Trial Outcomes & Findings for A Study to Assess the Hemodynamic Effects, Safety, Tolerability, and Pharmacokinetics of Intravenous APD418 in Adult Participants With Heart Failure With Reduced Ejection Fraction (NCT NCT05139615)

Results Overview

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

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

22 participants

Primary outcome timeframe

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

Results posted on

2023-11-09

Participant Flow

The study was planned to be conducted in two parts (Part A and B); however, study was terminated during Part A due to a business decision by Sponsor and Part B was not initiated and no participants were enrolled in Part B.

Participant milestones

Participant milestones
Measure	Cohort 1- 0.17 mg/kg/hr APD418 Participants were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 1- Placebo Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- 0.5 mg/kg/hr APD418 Participants were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- Placebo Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
Overall Study STARTED	4	3	11	4
Overall Study COMPLETED	4	3	11	4
Overall Study NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1- 0.17 mg/kg/hr APD418 n=4 Participants Participants were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 1- Placebo n=3 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- 0.5 mg/kg/hr APD418 n=11 Participants Participants were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- Placebo n=4 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Total n=22 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	2 Participants n=5 Participants	2 Participants n=7 Participants	8 Participants n=5 Participants	1 Participants n=4 Participants	13 Participants n=21 Participants
Age, Categorical >=65 years	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants	3 Participants n=4 Participants	9 Participants n=21 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants	0 Participants n=4 Participants	5 Participants n=21 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants	4 Participants n=4 Participants	17 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4 Participants n=5 Participants	3 Participants n=7 Participants	11 Participants n=5 Participants	4 Participants n=4 Participants	22 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) White	4 Participants n=5 Participants	3 Participants n=7 Participants	11 Participants n=5 Participants	4 Participants n=4 Participants	22 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants

PRIMARY outcome

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

Population: Full analysis set included all randomized participants, irrespective of whether they received any study treatment.

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

Outcome measures

Outcome measures
Measure	Cohort 1- 0.17 mg/kg/hr APD418 n=4 Participants Participants were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 1- Placebo n=3 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- 0.5 mg/kg/hr APD418 n=11 Participants Participants were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- Placebo n=4 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
Part A: Change in Cardiac Index (CI) Measured by Right Heart Catheterization (RHC) From Baseline to End of Intravenous (IV) Infusion at 6 Hours	0.33 Liter per minute per meter square Standard Deviation 0.660	0.10 Liter per minute per meter square Standard Deviation 0.100	0.25 Liter per minute per meter square Standard Deviation 0.372	0.10 Liter per minute per meter square Standard Deviation 0.245

SECONDARY outcome

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

Population: Full analysis set included all randomized participants, irrespective of whether they received any study treatment. Here, 'Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure.

SV is the volume of blood pumped from the left ventricle per beat. LVESV is the volume of blood in the left ventricle at the end of contraction and at diastole. LVEDV is the amount of blood in the heart's left ventricle just before the heart contracts. All these parameters were measured by ECHO.

Outcome measures

Outcome measures
Measure	Cohort 1- 0.17 mg/kg/hr APD418 n=4 Participants Participants were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 1- Placebo n=1 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- 0.5 mg/kg/hr APD418 n=9 Participants Participants were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- Placebo n=4 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
Part A: Change in Stroke Volume (SV), Left Ventricular End-Systolic Volume (LVESV) and Left Ventricular End-Diastolic Volume (LVEDV) Measured by Echocardiogram (ECHO) From Baseline to End of IV Infusion at 6 Hours Stroke Volume	3.13 Milliliter Standard Deviation 10.623	-0.80 Milliliter Standard Deviation NA Standard Deviation could not be calculated as a single participant was analyzed.	5.94 Milliliter Standard Deviation 10.183	-3.15 Milliliter Standard Deviation 7.152
Part A: Change in Stroke Volume (SV), Left Ventricular End-Systolic Volume (LVESV) and Left Ventricular End-Diastolic Volume (LVEDV) Measured by Echocardiogram (ECHO) From Baseline to End of IV Infusion at 6 Hours LVESV	-11.05 Milliliter Standard Deviation 22.837	4.10 Milliliter Standard Deviation NA Standard Deviation could not be calculated as a single participant was analyzed.	8.28 Milliliter Standard Deviation 25.689	8.92 Milliliter Standard Deviation 29.804
Part A: Change in Stroke Volume (SV), Left Ventricular End-Systolic Volume (LVESV) and Left Ventricular End-Diastolic Volume (LVEDV) Measured by Echocardiogram (ECHO) From Baseline to End of IV Infusion at 6 Hours LVEDV	-7.92 Milliliter Standard Deviation 15.531	3.30 Milliliter Standard Deviation NA Standard Deviation could not be calculated as a single participant was analyzed.	14.20 Milliliter Standard Deviation 31.021	7.30 Milliliter Standard Deviation 38.006

