A Method Validation Study for Evaluation of Novel Treatme... | NCT02135861

Status Module

Description Module

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.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Healthy volunteers	Experimental	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 Other: Gadobutrol
Heart failure patients	Experimental	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 Other: Gadobutrol
Acute decompensated heart failure	Experimental	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 Other: Gadobutrol

Interventions

Name	Type	Description	Arm Group Labels	Other Names
DCE-MRI scans	Procedure	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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Interstitial Volume (ve) in Heart Failure Participants and Healthy Volunteers at Baseline	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.	Day 1
Exchange Rate (Ktrans) in Heart Failure Participants and Healthy Volunteers at Baseline	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.	Day 1
Interstitial Volume (ve) in Heart Failure Participants and Healthy Volunteers Before and Following Exercise	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.	Day 11
Exchange Rate (Ktrans) in Heart Failure Participants and Healthy Volunteers Before and Following Exercise	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.	Day 11
Change in Interstitial Volume (ve) in ADHF Participants	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.	Up to Week 8

Secondary Outcomes

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

Eligibility Module

Eligibility Criteria

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).](streamdown:incomplete-link)

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Cambridge		CB2 2GG	United Kingdom

Arm/Group Information

ID	Title	Description
FG000	Healthy Volunteers	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.
FG001	Heart Failure Participants	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.
FG002	Acute Decompensated Heart Failure Participants	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.

ID	Title	Description
BG000	Healthy Volunteers	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.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Interstitial Volume (ve) in Heart Failure Participants and Healthy Volunteers at Baseline

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.

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

Posted

Least Squares Mean

Standard Error

Liter

Day 1

ID	Title	Description
OG000	Healthy Volunteers	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.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Healthy Volunteers	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.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Apr 8, 2016	Feb 13, 2018	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Apr 28, 2017	Feb 13, 2018	SAP_001.pdf

ID	Term
D006333	Heart Failure
D011654	Pulmonary Edema

ID	Term
D006331	Heart Diseases
D002318	Cardiovascular Diseases
D008171	Lung Diseases
D012140	Respiratory Tract Diseases