Efficacy and Safety of Ularitide for the Treatment of Acute Decompensated Heart Failure (TRUE-AHF)

• Length of stay of index hospitalization in hours after start of study drug infusion [ Time Frame: up to 30 days ]
• Length of stay in intensive care (intensive care unit [ICU] or critical care unit [CCU]) [ Time Frame: during the first 120 h following the start of the study drug infusion. ]
• Number of events of persistent or worsening HF requiring an intervention [ Time Frame: from the start of the study drug infusion to 120 h. ]
• Proportion of patients with persistent or worsening HF and requiring an intervention [ Time Frame: from the start of study drug infusion to 120 h. ]
• Reduction in rehospitalization for heart failure [ Time Frame: within 30 days after initial hospital ]
• Changes of N-terminal pro brain natriuretic peptide (NT-pro BNP) [ Time Frame: 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) [ Time Frame: for the first 120 h following the start of the drug infusion. ]
• Change in serum creatinine [ Time Frame: from baseline through 72 h. ]
• 180 days after start of study drug infusion, including patients still hospitalized at Day 30. [ Time Frame: All-cause mortality and cardiovascular rehospitalization ]

• Efficacy Endpoint [ Time Frame: Day 90 post infusion start ]
  All-cause mortality and cardiovascular rehospitalization at Day 90 after start of the study drug infusion.
• Efficacy Endpoint [ Time Frame: Day 90 post infusion start ]
  Cardiovascular mortality at Day 90

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.

• Drug: Ularitide
• Drug: Placebo

• Experimental: Ularitide
  Ularitide, lyophilizate for i.v. infusion, 15 ng/kg BW/min, for 48 hours
  Intervention: Drug: Ularitide
• Placebo Comparator: Placebo
  Placebo lyophilizate for i.v. infusion
  Intervention: Drug: Placebo

• Mitrovic V, Lüss H, Nitsche K, Forssmann K, Maronde E, Fricke K, Forssmann WG, Meyer M. Effects of the renal natriuretic peptide urodilatin (ularitide) in patients with decompensated chronic heart failure: a double-blind, placebo-controlled, ascending-dose trial. Am Heart J. 2005 Dec;150(6):1239.
• Mitrovic V, Seferovic PM, Simeunovic D, Ristic AD, Miric M, Moiseyev VS, Kobalava Z, Nitsche K, Forssmann WG, Lüss H, Meyer M. Haemodynamic and clinical effects of ularitide in decompensated heart failure. Eur Heart J. 2006 Dec;27(23):2823-32. Epub 2006 Oct 30.
• Packer M, O'Connor C, McMurray JJV, Wittes J, Abraham WT, Anker SD, Dickstein K, Filippatos G, Holcomb R, Krum H, Maggioni AP, Mebazaa A, Peacock WF, Petrie MC, Ponikowski P, Ruschitzka F, van Veldhuisen DJ, Kowarski LS, Schactman M, Holzmeister J; TRUE-AHF Investigators. Effect of Ularitide on Cardiovascular Mortality in Acute Heart Failure. N Engl J Med. 2017 May 18;376(20):1956-1964. doi: 10.1056/NEJMoa1601895. Epub 2017 Apr 12.

Inclusion Criteria:

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:

   • 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.
3. Ability to start infusion of the study drug within 12 h after initial clinical assessment.
4. Ability to reliably carry out self-assessment of symptoms.
5. Systolic blood pressure ≥116 mmHg and ≤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 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.
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).

Exclusion Criteria:

1. Known active myocarditis, obstructive hypertrophic cardiomyopathy, congenital heart disease, restrictive cardiomyopathy, constrictive pericarditis, uncorrected clinically significant primary valvular disease.
2. Treatment with dobutamine at a dose >5 μg/kg/min or use of drugs for support of BP at the time of randomization.
3. Treatment with levosimendan, milrinone, or any other phosphodiesterase inhibitor within 7 days before randomization.
4. Treatment with nesiritide within 30 days before randomization.
5. Creatinine clearance <25 mL/min/1.73m² (as measured by the MDRD formula) at the time of screening.
6. Planned coronary revascularization procedure (percutaneous coronary intervention or coronary artery bypass grafting) within 5 days of randomization.

7. Clinical diagnosis of acute coronary syndrome meeting any 2 of the following 3 criteria:

   1. Prolonged chest pain at rest, or an accelerated pattern of angina
   2. 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.
   3. Serum troponin >3 times upper limit of normal.
8. Clinically suspected acute mechanical cause of ADHF (e.g., papillary muscular rupture). The diagnosis need not be confirmed by imaging or cardiac catheterization.
9. Anemia (hemoglobin <9 g/dL or a hematocrit <25%).
10. Known vasculitis, active infective endocarditis, or suspected infections, e.g., pneumonia, acute hepatitis, systemic inflammatory response syndrome, or sepsis.
11. Body temperature ≥38°C just prior to randomization.
12. 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.
13. Terminal illness other than congestive HF with expected survival <180 days.
14. Any previous exposure to ularitide.
15. Known allergy to natriuretic peptides.
16. Participation in an investigational clinical drug study within 30 days prior to randomization.
17. Current drug abuse or chronic alcoholism sufficient to impair participation and compliance to the study protocol.
18. Women who are breast-feeding.
19. 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.
20. Any condition that, in the Investigator's opinion, makes the patient unsuitable for study participation.
21. Legal incapacity or limited legal capacity.
22. Patients requiring mechanical circulatory support.
23. Patients with severe hepatic impairment.