SECONDARY outcome

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

Population: Full analysis set included all randomized participants, irrespective of whether they received any study treatment. Here, 'Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure.

SVI was calculated as stroke volume divided by BSA. This was measured by ECHO.

Outcome measures

Outcome measures
Measure	Cohort 1- 0.17 mg/kg/hr APD418 n=4 Participants Participants were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 1- Placebo n=1 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- 0.5 mg/kg/hr APD418 n=9 Participants Participants were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- Placebo n=4 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
Part A: Change in Stroke Volume Index (SVI) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours	1.50 Milliliter per meter square Standard Deviation 5.518	-0.30 Milliliter per meter square Standard Deviation NA Standard Deviation could not be calculated as a single participant was analyzed.	2.62 Milliliter per meter square Standard Deviation 4.615	-2.00 Milliliter per meter square Standard Deviation 4.492

SECONDARY outcome

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

Population: Full analysis set included all randomized participants, irrespective of whether they received any study treatment.

LVEF is the central measure of left ventricular systolic function. LVEF is the fraction of chamber volume ejected in systole (stroke volume) in relation to the volume of the blood in the ventricle at the end of diastole (end-diastolic volume). This was measured by ECHO.

Outcome measures

Outcome measures
Measure	Cohort 1- 0.17 mg/kg/hr APD418 n=4 Participants Participants were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 1- Placebo n=3 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- 0.5 mg/kg/hr APD418 n=11 Participants Participants were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- Placebo n=4 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
Part A: Change in Left Ventricular Ejection Fraction (LVEF) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours	1.90 Percentage of end diastolic volume Standard Deviation 6.009	0.47 Percentage of end diastolic volume Standard Deviation 1.457	1.14 Percentage of end diastolic volume Standard Deviation 3.204	-1.68 Percentage of end diastolic volume Standard Deviation 0.900

SECONDARY outcome

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

Population: Full analysis set included all randomized participants, irrespective of whether they received any study treatment.

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

Outcome measures

Outcome measures
Measure	Cohort 1- 0.17 mg/kg/hr APD418 n=4 Participants Participants were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 1- Placebo n=3 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- 0.5 mg/kg/hr APD418 n=11 Participants Participants were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- Placebo n=4 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
Part A: Change in Fractional Shortening (FS) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours	-2.60 Percentage Standard Deviation 7.791	0.47 Percentage Standard Deviation 5.710	-1.55 Percentage Standard Deviation 1.924	-4.50 Percentage Standard Deviation 7.444

SECONDARY outcome

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

Population: Full analysis set included all randomized participants, irrespective of whether they received any study treatment.

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

Outcome measures

Outcome measures
Measure	Cohort 1- 0.17 mg/kg/hr APD418 n=4 Participants Participants were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 1- Placebo n=3 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- 0.5 mg/kg/hr APD418 n=11 Participants Participants were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- Placebo n=4 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
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	0.10 Centimeter (cm) Standard Deviation 0.361	-0.04 Centimeter (cm) Standard Deviation 0.384	0.22 Centimeter (cm) Standard Deviation 0.321	0.35 Centimeter (cm) Standard Deviation 0.544
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-diastolic diameter	-0.04 Centimeter (cm) Standard Deviation 0.087	-0.02 Centimeter (cm) Standard Deviation 0.098	0.15 Centimeter (cm) Standard Deviation 0.363	0.16 Centimeter (cm) Standard Deviation 0.243

SECONDARY outcome

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

Population: Full analysis set included all randomized participants, irrespective of whether they received any study treatment. Here, 'Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable for the specified rows.

