Phase 1 N=36 Randomized Basic Science

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

Heart Failure, Congestive

Bottom Line

View on ClinicalTrials.gov: NCT02135861 ↗

Enrolled (actual)

Serious AEs

0.0%

Results posted

Feb 2019

Primary outcome: Primary: Interstitial Volume (ve) in Heart Failure Participants and Healthy Volunteers at Baseline — 0.4946; 0.3346; 0.5078; 0.3253 Liter — p=0.0029

Study Design & Population

Study type: Interventional
Phase: Phase 1
Interventions: DCE-MRI scans (Procedure); Gadobutrol (Other)
Age: Adult, Older Adult · 18+ yrs
Sex: All
Sponsor: GlaxoSmithKline
Primary completion: Feb 2017

Outcome Measures

Outcome	Result	p-value
PRIMARY Interstitial Volume (ve) in Heart Failure Participants and Healthy Volunteers at Baseline	0.4946; 0.3346; 0.5078; 0.3253; 0.4960; 0.3395	0.0029 sig
PRIMARY Exchange Rate (Ktrans) in Heart Failure Participants and Healthy Volunteers at Baseline	0.2216; 0.2353; 0.2309; 0.2173; 0.2216; 0.2474	0.7381
PRIMARY Interstitial Volume (ve) in Heart Failure Participants and Healthy Volunteers Before and Following Exercise	0.4353; 0.3205; 0.4568; 0.3140; 0.4487; 0.3121	0.0156 sig
PRIMARY Exchange Rate (Ktrans) in Heart Failure Participants and Healthy Volunteers Before and Following Exercise	0.2044; 0.2567; 0.1841; 0.2108; 0.2102; 0.2525	0.1730
PRIMARY Change in Interstitial Volume (ve) in ADHF Participants	0.794; 0.9577; 0.5086; 0.4018; 0.354; 0.6356	—
PRIMARY Change in Exchange Rate (Ktrans) in ADHF Participants	0.4524; 0.5306; 0.3018; 0.1952; 0.1602; 0.4304	—
SECONDARY Assessment of Intra-subject Variability in Ve Between Session 1 and Session 2 of DCE-MRI	20.5; 14.1	—
SECONDARY Assessment of Intra-subject Variability in Ktrans Between Session 1 and Session 2 of DCE-MRI	32.4; 41.3	—

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 =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 dise

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Data sourced from ClinicalTrials.gov (NCT02135861). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.