A Method Validation Study for Evaluation of Novel Treatments Limiting Pulmonary Oedema in Cardiac Failure

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02135861
• Collaborator: (none)
• Enrollment: 41
• Location: 1
• Arms: 3
• Actual Duration (Months): 30.8
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

Transient receptor potential vanilloid 4 (TRPV4) channel blockade may be promising in the treatment of pulmonary oedema and dyspnoea in heart failure (HF) and acute decompensated heart failure (ADHF) patients by re-establishing the alveolar septal barrier. Dynamic contrast enhanced (DCE) Magnetic Resonance Imaging (MRI) is an established technique for assessing changes in vascular permeability and interstitial water volume. The aim of this study is to establish the potential utility of DCE-MRI as a novel endpoint for dose ranging and proof of mechanism studies of TRPV4 blockers. The DCE-MRI markers of vascular permeability and pulmonary oedema will be measured in subjects with HF (group 2) and healthy volunteers (HV) (group 1) at rest to determine if there is a difference between the two populations. Apart from this, exercise induced changes relative to rest in interstitial volume and exchange rate will be evaluated in both HV and subjects with HF. Additionally, the capability of DCE-MRI to detect changes in interstitial lung fluid in patients with acute decompensated heart failure (ADHF) (group 3) 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.This study will enrol a sufficient number of subjects to have at least 24 subjects in Group 1 and 2 (group 1:12 HV and group 2: 12 subjects with HF) and atleast 5 subjects in Group 3. For each subject, the MRI data must be of sufficient quality to enable DCE-MRI modelling from 2 Sessions. For group 1 and 2, the subjects will have screening visit and 3 MRI sessions. For the first scanning session, 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 group 3: Screening will occur during hospitalization for eligibility. Session 1of MRI will be conducted while the subject is still hospitalized. Session 2 will be conducted within 4 weeks of the first scan, when the signs of pulmonary oedema are considered to be resolved. If a subject's pulmonary oedema has not resolved at Session 2, 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.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure, Congestive	Procedure: DCE-MRI scans; Other: Gadobutrol	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official 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
• Actual Study Start Date: Jul 30, 2014
• Actual Primary Completion Date: Feb 22, 2017
• Actual Study Completion Date: Feb 22, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Healthy volunteers All subjects will undergo MRI scanning conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.	Procedure: DCE-MRI scans; Subjects will be placed supine in the scanner and will be prepared for intravenous contrast agent administration. The contrast agent is administered using a power injector before imaging.; Other: Gadobutrol; Gadobutrol at a dose less than or equal to 0.1 millimoles per kilogram (mmol/kg) will be given intravenously as a bolus using a power injector.
Experimental: Heart failure patients All subjects will undergo DCE-MRI scanning conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 T system.	Procedure: DCE-MRI scans; Subjects will be placed supine in the scanner and will be prepared for intravenous contrast agent administration. The contrast agent is administered using a power injector before imaging.; Other: Gadobutrol; Gadobutrol at a dose less than or equal to 0.1 millimoles per kilogram (mmol/kg) will be given intravenously as a bolus using a power injector.
Experimental: Acute decompensated heart failure All subjects will undergo DCE-MRI scanning conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 T system	Procedure: DCE-MRI scans; Subjects will be placed supine in the scanner and will be prepared for intravenous contrast agent administration. The contrast agent is administered using a power injector before imaging.; Other: Gadobutrol; Gadobutrol at a dose less than or equal to 0.1 millimoles per kilogram (mmol/kg) will be given intravenously as a bolus using a power injector.

Outcome Measures

Primary Outcome Measures

1. Interstitial Volume (ve) in Heart Failure Participants and Healthy Volunteers at Baseline [Day 1]

   Interstitial volume (ve) was measured by DCE-MRI. ve for total lung, left lung, right lung, left lung apical, left lung basal, right lung apical, right lung basal has been presented. Session 1 values were considered as Baseline values.

2. Exchange Rate (Ktrans) in Heart Failure Participants and Healthy Volunteers at Baseline [Day 1]

   Exchange rate (Ktrans) was measured by DCE-MRI. Ktrans for total lung, left lung, right lung, left lung apical, left lung basal, right lung apical, right lung basal has been presented. Session 1 values were considered as Baseline values.

