E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of acute heart failure with reduced ejection fraction (HFrEF) |
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E.1.1.1 | Medical condition in easily understood language |
Treatment of acute heart failure |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000803 |
E.1.2 | Term | Acute heart failure |
E.1.2 | System Organ Class | 100000004849 |
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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 assess the effect of intravenous (IV) infusion of APD418 on hemodynamic status based on cardiac index (CI) in subjects with heart failure with reduced ejection fraction (HFrEF) |
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E.2.2 | Secondary objectives of the trial |
• To assess the effect of IV infusion of APD418 on additional hemodynamic, vital sign, and systolic function parameters in subjects with HFrEF • To assess the pharmacokinetics (PK) of IV infusion of APD418 in subjects with HFrEF • To assess the safety and tolerability of IV infusion of APD418 in subjects with HFrEF |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. Optional pharmacogenetic (DNA research) sub-study, v 1.0, dated 09 March 2021 Objective: In addition to analyses performed during the study, samples will be saved for potential future exploratory research aimed at identifying/exploring genetic variations and response to APD418 that may affect its pharmacokinetics (PK), pharmacodynamics, safety, or tolerability, if warranted.
2. Pregnancy Follow-up, v 1.0, dated 09 March 2021 Objective: Assessment if there is any risk to the study participant or study participant's partner or unborn baby. Followed up to delivery (or outcome) and through to the first well-baby visit (if applicable).
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E.3 | Principal inclusion criteria |
• Advanced chronic Heart Failure with Reduced Ejection Fraction (HFrEF), defined as left ventricular ejection fraction (LVEF) ≤ 35% at Screening, including documented history of HFrEF (LVEF ≤ 35%) for at least 4 months prior to Screening • New York Heart Association Class II-IV • Cardiac index ≤ 2.5 liters per minute per square meter (L/min/m^2) and pulmonary capillary wedge pressure ≥ 15 millimeters of mercury (mm Hg) at Day 1 • Body mass index 18.0 to 37.0 kilograms per square meter (kg/m^2), inclusive |
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E.4 | Principal exclusion criteria |
• Hemodynamically unstable at Day 1 or in the opinion of the Investigator likely to progress to being hemodynamically unstable during the course of the study • Treated with dobutamine, dopamine, or milrinone within 7 days of Day 1 or with levosimendan within 21 days of Day 1, or expected to require therapy with these drugs any time from Day 1 through the end of study conduct • Treated with vasoactive or intravenous (IV) diuretic therapy within 24 hours of Day 1, or expected to require IV therapy any time from Day 1 through the end of the in-clinic observation Postdose Period |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in CI measured by RHC from Baseline to end of IV infusion at 6 hours |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline to end of intravenous (IV) infusion at 6 hours |
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E.5.2 | Secondary end point(s) |
Secondary endpoints: • Change in the following hemodynamic parameters measured by RHC from Baseline to end of IV infusion at 6 hours: − Cardiac output (CO) − Pulmonary capillary wedge pressure (PCWP) − Right atrial pressure (RAP) − Systolic/diastolic pulmonary arterial pressure (PAS/PAD) − Pulmonary artery pulsatility index (PAPi) − Systemic vascular resistance/systemic vascular resistance index (SVR/SVRI) − Pulmonary vascular resistance (PVR) • Change in the following vital sign parameters from Baseline to end of IV infusion at 6 hours: − Systolic blood pressure (SBP) − Diastolic blood pressure (DBP) − Mean arterial pressure (MAP) − Heart rate (HR) • Change in the following hemodynamic and systolic function parameters measured by echocardiogram (ECHO) from Baseline to end of IV infusion at 6 hours: − Stroke volume (SV) − SV index (SVI) − Left ventricular ejection fraction (LVEF) − Fractional shortening (FS) − Left ventricular end systolic/left ventricular end-diastolic volume (LVESV/LVEDV) and diameter − Left ventricular global longitudinal strain (LVGLS) − Left ventricular circumferential strain (LVGCS) • Change in hemodynamic (measured by RHC) and vital sign parameters listed above at intermediate timepoints during 6-hour IV infusion (during Dosing Period) • Plasma and urine PK parameters assessed for each dose of APD418 baseline, end of infusion at 6-hours, and intermediate timepoints during 6-hour infusion, as well as post-infusion timepoints • Safety and tolerability of APD418 by incidence of all treatment-emergent adverse events (TEAEs) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline, end of infusion at 6-hours, intermediate timepoints during 6-hour infusion |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 10 |
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 | No |
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 |
Serbia |
United States |
Germany |
Greece |
Poland |
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E.8.7 | Trial has a data monitoring committee | No |
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
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End of Study is defined as completion of the final Follow-Up phone call for the last subject. |
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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 | 7 |
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 | 7 |