| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Acute decompensated heart failure | |
| 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 | 10000803 | | E.1.2 | Term | Acute heart failure | |
| 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 efficacy and safety of ularitide with placebo in subjects hospitalized for symptomatic ADHF. | |
| E.2.2 | Secondary objectives of the trial | | To characterize the pharmacokinetic (limited to steady-state concentration [Css] and clearance [CL]) and immunogenicity profiles of ularitide versus placebo in subjects hospitalized for symptomatic ADHF. To assess a subject’s change in quality of life throughout dosing and during follow up compared with baseline. | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1) Males and females ≥ 18 years.
2) Unplanned hospitalization for ADHF.
3)Randomization within 24 hours after presentation to emergency department or hospital for ADHF.
4) Dyspnea at rest as assessed by the subject. Subject must have the ability to interpret and report self-assessed dyspnea
5) At least 1 of the following 2 criteria:
•Prior medical history of CHF (eg, prior hospitalization for CHF) or left ventricular ejection fraction <40%, as determined by appropriate imaging techniques, such as echocardiography, nuclear scintigraphy, or contrast left ventriculography in the past 12 months.
•Clinical evidence (at screening) of heart failure, including abnormal jugular venous pressure (JVP) (eg, >8 cm above the clavicle, assessed at 45°angle), rales or crackles more than a third above bases, or 2+ lower extremity edema.
6) Radiographic evidence (at screening) of pulmonary congestion (eg, redistribution, alveolar or interstitial edema, or pleural effusions).
7) On optimal background therapy for ADHF (as determined by the investigator); subjects are required to have received, at a minimum, at least one hour of oxygen supplementation and at least one dose of IV furosemide at a minimum dose of 40 mg (or another diuretic at a comparable dose; eg, 2 mg bumetanide or 20 mg torsemide), with the last bolus being delivered >2 hours before study drug administration is initiated.
8) If subject received IV opiate, the last dose should have been >3 hours before administration of study drug.
9) If the subject is a woman of potential childbearing age, documentation of a negative urine pregnancy test result within 24 hours prior to randomization.
10) 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 subject privacy regulations).
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| E.4 | Principal exclusion criteria | 1) Breathing rate <18 breaths per minute (measured during 60 seconds).
2) A systolic blood pressure (SBP) less than or equal to 110 mmHg or >200 mmHg within an hour before randomization, or SBP <120 mmHg for subjects receiving intravenous (IV) inotropics or vasodilators. A SBP <90 mmHg any time before randomization. (Subjects on baseline IV inotropes or vasodilators must be on a stable dose for ≥3 hours prior to randomization.)
3) Brain natriuretic peptide (BNP) <400 pg/mL or NT pro-BNP <1200 pg/mL, anytime from initial presentation to hospital to randomization.
4) Active ongoing myocardial ischemia, hospitalization for acute myocardial infarction, or administration of thrombolytic therapy in the last 30 days.
5) Any cardiogenic shock (SBP <90 mmHg with signs or symptoms of organ hypoperfusion) from initial presentation to randomization.
6) Body temperature ≥ 38ºC.
7) Acute unstable clinical condition such as a hemodynamically significant arrhythmia or a persistent heart rate ≥130 bpm or is refractory to treatment (at the time of screening), or any unstable heart failure syndrome requiring any mechanical-assist device or emergency surgery.
8) Acute decompensated heart failure associated with endocrine, metabolic, or drug-related toxicity.
9) Percutaneous coronary intervention, coronary artery bypass graft surgery, other cardiac surgery, or major noncardiac surgery within 90 days prior to randomization.
10) Any volume depletion or severe electrolyte imbalance.
11) Anemia (hemoglobin <10 mg/dL or hematocrit <30%).
12) Significant acute or chronic respiratory disorder (eg, severe chronic obstructive pulmonary disease) or primary pulmonary hypertension with baseline dyspnea that may interfere with the ability to interpret dyspnea assessments or hemodynamic measurements.
13) For subjects with concomitant invasive hemodynamic monitoring (ie, pulmonary artery catheter monitoring): Baseline PCWP of ≤ 20 mmHg.
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| E.5 End points |
| E.5.1 | Primary end point(s) | | A statistically significant improvement in the mean scores of subject-assessed dyspnea, as measured by the 7 point Likert scale, and SGA, as measured by the 7 point Likert scale, at 6 hours from initiation of study drug infusion for the ularitide group compared with the placebo group. Additionally, a trend towards improvement in dyspnea at 3 hours and SGA at 3 and 48 hours from initiation of study drug infusion for the ularitide group compared with the placebo group will also be assessed. | |
| 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 | No |
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | No |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 152 |
| 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 | |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
