations with significant radiation burden 
(a significant radiation burden being defined as 10 mSv in addition to natural 
background radiation, in the previous 3 years including the dose from this 
study).

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Section 4.3.1.1 Female Subjects
PREVIOUS TEXT
No specific forms of contraception are required for female subjects of childbearing 
potential, though they will be informed that they will be withdrawn from the study if they 
become pregnant.
REVISED TEXT
For subjects in Groups 1 and 2, nNo specific forms of contraception are required for 
female subjects of childbearing potential, though they will be informed that they will be 
withdrawn from the study if they become pregnant.  Female subjects under the age of 
50 years or of childbearing potential are not eligible for Group 3. 
Section 4.3.2 Exercise
ADDED TEXT
In Groups 1 and 2, participants will be told to avoid strenuous exercise for 24 hours 
prior to each scanning session.
Section 4.3.3 Caffeine and Alcohol 
ADDED TEXT
(GROUPS 1 AND 2) – to section title
Section 4.4 Withdrawal Criteria and Procedures
PREVIOUS TEXT
A subject may withdraw 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.
Subjects who withdraw or do not have evaluable DCE-MRI data from Sessions 1 and 2 
will be replaced in order to meet the designated number of subjects (see Section 4.1).
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and re-schedule the missed visit as soon as possible.  The site 
should also 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 based on previous non-compliance.  In cases where the subject does not return for 
the rescheduled visit or cannot be reached to reschedule the missed visit, the site should 
make every effort to regain contact with the subject so that they can be withdrawn 
appropriately from the study.

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REVISED TEXT
A subject may withdraw 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.
For Groups 1 and 2, sSubjects who withdraw or do not have evaluable DCE-MRI data 
from Sessions 1 and 2 will be replaced in order to meet the designated number of subjects 
(see Section 4.1).  For subjects in group 3, who withdraw or do not have evaluable 
DCE-MRI scans from either Session 1 and 2 or Session 1 and 3 will be replaced in 
order to meet the designated number of subjects.
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and re-schedule the missed visit as soon as possible.  The site 
should also 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 based on previous non-compliance.  In cases where the subject does not return for 
the rescheduled visit or cannot be reached to reschedule the missed visit, the site should 
make every effort to regain contact with the subject so that they can be withdrawn 
appropriately from the study. 
Section 4.5 Subject Completion
ADDED TEXT
A completed subject is defined as one who has completed all sessions of the study.
The end of the study is defined as the last subject’s last visit.
Section 5.1 Concomitant Medications and Therapies
PREVIOUS TEXT
Subjects in the healthy group may take all regularly prescribed and over-the-counter 
medication as planned throughout this study.
Subjects in the heart failure group will take all regularly prescribed and over the counter 
medication as planned - except for loop diuretics, aldosterone antagonists, and thiazide 
diuretics on the day of imaging.  These subjects will take their dose of these medicines 
after imaging has completed on that day.
REVISED TEXT
Group 1: Subjects in the healthy group may take all regularly prescribed and over-the-
counter medication as planned throughout this study.
Group 2: Subjects in the heart failure group will take all regularly prescribed and over 
the counter medication as planned - except for loop diuretics, aldosterone antagonists, 
and thiazide diuretics on the day of imaging.  These subjects will take their dose of these 
medicines after imaging has completed on that day.