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.

Outcome measures

Outcome measures
Measure	Cohort 1- 0.17 mg/kg/hr APD418 n=1 Participants Participants were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 1- Placebo n=1 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- 0.5 mg/kg/hr APD418 n=5 Participants Participants were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- Placebo n=4 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
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 LVGLS	0.30 Percentage Standard Deviation NA Standard Deviation could not be calculated as a single participant was analyzed.	-1.10 Percentage Standard Deviation NA Standard Deviation could not be calculated as a single participant was analyzed.	1.10 Percentage Standard Deviation 1.337	-1.29 Percentage Standard Deviation 0.987
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 LVGCS	-6.70 Percentage Standard Deviation NA Standard Deviation could not be calculated as a single participant was analyzed.	—	0.05 Percentage Standard Deviation 2.105	0.00 Percentage Standard Deviation 3.111

SECONDARY outcome

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

Population: Full analysis set included all randomized participants, irrespective of whether they received any study treatment.

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.

Outcome measures

Outcome measures
Measure	Cohort 1- 0.17 mg/kg/hr APD418 n=4 Participants Participants were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 1- Placebo n=3 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- 0.5 mg/kg/hr APD418 n=11 Participants Participants were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- Placebo n=4 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
Part A: Change in CI Measured by RHC at 0.5, 1, 2, 3, 4 and 5 Hours During 6 Hour IV Infusion 0.5 hours	-0.05 Liter per minute per meter square Standard Deviation 0.252	0.27 Liter per minute per meter square Standard Deviation 0.379	0.10 Liter per minute per meter square Standard Deviation 0.167	-0.10 Liter per minute per meter square Standard Deviation 0.183
Part A: Change in CI Measured by RHC at 0.5, 1, 2, 3, 4 and 5 Hours During 6 Hour IV Infusion 1 hour	0.35 Liter per minute per meter square Standard Deviation 0.252	0.27 Liter per minute per meter square Standard Deviation 0.379	0.06 Liter per minute per meter square Standard Deviation 0.112	0.05 Liter per minute per meter square Standard Deviation 0.208
Part A: Change in CI Measured by RHC at 0.5, 1, 2, 3, 4 and 5 Hours During 6 Hour IV Infusion 2 hours	0.45 Liter per minute per meter square Standard Deviation 0.370	0.13 Liter per minute per meter square Standard Deviation 0.058	0.11 Liter per minute per meter square Standard Deviation 0.104	-0.08 Liter per minute per meter square Standard Deviation 0.126
Part A: Change in CI Measured by RHC at 0.5, 1, 2, 3, 4 and 5 Hours During 6 Hour IV Infusion 3 hours	0.68 Liter per minute per meter square Standard Deviation 0.427	0.20 Liter per minute per meter square Standard Deviation 0.265	0.20 Liter per minute per meter square Standard Deviation 0.279	0.15 Liter per minute per meter square Standard Deviation 0.129
Part A: Change in CI Measured by RHC at 0.5, 1, 2, 3, 4 and 5 Hours During 6 Hour IV Infusion 4 hours	0.25 Liter per minute per meter square Standard Deviation 0.100	0.10 Liter per minute per meter square Standard Deviation 0.100	0.09 Liter per minute per meter square Standard Deviation 0.221	0.10 Liter per minute per meter square Standard Deviation 0.346
Part A: Change in CI Measured by RHC at 0.5, 1, 2, 3, 4 and 5 Hours During 6 Hour IV Infusion 5 hours	0.23 Liter per minute per meter square Standard Deviation 0.457	0.17 Liter per minute per meter square Standard Deviation 0.153	0.11 Liter per minute per meter square Standard Deviation 0.274	0.08 Liter per minute per meter square Standard Deviation 0.096

SECONDARY outcome

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

Population: Full analysis set included all randomized participants, irrespective of whether they received any study treatment.