3. Interstitial Volume (ve) in Heart Failure Participants and Healthy Volunteers Before and Following Exercise [Day 11]

   Interstitial volume (ve) was measured by DCE-MRI. ve for total lung, left lung, right lung, left lung apical, left lung basal, right lung apical, right lung basal before and following exercise has been presented.

4. Exchange Rate (Ktrans) in Heart Failure Participants and Healthy Volunteers Before and Following Exercise [Day 11]

   Exchange rate (Ktrans) was measured by DCE-MRI. Ktrans for total lung, left lung, right lung, left lung apical, left lung basal, right lung apical, right lung basal before and following exercise has been presented.

5. Change in Interstitial Volume (ve) in ADHF Participants [Up to Week 8]

   Interstitial volume (ve) was measured by DCE-MRI. Three participants underwent 3 DCE-MRI scans. The data has been presented for individual participant in each session. The data presented below is only for total lung.

6. Change in Exchange Rate (Ktrans) in ADHF Participants [Up to Week 8]

   Exchange rate (Ktrans) was measured by DCE-MRI. Three participants underwent 3 DCE-MRI scans. The data has been presented for individual participant in each session. The data presented below is only for total lung.

Secondary Outcome Measures

1. Assessment of Intra-subject Variability in Ve Between Session 1 and Session 2 of DCE-MRI [Day 1 (Session 1) and Day 9 (Session 2)]

   Coefficient of variation (percentage) of intra-subject variability in Ve between Session 1 and Session 2 for total lung has been presented.

2. Assessment of Intra-subject Variability in Ktrans Between Session 1 and Session 2 of DCE-MRI [Day 1 (Session 1) and Day 9 (Session 2)]

   Coefficient of variation (percentage) of intra-subject variability in Ktrans between Session 1 and Session 2 for total lung has been presented.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Male or females over 18 years of age at the time of signing the informed consent.

• Body weight >=50 kilogram (kg) and Body Mass Index (BMI) within the range 18.0-40.0 kilogram/square meter (kg/m^2) (inclusive).

• Able to understand and comply with protocol requirements, instructions and protocol stated restrictions and is willing to take part in the imaging sessions.

• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Inclusion Criteria for Heart Failure Group (group 2) - 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.

Inclusion Criteria for Healthy Volunteer Group (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 Electrocardiogram (ECG).

Inclusion Criteria for Subjects with ADHF (Group 3)

• 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 questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 million international units (MIU)/millilitre (mL) and oestradiol < 40picogram (pg)/mL (< 140 pmol/L) is confirmatory.

• 50 years of age or over at the time of signing the informed consent

• Hospitalized for the management of acute decompensated HF

• Presence of dyspnoea at rest or with minimal activity

• Presence of at least one of the following signs: Tachypnea with respiratory rate >=20 breaths/min or Rales or crackles audible on auscultation

• 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)

• Have received at least one treatment with an intravenous diuretic prior to the first MRI scan

• Body weight >= 50kg and BMI within the range 18-40 kg/m^2 (inclusive)

• Able to understand and comply with protocol requirements, instructions and protocol-stated restrictions and is willing to take part in the imaging sessions

• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form

Exclusion criteria:

Exclusion Criteria for Heart Failure Group

• History of known primary pulmonary disease requiring current medication or other therapy.

• Orthopnoea of sufficient severity to preclude supine scanning as determined at screening.

• Unstable angina within the past 3 months.

• Uncontrolled hypertension (resting systolic Blood Pressure (BP) >160 millimeters of mercury (mmHg) or resting diastolic BP >100 mmHg).

• Resting hypoxia while breathing room air (Saturation of Oxygen [SaO2] <88%). Exclusion Criteria for Healthy Volunteer Group and Heart Failure Groups

• Current smoker, defined as having smoked in the preceding 6 months.

• Contraindication for MRI scanning (as assessed by local MRI safety questionnaire) which includes but not limited to: Intracranial aneurysm clips or other metallic objects; Intra-orbital metal fragments that have not been removed ; Pacemakers or other implanted cardiac rhythm management devices and non-MRI compatible heart valves; Inner ear implants; and History of claustrophobia.

