Efficacy and Safety of Ularitide for the Treatment of Acute Decompensated Heart Failure

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy and safety of a continuous intravenous (IV) ularitide infusion on the clinical status and outcome of patients with acute decompensated heart failure (ADHF).

Detailed Description
-----------------
The objective of the TRUE-AHF study is to evaluate the effect of a 48-h continuous IV infusion of ularitide (15 ng/kg/min) versus placebo on the clinical status of patients with acute decompensated heart failure (ADHF). The study drug will be administered in addition to the standard treatment. The nature of standard therapy will be carried out according to the clinical judgment of the Investigator and may include vasodilator, inotropic, and diuretic drugs, as clinically indicated. There are two co-primary endpoints for this study. Co-primary endpoint 1 will be a hierarchical clinical composite variable that includes a patient-centered assessment of clinical progress, an assessment of lack of improvement or worsening of HF requiring a pre-specified intervention, and death. The endpoint is intended to mimic the assessment that would be carried out by a physician caring for the patient. If, during the 48 h infusion, a patient's clinical course deteriorates because he/she dies, fails to improve or develops worsening HF requiring a pre-specified intervention or if the patient considers his/her general clinical status as moderately or markedly worse, the patient will be considered to be worse. If the patient considers his/her general clinical status as moderately or markedly improved and if such improvement is sustained without fulfilling the criteria for worse throughout the 48-h infusion (from 0 h to 48 h), the patient will be considered to be improved. If the patient is neither improved nor worse, the patient's clinical status will be considered to be unchanged. Co-primary efficacy endpoint 2 evaluates freedom from cardiovascular mortality during follow up after randomization, for the entire duration of the trial.

Official Title
-----------------
Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Ularitide (Urodilatin) Intravenous Infusion in Patients Suffering From Acute Decompensated Heart Failure [TRUE-AHF]