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.

Outcome measures

Outcome measures
Measure	Cohort 1- 0.17 mg/kg/hr APD418 n=4 Participants Participants were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 1- Placebo n=3 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- 0.5 mg/kg/hr APD418 n=11 Participants Participants were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- Placebo n=4 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
Part A: Change in Cardiac Output (CO) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours 0.5 hours	-0.15 Liter per minute Standard Deviation 0.420	0.63 Liter per minute Standard Deviation 0.777	0.20 Liter per minute Standard Deviation 0.329	-0.15 Liter per minute Standard Deviation 0.300
Part A: Change in Cardiac Output (CO) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours 1 hour	0.68 Liter per minute Standard Deviation 0.457	0.67 Liter per minute Standard Deviation 0.907	0.15 Liter per minute Standard Deviation 0.230	0.13 Liter per minute Standard Deviation 0.340
Part A: Change in Cardiac Output (CO) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours 2 hours	0.90 Liter per minute Standard Deviation 0.876	0.43 Liter per minute Standard Deviation 0.231	0.21 Liter per minute Standard Deviation 0.212	-0.08 Liter per minute Standard Deviation 0.189
Part A: Change in Cardiac Output (CO) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours 3 hours	1.28 Liter per minute Standard Deviation 0.877	0.47 Liter per minute Standard Deviation 0.643	0.41 Liter per minute Standard Deviation 0.568	0.33 Liter per minute Standard Deviation 0.299
Part A: Change in Cardiac Output (CO) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours 4 hours	0.43 Liter per minute Standard Deviation 0.222	0.27 Liter per minute Standard Deviation 0.231	0.18 Liter per minute Standard Deviation 0.467	0.20 Liter per minute Standard Deviation 0.560
Part A: Change in Cardiac Output (CO) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours 6 hours	0.75 Liter per minute Standard Deviation 1.420	0.30 Liter per minute Standard Deviation 0.346	0.53 Liter per minute Standard Deviation 0.742	0.23 Liter per minute Standard Deviation 0.499
Part A: Change in Cardiac Output (CO) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours 5 hours	0.43 Liter per minute Standard Deviation 0.911	0.43 Liter per minute Standard Deviation 0.379	0.25 Liter per minute Standard Deviation 0.559	0.15 Liter per minute Standard Deviation 0.191

SECONDARY outcome

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

Population: Full analysis set included all randomized participants, irrespective of whether they received any study treatment. All participants reported under 'Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row. Here, 'Number Analyzed' (n) signifies number of participants evaluable for specified timepoints.

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.

Outcome measures

SECONDARY outcome

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

Population: Full analysis set included all randomized participants, irrespective of whether they received any study treatment. All participants reported under 'Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row. Here, 'Number Analyzed' (n) signifies number of participants evaluable for specified timepoints.

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.