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Group 3: Subjects who have been hospitalized for ADHF will receive standard of 
care treatment both during the hospitalization period and following discharge.   
Within 1 hour of a planned MRI scan appointment, subjects should not have any 
ongoing or planned intravenous diuretic treatment (i.e., any treatment should be 
given after the planned scan appointment). Current diuretic dose will be recorded at 
each session.
Section 6 Study Assessments and Procedures
ADDED TEXT AND TABLE
For Groups 1 and 2, the procedures and assessments related to exercise testing in 
Session 3, will be conducted on two separate visits as detailed in the Time and 
Events Table, Section 6.1.1.  The visits do not need to be on consecutive days.
Table 6.1.1. Time and Event Table for Healthy Volunteers and Subjects with 
HF (Groups 1 and 2)

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Table 6.1.2 Time and Event Table for Subjects with ADHF (Group 3)
PROCEDURE
SCREENING
SESSION 1
SESSION 24
SESSION 35
Following Hospital
Admission For ADHF
During Hospitalization
For ADHF
Up To 4 Weeks
After Session 1
Up To 4 Weeks
After Session 2
Informed Consent
X
Demography/Medical 
History/Concomitant Medications1
X
X8
X8
X8
Vital Signs including weight
X
X2
X
X
Lung Auscultation 
X
X2
X
X
Orthopnoea Assessment 
X
Chest X-Ray3
X2
X
X
Oximetry
X
X
X
X
Lung Ultrasound6
X7
X
X
Magnetic Resonance Imaging (DCE-
MRI)
X
X
X
Dyspnoea Score (5-Point Likert 
Scale)
X
X
X
X
Respiratory Rate
X
X
X
X
Creatinine
X
X
X
X
Haematocrit9
X
X
X
X
FSH and Estradiol10
X
NT proBNP
X
X
X
Record Any SAEs and any AEs 
Related To Study Procedures
X
X
X
1.
Information will be reviewed based on available hospital records 
2.
Assessment does not need to be repeated if Session 1 is conducted within 48 hours of Screening
3.
At any designated visit, a chest X-ray need not be repeated if one has already been conducted as part of standard care
4.
Session 2 will only be conducted when the pulmonary oedema is considered resolved.  If pulmonary oedema is considered unresolved, only CXR and LUS may be collected.
5.
Session 3 only in subjects deemed to not have pulmonary oedema resolved at session 2 by the Investigator.  

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6.
Where feasible, Ultrasound may be performed to assess pulmonary oedema in addition to lung auscultation and / or CXR.  The LUS may be completed at a separate visit (± 
3 Days). Additional anatomic structures may be assessed during any ultrasound.
7.
Multiple ultrasounds may be performed during hospitalization period of Session 1 up to one daily with a maximum of 3. 
8.
Sessions 1, 2 and 3 will include recording current diuretic dosage
9.
Haematocrit values that are no more than 1 week old may be used
10. In women of non child bearing potential only

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Section 6.3.1 Physical Examinations
ADDED TEXT
A brief physical examination will be performed at each session for both groups of 
subjects (Groups 1 and 2). In subjects with HF (Group 2), peripheral oedema (level 
above ankle, non-dependent limb) should be monitored at all sessions.  Height will be 
measured only on the first visit (Screening), and weight will be measured at every 
session. Lung auscultation will be performed on patients with ADHF in Group3 at 
Screening, Sessions 1, 2, and 3 by investigator or medically trained designee.
Section 6.3.2 Vital Signs
ADDED TEXT
For Groups 1 and 2, additional measurements of heart rate and blood pressure to be 
made during the exercise testing will be detailed in the SPM.
Group 3 will include a weight measurement at Sessions 1, 2 and 3 (if needed).
Section 6.3.3 Electrocradiogram
ADDED TEXT

For Groups 1 and 2, 12-lead ECGs will be obtained during the study using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and 
QTc intervals.

ECGs will be obtained in the semi-supine position after the subject has been resting 
for at least 5 minutes.
Section 6.3.4 Clinical Laboratory Assessments and Urinalysis
DELETED TEXT
eGRF (estimated Glomerular Filtration Rate)
ADDED TEXT
CrCl (estimated using Cockcroft-Gault)
Section 6.3.4.1 Pregnancy Testing
ADDED TEXT
For Groups 1 and 2, a standard urine pregnancy test will be performed at Screening and 
at every Session (first day of Session 3) in women of childbearing potential.  If the test is 
positive, the subject will be withdrawn from the study.  For Group 3, FSH and estradiol 
will be testing if needed to confirm non child bearing potential status.