• Pregnant females as determined by positive urine human chorionic gonadotropin (HCG) test at screening or any scanning session.

• Positive test for drugs of abuse, not due to current prescription drugs as determined by the GSK Medical Monitor and principal investigator (PI), and alcohol screen.

• Estimated Creatinine Clearance (Cockcroft-Gault) <60 millilitre (mL)/minute.

Exclusion Criteria for Subjects with ADHF (Group 3)

• End-stage heart failure defined as requiring left ventricular assist devices, intra-aortic balloon pump or any type of mechanical support

• Chronic or intermittent renal support therapy (hemodialysis, ultrafiltration, or peritoneal dialysis)

• Ongoing or planned intravenous diuretic treatment within 1 hour of MRI scan appointment

• History of known primary pulmonary disease requiring current medication or other therapy

• 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)

• Contraindication for MRI scanning (as assessed by local MRI safety questionnaire), which includes but is not limited to: Intracranial aneurysm clips (except Sugita) or other metallic objects OR intra-orbital metal fragments that have not been removed OR pacemakers or other implanted cardiac rhythm management devices and non-MRI compatible heart valves OR inner ear implants OR history of claustrophobia

• Estimated creatinine clearance (Cockcroft-Gault) <40mL/minute

• Contraindication to MRI contrast agents

• 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 millisieverts (mSv) in addition to natural background radiation, in the previous 3 years including the dose from this study).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Cambridge		United Kingdom	CB2 2GG

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

• Study Protocol - Apr 8, 2016
• Statistical Analysis Plan - Apr 28, 2017

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT02135861
• Other Study ID Numbers: 201137
• First Posted: May 12, 2014
• Last Update Posted: Feb 27, 2019
• Last Verified: Jul 1, 2018

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by GlaxoSmithKline: Acute decompensated heart failure; heart failure; MRI; trpV4 channel inhibitors; pulmonary oedema
• Additional relevant MeSH terms: Pulmonary Edema; Heart Failure

Study Results

Participant Flow

Recruitment Details	This study included healthy volunteers (HV, group 1), participants (par) with heart failure (HF, group 2) and participants with acute decompensated heart failure (ADHF, group 3) who were hospitalized with evidence of pulmonary edema and received standard of care treatment.
Pre-assignment Detail	Dynamic Contrast Enhanced-Magnetic Resonance Imaging (DCE-MRI) markers were used to measure vascular permeability and pulmonary edema in HV and par. with HF. Forty one par. were enrolled and 36 entered the study. Three par. did not continue due to habitus and 2 par. did not participate as they required clinical investigations.

Arm/Group Title	Healthy Volunteers	Heart Failure Participants	Acute Decompensated Heart Failure Participants
Arm/Group Description	Healthy volunteers were placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.	Heart failure participants were placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.	Acute Decompensated Heart Failure participants following hospitalization due to pulmonary oedema was placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.
Period Title: Overall Study
STARTED	21	12	3
COMPLETED	21	12	3
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Healthy Volunteers	Heart Failure Participants	Acute Decompensated Heart Failure Participants	Total
Arm/Group Description	Healthy volunteers were placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.	Heart failure participants were placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.	Acute Decompensated Heart Failure participants following hospitalization due to pulmonary oedema was placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.	Total of all reporting groups
Overall Participants	21	12	3	36
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	53.8 (18.66)	67.8 (13.42)	79.3 (4.93)	66.9 (6.9)
Sex: Female, Male (Count of Participants)
Female	2 9.5%	2 16.7%	1 33.3%	5 13.9%
Male	19 90.5%	10 83.3%	2 66.7%	31 86.1%
Race/Ethnicity, Customized (Count of Participants)
African American/African Heritage	0 0%	1 8.3%	0 0%	1 2.8%
White	21 100%	11 91.7%	3 100%	35 97.2%

Outcome Measures

1. Primary Outcome

Title	Interstitial Volume (ve) in Heart Failure Participants and Healthy Volunteers at Baseline
Description	Interstitial volume (ve) was measured by DCE-MRI. ve for total lung, left lung, right lung, left lung apical, left lung basal, right lung apical, right lung basal has been presented. Session 1 values were considered as Baseline values.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

