A Study to Explore the Efficacy of TRV027 in Patients Hospitalized for Acute Decompensated Heart Failure

Inclusion criteria

• Men or women aged ≥21 years and ≤ 85 years 1a.Women of non-child-bearing potential
• Able to provide written informed consent
• Pre-existing diagnosis of heart failure and at least 30 days treatment with daily oral loop diuretics
• Systolic blood pressure ≥105 mmHg and ≤ 160 mmHg within 30 minutes of randomization
• Ventricular rate ≤125 bpm. Patients with rate-controlled persistent or permanent atrial fibrillation (aFib) at screening are permitted.
• Presence of ADHF defined by:

• BNP > 400 pg/mL or NT-proBNP > 1600 pg/mL

• For patients with BMI >30 kg/m2: BNP > 200 pg/mL or NT-proBNP > 800 pg/mL
• For patients with rate-controlled persistent or permanent aFib: BNP > 600 pg/mL or NT-proBNP > 2400 pg/mL
• Congestion on chest radiograph (CXR)

AND at least two (2) of the following:

• Rales by chest auscultation
• Edema ≥ +1 on a 0-3 + scale, indicating indentation of skin with mild digital pressure that requires 10 or more seconds to resolve in any dependent area including extremities or sacral region.
• Elevated jugular venous pressure (≥8 cm H2O)
• Receipt of a IV loop diuretic at a minimum dose 40 mg furosemide (or equivalent loop diuretic) for the treatment of dyspnea due to ADHF at least 1 hour prior to anticipated randomization and the initiation of study medication
• Patient report of dyspnea at rest or upon minimal exertion during screening at least one hour after administration of IV loop diuretic

Exclusion criteria

• Women who are pregnant or breast-feeding
• Clinical presentation:

• Suspected ACS based on clinical judgment
• Coronary revascularization in the 3 months prior to screening or planned during current admission.
• Temperature >38.5oC
• Clinically significant anemia
• Serum sodium >145 mEq/L (145 mmol/L)
• Current or planned ultrafiltration, paracentesis, hemofiltration or dialysis at time of screening
• Any mechanical ventilation
• CPAP/BiPAP discontinued less than 1 hour prior to randomization
• History of LVAD or IABP within the last year
• Intravenous radiographic contrast agent within 72 hours prior to screening or presence of acute contrast induced nephropathy at the time of screening
• Presence of clinically significant arrhythmia
• Uncertainty of ability to complete follow up
• Medications:

• nitroprusside or nesiritide
• Intravenous nitrates
• use of inotropes
• Use of ARBs within 7 days of prior to randomization
• Use of any investigational medication within 30 days
• clinically significant hypersensitivity or allergy to, or intolerance of, angiotensin receptor blockers
• Medical history:

• Major surgery within 8 weeks prior to screening
• Stroke within 3 months prior to screening
• eGFR (sMDRD) <20 mL/min/1.73m2 or >75 mL/min/1.73m2 between presentation and randomization
• Post cardiac or renal transplant
• Listed for renal transplant or cardiac transplant with anticipated transplant time to transplant < 6 months
• History of severe left ventricular outlet obstruction (either valvular or sub-valvular), severe mitral valve stenosis or severe aortic regurgitation
• Cardiac valvular abnormality that requires surgical correction
• Complex congenital heart disease
• Hypertrophic or restrictive cardiomyopathy
• significant pulmonary or hepatic disease that could interfere with the evaluation of safety or efficacy of TRV027
• life expectancy of less than 6 months