| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Decompensated Heart Failure |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064653 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the safety and efficacy of ularitide (15 ng/kg/min IV over 48 hours) to placebo in subjects with symptomatic acute decompensated heart failure. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the pharmacokinetics, pharmacodynamics, and immunogenicity of intravenous ularitide, in subjects with symptomatic acute decompensated heart failure. |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1) Adult males and non-pregnant females age 18 or older who require hospitalization for ADHF with the following:
· Dyspnea at rest despite initial treatment (with symptoms occurring during talking, eating, grooming, or other forms of minimal activity).
· Plasma BNP >400 pg/mL or NT-pro-BNP >1200 pg/mL.
2) A negative urine pregnancy test result in women of childbearing potential within 24 hours prior to study drug administration.
3) Ability to understand the purpose and risks of the study and provide signed and dated informed consent, and for US sites, an authorization to use protected health information (in accordance with the Health Insurance Portability and Accountability Act or HIPAA in the US). An authorized guardian may provide consent and authorize use of protected health information for subjects.
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| E.4 | Principal exclusion criteria |
1) Systolic blood pressure (BP) ≤110 mmHg or >180 mmHg at initial presentation to the ED or hospital and at randomization.
2) Ongoing acute coronary syndrome, acute myocarditis or constrictive pericarditis, known obstructive hypertrophic cardiomyopathy, hemodynamically significant arrhythmias (including atrial fibrillation with a rapid ventricular response), hemodynamically significant stenotic or regurgitant valvular disease, or congenital heart disease.
3) Acute myocardial infarction or invasive cardiac procedure (including coronary angiography, percutaneous coronary intervention, and pacemaker implantation) within 30 days prior to randomization; coronary artery bypass grafting within 90 days prior to randomization; or a history of cardiac transplant.
4) History of known CHF that began less than 90 days prior to randomization.
5) Use of restricted medications or procedures, as specified below:
a) For subjects enrolled into the “early enrollment” stratum (ie, presenting to the ED or hospital <6 hours prior to randomization), use of any of the following within 6 hours prior to randomization:
· Invasive or noninvasive ventilation (including continuous positive airway pressure [CPAP] and biphasic positive airway pressure [BiPAP]).
· Intravenous vasoactive agents (including angiotensin-converting enzyme [ACE] inhibitors, nitroprusside, nitroglycerin, and nesiritide).
· Intravenous or PO diuretics equivalent in potency to >80 mg furosemide or any continuous diuretic infusion regardless of dose.
b) For subjects enrolled in the “delayed enrollment” stratum (ie, presenting to the ED or hospital 6-24 hours prior to randomization), use of any of the following within 3 hours prior to randomization:
· Invasive or noninvasive ventilation (including CPAP and BiPAP).
· Intravenous vasoactive agents (including angiotensin-converting enzyme [ACE] inhibitors, nitroprusside, nitroglycerin, and nesiritide).
· Intravenous or PO diuretics.
c) Use of IV inotropics, including phosphodiesterase (PDE) inhibitors, dopamine, and dobutamine, within the last 14 days prior to randomization.
d) Inability to discontinue nitro paste or other forms of nitroglycerin preparations prior to study treatment.
6) Cardiogenic shock; volume depletion; severe electrolyte imbalance; renal disorder with serum creatinine >2.5 mg/dL (220 micromol/L), unstable renal function with a known rise in serum creatinine of >25% or 0.5 mg/dL within 30 days prior to randomization, or planned ultrafiltration or dialysis; or any other clinical condition that would contraindicate the use of an IV vasodilator.
7) Suspicion of active or on-going pulmonary embolism.
8) Disabling cerebrovascular accident (CVA) within 180 days prior to randomization.
9) Clinically significant systemic illnesses, such as anemia (hemoglobin <10 mg/dL); known or suspected pneumonia or sepsis; or, vasculitis.
10) Previous exposure to study drug or known allergy to natriuretic peptides.
11) Participation in a clinical drug trial within 30 days prior to randomization.
12) Terminal illness other than CHF with expected survival less than 180 days.
13) Current drug abuse or chronic alcoholism.
14) Women who are breast-feeding.
15) Use of phosphodiesterase type 5 (PDE 5) inhibitor such as sildenafil within 24 to 48 hours prior to randomization.
16) Severe respiratory disorder or primary pulmonary hypertension with moderate to severe dyspnea (including use of oxygen).
17) Known use of significantly nephrotoxic agents (such as IV contrast) within 7 days prior to randomization.
18) Any condition that, in the investigator's opinion, makes the subject unsuitable for study participation. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| A comparison of the proportion of subjects in the ularitide and placebo groups who are “responders” in the assessment of the composite clinical response. This is an endpoint based on subject’s assessment of dyspnea, the investigator’s judgment of overall status (“physician’s global assessment”), and need for co-intervention (diuretics or other forms of rescue therapy) for worsening symptoms at both 24 and 48 hours after the initiation of study drug administration. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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