The Evaluable Population will include participants in safety population who are 40 years and older .The safety Population includes all enrolled participants who have initiated Session 1 DCE-MRI scan

Arm/Group Title	Healthy Volunteers	Heart Failure Participants
Arm/Group Description	Healthy volunteers were placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.	Heart failure participants were placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.
Measure Participants	17	12
Total lung	0.4946 (0.0362)	0.3346 (0.0325)
Left lung	0.5078 (0.0349)	0.3253 (0.0317)
Right lung	0.4960 (0.0417)	0.3395 (0.0371)
Left lung apical	0.4952 (0.0339)	0.3188 (0.0306)
Left lung basal	0.5349 (0.0397)	0.3350 (0.0362)
Right lung apical	0.4865 (0.0392)	0.3506 (0.0352)
Right lung basal	0.5045 (0.0444)	0.3297 (0.0390)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0029
	Comments	estimates of total lung
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1600
	Confidence Interval	(2-Sided) 95%; 0.0600 to 0.2600
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0007
	Comments	estimates of left lung
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1825
	Confidence Interval	(2-Sided) 95%; 0.0855 to 0.2795
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0093
	Comments	estimates of right lung
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1565
	Confidence Interval	(2-Sided) 95%; 0.0419 to 0.2711
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0007
	Comments	estimates of left lung apical
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1764
	Confidence Interval	(2-Sided) 95%; 0.0823 to 0.2704
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	Comments	estimates of left lung basal
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1999
	Confidence Interval	(2-Sided) 95%; 0.0894 to 0.3103
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0159
	Comments	estimates of right lung apical
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1360
	Confidence Interval	(2-Sided) 95%; 0.0276 to 0.2443
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0064
	Comments	estimates of right lung basal
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1748
	Confidence Interval	(2-Sided) 95%; 0.0535 to 0.2961
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

2. Primary Outcome

Title	Exchange Rate (Ktrans) in Heart Failure Participants and Healthy Volunteers at Baseline
Description	Exchange rate (Ktrans) was measured by DCE-MRI. Ktrans for total lung, left lung, right lung, left lung apical, left lung basal, right lung apical, right lung basal has been presented. Session 1 values were considered as Baseline values.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

The Evaluable Population

Arm/Group Title	Heart Failure Participants	Healthy Volunteers
Arm/Group Description	Heart failure participants were placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.	Healthy volunteers were placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.
Measure Participants	12	17
Total lung	0.2216 (0.0298)	0.2353 (0.0273)
Left lung	0.2309 (0.0256)	0.2173 (0.0236)
Right lung	0.2216 (0.0338)	0.2474 (0.0309)
Left lung apical	0.2166 (0.0265)	0.2161 (0.0244)
Left lung basal	0.2621 (0.0270)	0.2225 (0.0249)
Right lung apical	0.2166 (0.0355)	0.2528 (0.0326)
Right lung basal	0.2313 (0.0329)	0.2431 (0.0301)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7381
	Comments	estimates of total lung
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0137
	Confidence Interval	(2-Sided) 95%; -0.0968 to 0.0695
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6992
	Comments	estimates of left lung
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0136
	Confidence Interval	(2-Sided) 95%; -0.0580 to 0.0852
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5778
	Comments	estimates of right lung
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0258
	Confidence Interval	(2-Sided) 95%; -0.1201 to 0.0684
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9899
	Comments	estimates of left lung apical
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0005
	Confidence Interval	(2-Sided) 95%; -0.0738 to 0.0747
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2912
	Comments	estimates of left lung basal
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0396
	Confidence Interval	(2-Sided) 95%; -0.0360 to 0.1153
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4592
	Comments	estimates of right lung apical
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0362
	Confidence Interval	(2-Sided) 95%; -0.1355 to 0.0631
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7936
	Comments	estimates of right lung basal
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0118
	Confidence Interval	(2-Sided) 95%; -0.1036 to 0.0800
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

3. Primary Outcome

Title	Interstitial Volume (ve) in Heart Failure Participants and Healthy Volunteers Before and Following Exercise
Description	Interstitial volume (ve) was measured by DCE-MRI. ve for total lung, left lung, right lung, left lung apical, left lung basal, right lung apical, right lung basal before and following exercise has been presented.
Time Frame	Day 11

