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

NCT ID: NCT02135861

Last Updated: 2019-02-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 41 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-07-30
• Study Completion Date: 2017-02-22

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.

Conditions

Heart Failure, Congestive

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

DCE-MRI scans

Intervention Type: 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.

Gadobutrol

Intervention Type: OTHER

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.

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.

Group Type: EXPERIMENTAL

DCE-MRI scans

Intervention Type: 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.

Gadobutrol

Intervention Type: OTHER

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.

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

Group Type: EXPERIMENTAL

DCE-MRI scans

Intervention Type: 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.

Gadobutrol

Intervention Type: OTHER

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.

Interventions

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.

Intervention Type: PROCEDURE

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.

Intervention Type: OTHER

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.

• 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).

• 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

• 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).
• 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.

• 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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Cambridge, , United Kingdom

Countries

United Kingdom

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

201137

Identifier Type: -

Identifier Source: org_study_id