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

Study Overview
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Brief Summary
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To evaluate the overall safety and efficacy of TRV027 when administered in addition to standard of care (SOC) on mortality, morbidity, dyspnea, and length of stay in patients hospitalized with Acute Decompensated Heart Failure (ADHF).

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Dose Ranging Study to Explore the Efficacy of TRV027 in Patients Hospitalized for Acute Decompensated Heart Failure

Conditions
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Acute Decompensated Heart Failure

Intervention / Treatment
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* Drug: TRV027 Dose #1
* Drug: TRV027 Dose #2
* Drug: TRV027 Dose #3
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TRV027 dose #1<br>TRV027 dose #1 via continuous IV infusion | Drug: TRV027 Dose #1<br>* TRV027 continuous intravenous infusion Dose #1<br>* Other names: Formerly known as TRV120027;|
| Experimental: TRV027 dose #2<br>TRV027 dose #2 via continuous IV infusion | Drug: TRV027 Dose #2<br>* TRV027 continuous intravenous infusion Dose #2<br>* Other names: Formerly known as TRV120027;|
| Experimental: TRV027 dose #3<br>TRV027 dose #3 via continuous IV infusion | Drug: TRV027 Dose #3<br>* TRV027 continuous intravenous infusion Dose #3<br>* Other names: Formerly known as TRV120027;|
| Placebo Comparator: Placebo<br>Placebo via continuous IV infusion | Drug: Placebo<br>* Placebo continuous intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| composite z score | The primary clinical endpoint is a of the following outcomes: (1) time from randomization to death through day 30, (2) time from randomization to heart failure re-hospitalization through day 30, (3) time from randomization to worsening heart failure through day 5, (4) change in dyspnea VAS score (calculated area under the curve) from baseline through day 5, and (5) length of initial hospital stay (in days) from randomization. The component outcomes will be combined by deriving an average Z for each patient. | 30 days |