Outcome Measure Data

Analysis Population Description

The Evaluable Population

Arm/Group Title	Heart Failure Participants	Healthy Volunteers
Arm/Group Description	Heart failure participants were placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.	Healthy volunteers were placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.
Measure Participants	12	17
Pre-exercise; Total lung	0.4353 (0.0335)	0.3205 (0.0292)
Post-exercise; Total lung	0.4568 (0.0307)	0.3140 (0.0263)
Pre-exercise; Left lung	0.4487 (0.0311)	0.3121 (0.0267)
Post-exercise; Left lung	0.4832 (0.0266)	0.3055 (0.0228)
Pre-exercise; Right lung	0.4361 (0.0357)	0.3294 (0.0311)
Post-exercise; Right lung	0.4534 (0.0355)	0.3274 (0.0298)
Pre-exercise; Left lung apical	0.4272 (0.0335)	0.3126 (0.0289)
Post-exercise; Left lung apical	0.4449 (0.0257)	0.2986 (0.0216)
Pre-exercise; Left lung basal	0.4890 (0.0318)	0.3114 (0.0272)
Post-exercise; Left lung basal	0.5310 (0.0323)	0.3173 (0.0276)
Pre-exercise; Right lung apical	0.4343 (0.0378)	0.3387 (0.0324)
Post-exercise; Right lung apical	0.4504 (0.0358)	0.3393 (0.0301)
Pre-exercise; Right lung basal	0.4400 (0.0347)	0.3206 (0.0301)
Post-exercise; Right lung basal	0.4591 (0.0367)	0.3133 (0.0308)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0156
	Comments	estimates of total lung- Pre-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1148
	Confidence Interval	(2-Sided) 95%; 0.0236 to 0.2061
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0026
	Comments	estimates of left lung- Pre-exercise
	Method	ANOVA
	Comments	estimates of left lung- Pre-exercise
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1366
	Confidence Interval	(2-Sided) 95%; 0.0523 to 0.2209
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0328
	Comments	estimates of right lung- Pre-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1067
	Confidence Interval	(2-Sided) 95%; 0.0094 to 0.2040
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0158
	Comments	estimates of left lung apical-Pre-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1145
	Confidence Interval	(2-Sided) 95%; 0.0235 to 0.2056
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	estimates of left lung basal-Pre-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1776
	Confidence Interval	(2-Sided) 95%; 0.0917 to 0.2635
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0658
	Comments	estimates of right lung apical-Pre-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0956
	Confidence Interval	(2-Sided) 95%; -0.0067 to 0.1979
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0150
	Comments	estimates of right lung basal-Pre-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1194
	Confidence Interval	(2-Sided) 95%; 0.0251 to 0.2137
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments	estimates of total lung-Post-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1428
	Confidence Interval	(2-Sided) 95%; 0.0598 to 0.2259
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	estimates of left lung-Post-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1776
	Confidence Interval	(2-Sided) 95%; 0.1057 to 0.2496
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0114
	Comments	estimates of right lung-Post-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1260
	Confidence Interval	(2-Sided) 95%; 0.0308 to 0.2212
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	estimates of left lung apical-Post-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1464
	Confidence Interval	(2-Sided) 95%; 0.0774 to 0.2153
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	estimates of left lung basal-Post-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2137
	Confidence Interval	(2-Sided) 95%; 0.1266 to 0.3008
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0250
	Comments	estimates of right lung apical-Post-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1111
	Confidence Interval	(2-Sided) 95%; 0.0151 to 0.2071
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0052
	Comments	estimates of right lung basal-Post-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1458
	Confidence Interval	() 95%; 0.0475 to 0.2442
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ve was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

4. Primary Outcome

Title	Exchange Rate (Ktrans) in Heart Failure Participants and Healthy Volunteers Before and Following Exercise
Description	Exchange rate (Ktrans) was measured by DCE-MRI. Ktrans for total lung, left lung, right lung, left lung apical, left lung basal, right lung apical, right lung basal before and following exercise has been presented.
Time Frame	Day 11