Outcome measures

Outcome measures
Measure	Cohort 1- 0.17 mg/kg/hr APD418 n=4 Participants Participants were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 1- Placebo n=3 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- 0.5 mg/kg/hr APD418 n=11 Participants Participants were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- Placebo n=4 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
Part A: Change in Pulmonary Artery Pulsatility Index (PAPi) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours PAPi: 0.5 hours	0.28 Ratio Standard Deviation 0.411	-0.17 Ratio Standard Deviation 0.833	-0.11 Ratio Standard Deviation 0.713	0.37 Ratio Standard Deviation 1.343
Part A: Change in Pulmonary Artery Pulsatility Index (PAPi) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours PAPi: 3 hours	0.65 Ratio Standard Deviation 0.624	0.43 Ratio Standard Deviation 0.777	0.03 Ratio Standard Deviation 0.897	-0.33 Ratio Standard Deviation 0.611
Part A: Change in Pulmonary Artery Pulsatility Index (PAPi) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours PAPi: 4 hours	1.35 Ratio Standard Deviation 1.838	0.83 Ratio Standard Deviation 1.834	0.27 Ratio Standard Deviation 1.203	-1.03 Ratio Standard Deviation 0.907
Part A: Change in Pulmonary Artery Pulsatility Index (PAPi) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours PAPi: 5 hours	0.95 Ratio Standard Deviation 0.597	2.33 Ratio Standard Deviation 1.818	-0.01 Ratio Standard Deviation 0.872	0.87 Ratio Standard Deviation 2.639
Part A: Change in Pulmonary Artery Pulsatility Index (PAPi) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours PAPi: 6 hours	0.93 Ratio Standard Deviation 0.929	1.27 Ratio Standard Deviation 0.929	0.77 Ratio Standard Deviation 2.470	-0.90 Ratio Standard Deviation 0.173
Part A: Change in Pulmonary Artery Pulsatility Index (PAPi) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours PAPi: 1 hour	-0.08 Ratio Standard Deviation 0.562	0.17 Ratio Standard Deviation 0.306	-0.21 Ratio Standard Deviation 0.835	-0.17 Ratio Standard Deviation 0.603
Part A: Change in Pulmonary Artery Pulsatility Index (PAPi) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours PAPi: 2 hours	0.38 Ratio Standard Deviation 0.435	0.33 Ratio Standard Deviation 0.058	-0.14 Ratio Standard Deviation 1.011	0.20 Ratio Standard Deviation 0.900

SECONDARY outcome

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

Population: Full analysis set included all randomized participants, irrespective of whether they received any study treatment. All participants reported under 'Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row. Here, 'Number Analyzed' (n) signifies number of participants evaluable for specified timepoints.

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.

Outcome measures

Outcome measures
Measure	Cohort 1- 0.17 mg/kg/hr APD418 n=4 Participants Participants were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 1- Placebo n=3 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- 0.5 mg/kg/hr APD418 n=11 Participants Participants were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- Placebo n=4 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
Part A: Change in Systemic Vascular Resistance Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours SVR: 2 hours	-48.83 Millimeter of mercury*minutes/milliliter Standard Deviation 71.811	-46.23 Millimeter of mercury*minutes/milliliter Standard Deviation 28.762	-42.16 Millimeter of mercury*minutes/milliliter Standard Deviation 205.772	-49.40 Millimeter of mercury*minutes/milliliter Standard Deviation 136.124
Part A: Change in Systemic Vascular Resistance Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours SVR: 4 hours	-27.20 Millimeter of mercury*minutes/milliliter Standard Deviation 104.351	73.90 Millimeter of mercury*minutes/milliliter Standard Deviation 136.245	-33.91 Millimeter of mercury*minutes/milliliter Standard Deviation 241.040	-311.03 Millimeter of mercury*minutes/milliliter Standard Deviation 145.094
Part A: Change in Systemic Vascular Resistance Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours SVR: 5 hours	21.10 Millimeter of mercury*minutes/milliliter Standard Deviation 112.824	132.63 Millimeter of mercury*minutes/milliliter Standard Deviation 171.630	-92.29 Millimeter of mercury*minutes/milliliter Standard Deviation 94.834	-110.57 Millimeter of mercury*minutes/milliliter Standard Deviation 222.498
Part A: Change in Systemic Vascular Resistance Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours SVR: 6 hours	33.10 Millimeter of mercury*minutes/milliliter Standard Deviation 106.652	90.37 Millimeter of mercury*minutes/milliliter Standard Deviation 137.576	-70.00 Millimeter of mercury*minutes/milliliter Standard Deviation 116.681	-104.23 Millimeter of mercury*minutes/milliliter Standard Deviation 90.537
Part A: Change in Systemic Vascular Resistance Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours SVR: 0.5 hours	10.30 Millimeter of mercury*minutes/milliliter Standard Deviation 74.776	-71.27 Millimeter of mercury*minutes/milliliter Standard Deviation 55.492	-47.30 Millimeter of mercury*minutes/milliliter Standard Deviation 139.874	74.13 Millimeter of mercury*minutes/milliliter Standard Deviation 198.427
Part A: Change in Systemic Vascular Resistance Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours SVR: 1 hour	-80.50 Millimeter of mercury*minutes/milliliter Standard Deviation 57.295	-86.30 Millimeter of mercury*minutes/milliliter Standard Deviation 80.694	16.71 Millimeter of mercury*minutes/milliliter Standard Deviation 231.657	-131.93 Millimeter of mercury*minutes/milliliter Standard Deviation 91.886
Part A: Change in Systemic Vascular Resistance Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours SVR: 3 hours	-67.63 Millimeter of mercury*minutes/milliliter Standard Deviation 56.169	-8.10 Millimeter of mercury*minutes/milliliter Standard Deviation 102.327	-101.20 Millimeter of mercury*minutes/milliliter Standard Deviation 188.863	-195.77 Millimeter of mercury*minutes/milliliter Standard Deviation 101.041

