Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Ularitide (Urodilantin) Intravenous Infusion in Patients Suffering from Acute Decompensated Heart Failure [TRUE-AHF]
This is a Phase iii, double-blind, randomized, placebo-controlled, multinational, multicenter study that will be conducted in north america, Western and eastern europe, Latin america, and australia/new Zealand in approximately 190 centers.
approximately 2,152 aDHF patients will be randomized within 12 hrs after clinical assessment at the emergency room. To be randomized, the subject will still have to have dyspnea at rest in a recumbent position as well as a temperature [Less Than]38 degrees C and a BP (blood pressure) greater than or equal to 110 mmHg. Randomization will take place when the subject is registered in iVRS. Following randomization, patients will receive a 48-hr infusion of either ularitide 15 ng/kg/min or matching placebo (1:1 ratio) in a double-blind manner.
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 and in accordance with the current european Society of Cardiology (eSC) Guidelines for the diagnosis and treatment of acute and chronic HF.
Co-primary endpoint for this study will be a hierarchical clinical composite variable that includes a patient-centered assessment of clinical progress, assessment of persistence 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, has persisting or 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-hr 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. This clinical composite has been used in several trials of aDHF and closely resembles the clinical composite that has been used successfully in many trials of oral drugs for the treatment of chronic HF. Secondary endpoints include changes in nT proBnP from baseline to 48 hours of treatment and all cause mortality, combined all cause mortality and cardiovascular rehospitalization at day 90 after the start of study drug infusion including patients still hospitalized at Day 30, and cardiovascular rehospitalization at Day 90 after start of study drug infusion, including patients still hospitalized at Day 30. The occurrence of death for any reason and cardiovascular rehospitalizations will be assessed at Day 30, Day 60, Day 90 and Day 180 after start of study drug infusion. Patients will then be followed until the end of the study by a phone call every 90 days for a mortality assessment.
1) Males and females aged 18 to 85 years.
2) Unplanned hospitalization or emergency department visit for ADHF. Acute HF is defined as including all of the following:
a) Dyspnea at rest in a recumbent sitting position (30 to 45 degrees), which has worsened within the past week
b) Radiological evidence of HF on a chest X-ray (if an appropriate chest computerized tomography scan is done; the Xray need not be performed.
c) Brain natriuretic peptide (BNP) >500 pg/mL or N-terminal pro-brain natriuretic peptide (NT-pro BNP) >2000 pg/mL.
3) Ability to start infusion of the study drug within 12 h after initial clinical assessment performed by a physician at the emergency room/hospital.
4) Ability to reliably carry out self-assessment of symptoms.
5) Systolic blood pressure greater than or equal to 116 mmHg and less than or equal to 180 mmHg at the time of randomization.
6) 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 hr prior to randomization, and the infusion rates of ongoing IV infusions of medication to treat HF must not have been increased or decreased for at least 2 h prior to randomization.
7) 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).