Outcome Measure Data

Analysis Population Description

The Evaluable Population

Arm/Group Title	Heart Failure Participants	Healthy Volunteers
Arm/Group Description	Heart failure participants were placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.	Healthy volunteers were placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.
Measure Participants	12	17
Pre-exercise; Total lung	0.2044 (0.0281)	0.2567 (0.0247)
Post-exercise; Total lung	0.1841 (0.0221)	0.2108 (0.0190)
Pre-exercise; Left lung	0.2102 (0.0285)	0.2525 (0.0245)
Post-exercise; Left lung	0.1785 (0.0200)	0.1986 (0.0172)
Pre-exercise; Right lung	0.2034 (0.0299)	0.2550 (0.0263)
Post-exercise; Right lung	0.1926 (0.0269)	0.2114 (0.0226)
Pre-exercise; Left lung apical	0.1856 (0.0293)	0.2459 (0.0253)
Post-exercise; Left lung apical	0.1621 (0.0199)	0.1780 (0.0167)
Pre-exercise; Left lung basal	0.2552 (0.0296)	0.2630 (0.0254)
Post-exercise; Left lung basal	0.2060 (0.0227)	0.2185 (0.0196)
Pre-exercise; Right lung apical	0.1934 (0.0281)	0.2440 (0.0243)
Post-exercise; Right lung apical	0.1892 (0.0267)	0.2141 (0.0224)
Pre-exercise; Right lung basal	0.2181 (0.0319)	0.2593 (0.0281)
Post-exercise; Right lung basal	0.2052 (0.0284)	0.2081 (0.0238)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1730
	Comments	estimates of total lung-Pre-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0524
	Confidence Interval	(2-Sided) 95%; -0.1292 to 0.0244
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2704
	Comments	estimates of left lung-Pre-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0423
	Confidence Interval	(2-Sided) 95%; -0.1196 to 0.0349
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2072
	Comments	estimates of right lung-Pre-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0515
	Confidence Interval	(2-Sided) 95%; -0.1334 to 0.0303
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1307
	Comments	estimates of left lung apical-Pre-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0603
	Confidence Interval	(2-Sided) 95%; -0.1398 to 0.0191
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8427
	Comments	estimates of left lung basal-Pre-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0078
	Confidence Interval	(2-Sided) 95%; -0.0879 to 0.0722
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1848
	Comments	estimates of right lung apical-Pre-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0506
	Confidence Interval	(2-Sided) 95%; -0.1269 to 0.0257
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3408
	Comments	estimates of right lung basal-Pre-exercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0413
	Confidence Interval	(2-Sided) 95%; -0.1286 to 0.0461
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3682
	Comments	estimates of total lung-Post-excercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0267
	Confidence Interval	(2-Sided) 95%; -0.0866 to 0.0332
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4531
	Comments	estimates of left lung-Post-excercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.0201
	Confidence Interval	(2-Sided) 95%; -0.0744 to 0.0342
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5970
	Comments	estimates of right lung-Post-excercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0188
	Confidence Interval	(2-Sided) 95%; -0.0909 to 0.0533
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5472
	Comments	estimates of left lung apical-Post-excercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0159
	Confidence Interval	(2-Sided) 95%; -0.0693 to 0.0375
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6793
	Comments	estimates of left lung basal-Post-excercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0125
	Confidence Interval	(2-Sided) 95%; -0.0742 to 0.0491
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4806
	Comments	estimates of right lung apical-Post-excercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0249
	Confidence Interval	(2-Sided) 95%; -0.0964 to 0.0466
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteers, Heart Failure Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9379
	Comments	estimates of right lung basal-Post-excercise
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0029
	Confidence Interval	(2-Sided) 95%; -0.0789 to 0.0731
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ktrans was fitted using a repeat measure ANOVA model with terms including participant population (HF or HV), visit (i.e. sessions), interaction of participant population and visit, with participant ID as block of the repeat factor

5. Primary Outcome

Title	Change in Interstitial Volume (ve) in ADHF Participants
Description	Interstitial volume (ve) was measured by DCE-MRI. Three participants underwent 3 DCE-MRI scans. The data has been presented for individual participant in each session. The data presented below is only for total lung.
Time Frame	Up to Week 8