Conditions
-----------------
Acute Decompensated Heart Failure

Intervention / Treatment
-----------------
* Drug: Ularitide
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males and females aged 18 to 85 years. Unplanned hospitalization or emergency department visit for ADHF. Acute HF is defined as including all of the following: Dyspnea at rest in a recumbent sitting position (30 to 45 degrees), which has worsened within the past week; Radiological evidence of HF on a chest X-ray (if an appropriate chest; computerized tomography scan is done; the X-ray need not be performed); Brain natriuretic peptide (BNP) >500 pg/mL or NT-pro BNP >2000 pg/mL. Ability to start infusion of the study drug within 12 h after initial clinical assessment. Ability to reliably carry out self-assessment of symptoms. Systolic blood pressure ≥116 mmHg and ≤180 mmHg at the time of randomization. Persisting dyspnea at rest despite standard background therapy for ADHF (as determined by the Investigator) which must include IV furosemide (or equivalent diuretic) at ≥40 mg (or its equivalent) at any time after start of emergency services (ambulance, emergency department, or hospital). At the time of randomization, the patient must still be symptomatic. In addition, the patient should not have received an IV bolus of a diuretic for at least 2 h prior to randomization, and the infusion rates of all ongoing IV infusions of medications to treat HF must not have been increased or decreased for at least 2 h prior to randomization. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local privacy regulations). Exclusion Criteria: Known active myocarditis, obstructive hypertrophic cardiomyopathy, congenital heart disease, restrictive cardiomyopathy, constrictive pericarditis, uncorrected clinically significant primary valvular disease. Treatment with dobutamine at a dose >5 μg/kg/min or use of drugs for support of BP at the time of randomization. Treatment with levosimendan, milrinone, or any other phosphodiesterase inhibitor within 7 days before randomization. Treatment with nesiritide within 30 days before randomization. Creatinine clearance <25 mL/min/1.73m² (as measured by the MDRD formula) at the time of screening. Planned coronary revascularization procedure (percutaneous coronary intervention or coronary artery bypass grafting) within 5 days of randomization. Clinical diagnosis of acute coronary syndrome meeting any 2 of the following 3 criteria: Prolonged chest pain at rest, or an accelerated pattern of angina Electrocardiogram changes indicative of ischemia or myocardial injury defined as: a new ST elevation at the J point of two anatomically contiguous leads with the cut-off points: ≥0.2 mV in men ≥40 years (>0.25 mV in men <40 years) or ≥0.15 mV in women in leads V2-V3 and/or ≥0.1 mV in other leads; or ST depression and T wave changes. New horizontal or down sloping ST depression ≥0.05 mV in two contiguous leads; and/or new T inversion ≥0.3 mV in two contiguous leads. Serum troponin >3 times upper limit of normal. Clinically suspected acute mechanical cause of ADHF (e.g., papillary muscular rupture). The diagnosis need not be confirmed by imaging or cardiac catheterization. Anemia (hemoglobin <9 g/dL or a hematocrit <25%). Known vasculitis, active infective endocarditis, or suspected infections, e.g., pneumonia, acute hepatitis, systemic inflammatory response syndrome, or sepsis. Body temperature ≥38°C just prior to randomization. Acute or chronic respiratory disorder (e.g., severe chronic obstructive pulmonary disease) or primary pulmonary hypertension sufficient to cause dyspnea at rest, which may interfere with the ability to interpret dyspnea assessments or hemodynamic measurements. Terminal illness other than congestive HF with expected survival <180 days. Any previous exposure to ularitide. Known allergy to natriuretic peptides. Participation in an investigational clinical drug study within 30 days prior to randomization. Current drug abuse or chronic alcoholism sufficient to impair participation and compliance to the study protocol. Women who are breast-feeding. Women of child-bearing potential (i.e., pre-menopausal women) without documentation of a negative urine/blood pregnancy assay within 12 h prior to randomization. Any condition that, in the Investigator's opinion, makes the patient unsuitable for study participation. Legal incapacity or limited legal capacity. Patients requiring mechanical circulatory support. Patients with severe hepatic impairment.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ularitide<br>Ularitide, lyophilizate for i.v. infusion, 15 ng/kg BW/min, for 48 hours | Drug: Ularitide<br> <br> |
| Placebo Comparator: Placebo<br>Placebo lyophilizate for i.v. infusion | Drug: Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Two Co-primary Efficacy Endpoints | Improvement in a hierarchical clinical composite comprised of elements associated with: patient global assessment using a 7-point scale of symptomatic improvement, lack of improvement, or worsening; persistent or worsening heart failure (HF) requiring an intervention (initiation or intensification of IV therapy, circulatory or ventilatory mechanical support, surgical intervention, ultrafiltration, hemofiltration or dialysis); and all-cause mortality. Assessment of the clinical composite will be performed at 6 hour (h), 24 h and 48 h after start of IV ularitide infusion Freedom from cardiovascular mortality during follow up after randomization, for the entire duration of the trial. | 6, 24, 48 hours post infusion through the entire duration of the trial | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of stay of index hospitalization in hours after start of study drug infusion |  | up to 30 days | 
| Length of stay in intensive care (intensive care unit [ICU] or critical care unit [CCU]) |  | during the first 120 h following the start of the study drug infusion. | 
| Number of events of persistent or worsening HF requiring an intervention |  | from the start of the study drug infusion to 120 h. | 
| Proportion of patients with persistent or worsening HF and requiring an intervention |  | from the start of study drug infusion to 120 h. | 
| Reduction in rehospitalization for heart failure |  | within 30 days after initial hospital | 
| Changes of N-terminal pro brain natriuretic peptide (NT-pro BNP) |  | 48 h of treatment compared to baseline. | 
| Time to completion of last dose of any IV drugs that can be used for the treatment of HF (e.g., diuretics, vasodilators, or positive inotropic agents) |  | for the first 120 h following the start of the drug infusion. | 
| Change in serum creatinine |  | from baseline through 72 h. | 
| 180 days after start of study drug infusion, including patients still hospitalized at Day 30. |  | All-cause mortality and cardiovascular rehospitalization | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Acute decompensated heart failure