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Section 6.4 N-terminal pro-Brain-type Natriuretic Peptide (NT-pro-
BNP)
ADDED TEXT
For subjects in Group 2, blood samples for NT-proBNP determinations will be drawn 
at screening and in Session 3 before and after the maximal exercise test, before the 
constant workload exercise test and after MRI scanning only in subjects with HF.  For 
subjects participating in Group 3, blood samples for NT proBNP levels will be 
drawn according to the time and events table. Record the date and time that each 
sample is collected.  Details of the processing, storage, and shipping of samples are 
located in the SPM.
Section 6.5 Dyspnea Score
ADDED TEXT 
After the MRI scan in Sessions 1 and 2, a standardised, validated dyspnoea 5-point Likert 
scale (Mebazza, 2010) will be completed for Groups 1 and 2.  In Session 3 only, the 
score will be completed before and after the maximal exercise test, and before and after 
the constant workload exercise test (before scanning) and after MRI scanning.  
For Group 3, the dyspnoea 5-point Likert scale will be completed at Screening and 
before and after the MRI scan in Sessions 1, 2, and 3 (if needed).
Details of the scale and administration are located in Appendix 2 (Section 11.2) and the 
SPM.
Section 6.6 Respiratory Rate
ADDED TEXT
Respiratory rate will be recorded over a 60-second period.  
For Groups 1 and 2, respiratory rate will be measured after the MRI scan in Sessions 1 and 2.  In 
Session 3 only, respiratory rate will be measured immediately before and after the maximal
exercise test, and before and after the constant workload exercise test (before scanning), and after 
MRI scanning.  Any additional measurements to be taken during the exercise testing procedure 
will be detailed in the SPM. 
For Group 3, the respiratory rate will be measured at Screening and before the 
MRI scan in Sessions 1, 2 and 3 (if needed).
Section 6.7 Chest X Rays
ADDED SECTION
For subjects with ADHF in Group 3, a clinically indicated chest X-ray (CXR) will be 
performed to assess cardiogenic pulmonary oedema.  CXRs used as part of standard 
clinical care may be used when a CXR is acquired within 48 hours of a scheduled 

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CXR per T&E Table Section 6.1.2. A maximum of 3 CXR scans will be performed 
as part of this study, each with a maximum of 20 microsievert. Additional details 
regarding the chest X-rays and the designation of resolution of pulmonary oedema 
may be found in the SPM.
Section 6.8 Lung Ultrasound
ADDED SECTION
For subjects with ADHF in Group 3, lung ultrasound may be used to assess 
pulmonary oedema, where feasible, specifically through measurement of the 
number of B lines. Additional anatomic structures may be assessed during any 
ultrasound. Additional details regarding the ultrasounds will be included within the 
SPM.
Section 6.9 Magnetic Resonance Imaging 
ADDED TEXT
Subjects within Group 3 may receive medical oxygen during the exam provided they 
receive oxygen during all MRI sessions and delivery rate is kept constant during a 
scanning session and matched for both scanning sessions.  Further details of scanning 
site training procedures and scanning protocols will be provided in a dedicated Imaging 
Manual.
Section 6.10 Exercise Test
ADDED TEXT
In Session 3, subjects in Groups 1 and 2 will perform two exercise tests.
Section 6.11 DLco and DLno
ADDED TEXT
For Groups 1 and 2, DLco and DLno measurements will be made after each MRI scan 
has been completed and prior to the constant workload exercise test in Session 3, Visit 2.  
Section 6.12.2  Definition of Adverse Events
PREVIOUS TEXT
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.  An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a medicinal product.
Since no investigational product will be administered in this study, information regarding 
the occurrence of adverse events will not be routinely collected.   Medical occurrences 