SECONDARY outcome

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

Population: Full analysis set included all randomized participants, irrespective of whether they received any study treatment. All participants reported under 'Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row. Here, 'Number Analyzed' (n) signifies number of participants evaluable for specified timepoints.

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.

Outcome measures

Outcome measures
Measure	Cohort 1- 0.17 mg/kg/hr APD418 n=4 Participants Participants were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 1- Placebo n=3 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- 0.5 mg/kg/hr APD418 n=11 Participants Participants were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- Placebo n=4 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
Part A: Change in Systemic Vascular Resistance Index (SVRI) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours SVRI: 0.5 hours	5.00 Dynessecondmeter^2 per centimeter^5 Standard Deviation 157.514	-171.20 Dynessecondmeter^2 per centimeter^5 Standard Deviation 154.962	-98.41 Dynessecondmeter^2 per centimeter^5 Standard Deviation 270.327	107.83 Dynessecondmeter^2 per centimeter^5 Standard Deviation 428.022
Part A: Change in Systemic Vascular Resistance Index (SVRI) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours SVRI: 1 hour	-156.58 Dynessecondmeter^2 per centimeter^5 Standard Deviation 105.011	-202.73 Dynessecondmeter^2 per centimeter^5 Standard Deviation 185.527	16.20 Dynessecondmeter^2 per centimeter^5 Standard Deviation 404.144	-289.57 Dynessecondmeter^2 per centimeter^5 Standard Deviation 102.838
Part A: Change in Systemic Vascular Resistance Index (SVRI) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours SVRI: 2 hours	-115.13 Dynessecondmeter^2 per centimeter^5 Standard Deviation 165.795	-85.30 Dynessecondmeter^2 per centimeter^5 Standard Deviation 63.286	-94.82 Dynessecondmeter^2 per centimeter^5 Standard Deviation 407.893	-64.77 Dynessecondmeter^2 per centimeter^5 Standard Deviation 281.682
Part A: Change in Systemic Vascular Resistance Index (SVRI) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours SVRI: 3 hours	-152.98 Dynessecondmeter^2 per centimeter^5 Standard Deviation 108.934	-42.57 Dynessecondmeter^2 per centimeter^5 Standard Deviation 192.932	-190.53 Dynessecondmeter^2 per centimeter^5 Standard Deviation 315.500	-403.47 Dynessecondmeter^2 per centimeter^5 Standard Deviation 271.919
Part A: Change in Systemic Vascular Resistance Index (SVRI) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours SVRI: 4 hours	-85.05 Dynessecondmeter^2 per centimeter^5 Standard Deviation 224.198	201.20 Dynessecondmeter^2 per centimeter^5 Standard Deviation 357.587	-31.66 Dynessecondmeter^2 per centimeter^5 Standard Deviation 414.786	-649.80 Dynessecondmeter^2 per centimeter^5 Standard Deviation 360.988
Part A: Change in Systemic Vascular Resistance Index (SVRI) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours SVRI: 5 hours	12.80 Dynessecondmeter^2 per centimeter^5 Standard Deviation 208.554	350.47 Dynessecondmeter^2 per centimeter^5 Standard Deviation 458.646	-172.77 Dynessecondmeter^2 per centimeter^5 Standard Deviation 186.678	-260.83 Dynessecondmeter^2 per centimeter^5 Standard Deviation 484.601
Part A: Change in Systemic Vascular Resistance Index (SVRI) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours SVRI: 6 hours	61.47 Dynessecondmeter^2 per centimeter^5 Standard Deviation 205.227	152.63 Dynessecondmeter^2 per centimeter^5 Standard Deviation 171.695	-94.08 Dynessecondmeter^2 per centimeter^5 Standard Deviation 306.599	-227.17 Dynessecondmeter^2 per centimeter^5 Standard Deviation 126.337