Outcome Measure Data

Analysis Population Description

The safety population will include all enrolled participants who have initiated at least one session of DCE-MRI or Lung Ultrasound Scan

Arm/Group Title	Acute Decompensated Heart Failure Participants
Arm/Group Description	Acute Decompensated Heart Failure participants following hospitalization due to pulmonary oedema was placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.
Measure Participants	3
Par.1; Session 1	0.794
Par.1; Session 2	0.9577
Par. 2; Session 1	0.5086
Par. 2; Session 2	0.4018
Par. 3; Session 1	0.354
Par. 3; Session 2	0.6356
Par. 3 Session 3	0.6083

6. Primary Outcome

Title	Change in Exchange Rate (Ktrans) in ADHF Participants
Description	Exchange rate (Ktrans) was measured by DCE-MRI. Three participants underwent 3 DCE-MRI scans. The data has been presented for individual participant in each session. The data presented below is only for total lung.
Time Frame	Up to Week 8

Outcome Measure Data

Analysis Population Description

The Safety Population

Arm/Group Title	Acute Decompensated Heart Failure Participants
Arm/Group Description	Acute Decompensated Heart Failure participants following hospitalization due to pulmonary oedema was placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.
Measure Participants	3
Par.1; Session 1	0.4524
Par.1; Session 2	0.5306
Par. 2; Session 1	0.3018
Par. 2; Session 2	0.1952
Par. 3; Session 1	0.1602
Par. 3; Session 2	0.4304
Par. 3 Session 3	0.4264

7. Secondary Outcome

Title	Assessment of Intra-subject Variability in Ve Between Session 1 and Session 2 of DCE-MRI
Description	Coefficient of variation (percentage) of intra-subject variability in Ve between Session 1 and Session 2 for total lung has been presented.
Time Frame	Day 1 (Session 1) and Day 9 (Session 2)

Outcome Measure Data

Analysis Population Description

The Evaluable Population

Arm/Group Title	Heart Failure Participants	Healthy Volunteers
Arm/Group Description	Heart failure participants were placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.	Healthy volunteers were placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.
Measure Participants	12	17
Number [Percentage]	20.5	14.1

8. Secondary Outcome

Title	Assessment of Intra-subject Variability in Ktrans Between Session 1 and Session 2 of DCE-MRI
Description	Coefficient of variation (percentage) of intra-subject variability in Ktrans between Session 1 and Session 2 for total lung has been presented.
Time Frame	Day 1 (Session 1) and Day 9 (Session 2)

Outcome Measure Data

Analysis Population Description

The Evaluable Population

Arm/Group Title	Heart Failure Participants	Healthy Volunteers
Arm/Group Description	Heart failure participants were placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.	Healthy volunteers were placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.
Measure Participants	12	17
Number [Percentage]	32.4	41.3

Adverse Events

Time Frame	Serious adverse events (SAEs) and AEs related to study procedure were planned to be collected from the start of study procedure and up to last visit (Up to Week 8)
Adverse Event Reporting Description	SAEs and non-serious AEs related to study procedure were planned to be reported for Safety Population
Arm/Group Title	Healthy Volunteers		Heart Failure Patients		Acute Decompensated Heart Failure
Arm/Group Description	Healthy volunteers were placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.		Heart failure participants were placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.		Acute Decompensated Heart Failure participants following hospitalization due to pulmonary oedema was placed in supine position under the scanner and intravenous contrast agent was administered. Contrast agent was administered as a bolus using a power injector during the dynamic series. MRI scanning was conducted by experienced radiographers and radiologists in the nominated scanning sites, using a 1.5 Tesla (T) system.
All Cause Mortality
	Healthy Volunteers		Heart Failure Patients		Acute Decompensated Heart Failure
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/12 (0%)		0/3 (0%)
Serious Adverse Events
	Healthy Volunteers		Heart Failure Patients		Acute Decompensated Heart Failure
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/12 (0%)		0/3 (0%)
Other (Not Including Serious) Adverse Events
	Healthy Volunteers		Heart Failure Patients		Acute Decompensated Heart Failure
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/12 (0%)		0/3 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.