A Method Validation Study for Evaluation of Novel Treatments Limiting Pulmonary Oedema in Cardiac Failure
Condition: Heart Failure, Congestive
MeSH terms: Pulmonary Edema; Heart Failure
Intervention: DCE-MRI scans; Gadobutrol
Intervention description: 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 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.
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 41.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Acute decompensated heart failure; heart failure; MRI; trpV4 channel inhibitors; pulmonary oedema

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.
    

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).