A Study to Assess the Hemodynamic Effects, Safety, Tolerability, and Pharmacokinetics of Intravenous APD418 in Adult Participants With Heart Failure With Reduced Ejection Fraction

Part A: Change in Fractional Shortening (FS) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours

FS was calculated by measuring the percentage reduction in left ventricular diameter during systole. This was measured by ECHO.

Time frame: Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)

Part A: Change in Left Ventricular End-Systolic and Left Ventricular End-Diastolic Diameter Measured by ECHO From Baseline to End of IV Infusion at 6 Hours

Left ventricular end-systolic diameter and left ventricular end-diastolic diameter were measured using ECHO.

Time frame: Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)

Part A: Change in Left Ventricular Global Longitudinal Strain (LVGLS) and Left Ventricular Global Circumferential Strain (LVGCS) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours

Left ventricular global strain is the average strain of the cardiac chamber wall, where LVGLS presents longitudinal shortening as a percentage (change in length as a proportion to baseline length). LVGCS measures the chamber deformation along the circumference of the cardiac wall in a tangential xy-direction and similarly presents the circumferential shortening as a percentage. Both the parameters were measured by ECHO.

Time frame: Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)

Part A: Change in CI Measured by RHC at 0.5, 1, 2, 3, 4 and 5 Hours During 6 Hour IV Infusion

CI is a hemodynamic parameter that relates the CO from left ventricle in one minute to BSA, thus relating heart performance to the body size of the participant. It was measured by RHC.

Time frame: Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4 and 5 hours of IV infusion

Part A: Change in Cardiac Output (CO) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours

Change in CO measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 hours during the 6-hour IV infusion was reported in this outcome measure.

Time frame: Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion

Part A: Change in Pulmonary Capillary Wedge Pressure (PCWP), Right Atrial Pressure (RAP), Systolic Pulmonary Arterial Pressure/Diastolic Pulmonary Arterial Pressure (PAS/PAD) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours

PCWP estimated the left atrial pressure and was the pressure measured by wedging a pulmonary artery catheter with an inflated balloon into a small pulmonary arterial branch. PCWP was assessed by 2 successive measurements at least 10 minutes apart. RAP is the blood pressure in the right atrium of the heart. Change in PCWP, RAP, PAS/PAD at 0.5, 1, 2, 3, 4, 5 and 6 hours during the 6-hour IV infusion was reported in this outcome measure. All the parameters were measured by RHC.

Time frame: Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion

Part A: Change in Pulmonary Artery Pulsatility Index (PAPi) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours

PAPi is a hemodynamic parameter that is derived from right atrial and pulmonary artery pulse pressures. PAPi = (PAS - PAD)/right atrial pressure. Change in PAPi measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 hours during the 6-hour IV infusion was reported in this outcome measure.

Time frame: Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion

Part A: Change in Systemic Vascular Resistance Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours

Systemic vascular resistance (SVR) is the amount of force exerted on circulating blood by the vasculature of the body. SVR was calculated as 80\*(mean arterial pressure - mean venous pressure) divided by cardiac output. Change in SVR measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 hours during the 6-hour IV infusion was reported in this outcome measure.

Time frame: Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion

Part A: Change in Systemic Vascular Resistance Index (SVRI) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours

SVRI was calculated by dividing the difference between mean arterial pressure and central venous pressure by cardiac index and multiplying by 80. Change in SVRI measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 hours during the 6 hour IV infusion was reported in this outcome measure.

Time frame: Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion

Part A: Change in Pulmonary Vascular Resistance (PVR) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours

PVR is the resistance against blood flow from the pulmonary artery to the left atrium. Change in PVR measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 hours during the 6 hour IV infusion was reported in this outcome measure.

Time frame: Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion

Part A: Change in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Pressure (MAP) at 0.5, 1, 2, 3, 4, 5 and 6 Hours

SBP, DBP and MAP were measured in a supine or seated position after participant had at least 5 minutes of rest. MAP is the average pressure of the blood circulating through a participant's arteries during the cardiac cycle. MAP was derived by using the following formula: DBP + 1/3(SBP-DBP).

Time frame: Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion

Part A: Change in Heart Rate at 0.5, 1, 2, 3, 4, 5 and 6 Hours

Heart rate was measured in a supine or seated position after participant had at least 5 minutes of rest.

Time frame: Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion

Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

An AE was any untoward medical occurrence that did not necessarily have a causal relationship with study treatment. TEAEs were defined as those AEs with onset after start date/timepoint of study drug administration.

Time frame: From start of study treatment on Day 1 up to Day 9

Part A: Area Under the Plasma Concentration Time Curve From Time Zero to 6 Hours (AUC[0-6]) of APD418

AUC \[0-6\] was reported in this outcome measure.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6 hours post infusion start

Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Last Quantifiable Plasma Concentration (AUCLast) of APD418

AUClast was reported in this outcome measure.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start

Part A: Area Under the Plasma Concentration Time Curve From Time Zero up to Infinity (AUC[0-Infinity]) of APD418

AUC \[0-infinity\] was reported in this outcome measure.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start

Part A: Maximum Observed Plasma Concentration (Cmax) of APD418

Cmax of APD418 was reported in this outcome measure.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start

Part A: Terminal Elimination Half-Life (t1/2) for APD418

Terminal t1/2 of APD418 was reported in this outcome measure.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start

Part A: Distributional Half-Life (t1/2a) for APD418

Distributional t1/2 of APD418 was reported in this outcome measure.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start

Part A: Time to Maximum Observed Plasma Concentration (Tmax) for APD418

Tmax of APD418 was reported in this outcome measure.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start

Part A: Total Clearance (CL) for APD418

IV CL of APD418 was reported in this outcome measure.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start

Part A: Total Volume of Distribution Based on the Terminal Phase (Vdz) for APD418

Vdz of APD418 was reported in this outcome measure.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start

Part A: Volume of Distribution at Steady State (Vdss) for APD418

Vdss of APD418 was reported in this outcome measure.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start

Part A: Mean Residence Time From Time Zero to Time of Last Quantifiable Plasma Concentration (MRTlast) for APD418

MRTlast of APD418 was reported in this outcome measure.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start

Part A: Average Plasma Concentration During Dosing Interval (Cave) for ADP418

Average plasma concentration calculated over the 6-hour infusion time was reported in this outcome measure.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6 hours post infusion start

Part A: Renal Clearance (CLr) for ADP418

CLr for APD418 was reported in this outcome measure.

Time frame: Pre-dose (0) to 24 hours post infusion start, collected over 0 to 6 hour, 6 to 10 hour and 10 to 24-hour intervals