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(non-serious events) that begin during the study may be recorded under Medical 
History/Current Medical Conditions.  Non-serious events related to study procedures may 
also be recorded.  
REVISED TEXT
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.  An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a medicinal product.
Since no investigational product will be administered in this study, information regarding 
the occurrence of adverse events will not be routinely collected.   Medical occurrences 
(non-serious events) and non-serious events related to study procedures that begin during 
the study will be recorded in the medical notes.  
Section 8 Data Analysis and Statistical Comparisons
ADDED TEXT
Section 8.1 Hypotheses Comparisons
Estimation approach will be used for the comparison of interests.  No formal hypothesis 
testing will be performed.  There are two comparisons of interest in this study to be 
performed between Group 1 and Group 2.  The first is to estimate the feasibility of 
whether DCE-MRI can detect differences in DCE-MRI measures of pulmonary oedema 
or vascular permeability between HF and HV groups.  The second comparison is to 
determine whether a burst of exercise activity can enhance the interstitial lung fluid 
(and/or exchange rate) from baseline.
Section 8.2 Sample Size Considerations
Sample size is based on feasibility.  A similarly sized study using DCE-MRI was able to 
detect statistically significant differences in the lungs of smokers compared to HVs 
(Naish, 2008).
Section 8.4 Data Analysis Considerations
Anonymised data may be transferred within GSK or to external sites.  In some cases, we 
may use pooled or anonymised individual image data to support scientific reports.
All imaging data will be anonymised and stored on a Picture Archiving and 
Communication System (PACS) and RIS.
Section 8.4 Interim Analysis
Interim analysis will be conducted as described in Section 3.1.

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Section 8.5 Final Analyses
The formal statistical analysis described below will be performed for Groups 1 and 
2.  For the primary endpoints, contrast agent interstitial volume (ve) and exchange rate 
(ktrans) data will be fitted separately using a mixed effect model with subject treated as a 
random effect, patient population (HF or HV) and scanning session as a fixed effect.  
Point estimates and associated 95% confidence intervals (CI) will be constructed to 
provide a plausible range of values for the true comparisons of interest such as the mean 
difference DCE-MRI measures of interests between HF and HV groups for the different 
scanning sessions of interest.  If model assumptions of normality appear grossly violated, 
alternative methods (e.g., use of raw data with log transformation or non-parametric 
methods) will be considered.
For the secondary endpoint, the estimation of the within subject variability of DCE-MRI 
measures of pulmonary oedema and vascular permeability between study visits will be 
calculated based on the mixed model above using data from baseline scans by group.
For the exploratory analysis on the differences in plasma volume, relaxation rate, and 
proton density between HF and HV groups as measured using DCE-MRI, the similar 
analysis will be provided as above if data permit.  The correlations of  MRI measures 
with clinical and biochemical measures:  dyspnoea score, NYHA grade, respiratory rate, 
NT-proBNP, exercise capacity, DLco, DLno, body weight, urine specific gravity, 
fractional excretion of sodium (FENa), blood urea to creatinine ratio and others will also 
be explored as data permit.
The distribution of DCE-MRI measures of pulmonary physiology (interstitial volume 
(ve), exchange rate (ktrans) and others) in HF and HV groups both before and after exercise 
will be explored using empirical cdf/pdf and/or scatter plots for each subgroup of interest 
to help visualize the univariate distribution and the change.
For Group 3, DCE-MRI measures, lung ultrasound (B Line count), NT proBNP, 
dyspnoea score, and respiratory rate will be summarized by visit/session.  Individual 
line plots will be provided for each endpoint of interest to visualize the change in 
these measurements during hospitalization and after standard treatment. For 
subjects in Group 3 who withdrew after Session 1, the DCE-MRI measures from 
this scan may be included in the analyses.
Section 9.7 Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers and 
Publication
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GSK will provide the Investigator with the randomization codes for their site only 
after completion of the full statistical analysis.