SECONDARY outcome

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

Population: Full analysis set included all randomized participants, irrespective of whether they received any study treatment. All participants reported under 'Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row. Here, 'Number Analyzed' (n) signifies number of participants evaluable for specified timepoints.

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.

Outcome measures

Outcome measures
Measure	Cohort 1- 0.17 mg/kg/hr APD418 n=4 Participants Participants were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 1- Placebo n=3 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- 0.5 mg/kg/hr APD418 n=11 Participants Participants were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- Placebo n=4 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
Part A: Change in Pulmonary Vascular Resistance (PVR) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours PVR: 1 hour	5.80 dynes*second per centimeter^5 Standard Deviation 108.571	-37.57 dynes*second per centimeter^5 Standard Deviation 102.284	78.37 dynes*second per centimeter^5 Standard Deviation 235.884	6.40 dynes*second per centimeter^5 Standard Deviation 115.783
Part A: Change in Pulmonary Vascular Resistance (PVR) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours PVR: 2 hours	37.68 dynes*second per centimeter^5 Standard Deviation 106.364	46.43 dynes*second per centimeter^5 Standard Deviation 27.918	-1.64 dynes*second per centimeter^5 Standard Deviation 290.121	-0.10 dynes*second per centimeter^5 Standard Deviation 136.989
Part A: Change in Pulmonary Vascular Resistance (PVR) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours PVR: 3 hours	29.70 dynes*second per centimeter^5 Standard Deviation 99.607	-11.60 dynes*second per centimeter^5 Standard Deviation 69.295	36.04 dynes*second per centimeter^5 Standard Deviation 171.091	18.13 dynes*second per centimeter^5 Standard Deviation 107.316
Part A: Change in Pulmonary Vascular Resistance (PVR) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours PVR: 4 hours	32.28 dynes*second per centimeter^5 Standard Deviation 190.279	10.03 dynes*second per centimeter^5 Standard Deviation 72.673	32.44 dynes*second per centimeter^5 Standard Deviation 191.341	-44.03 dynes*second per centimeter^5 Standard Deviation 121.310
Part A: Change in Pulmonary Vascular Resistance (PVR) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours PVR: 5 hours	29.08 dynes*second per centimeter^5 Standard Deviation 163.825	44.57 dynes*second per centimeter^5 Standard Deviation 38.099	22.61 dynes*second per centimeter^5 Standard Deviation 195.626	53.70 dynes*second per centimeter^5 Standard Deviation 211.590
Part A: Change in Pulmonary Vascular Resistance (PVR) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours PVR: 0.5 hours	-28.98 dynes*second per centimeter^5 Standard Deviation 21.955	-97.13 dynes*second per centimeter^5 Standard Deviation 134.474	14.83 dynes*second per centimeter^5 Standard Deviation 115.974	83.40 dynes*second per centimeter^5 Standard Deviation 80.442
Part A: Change in Pulmonary Vascular Resistance (PVR) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours PVR: 6 hours	2.70 dynes*second per centimeter^5 Standard Deviation 150.529	54.57 dynes*second per centimeter^5 Standard Deviation 15.245	38.10 dynes*second per centimeter^5 Standard Deviation 291.188	19.53 dynes*second per centimeter^5 Standard Deviation 86.649

SECONDARY outcome

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

Population: Full analysis set included all randomized participants, irrespective of whether they received any study treatment.

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).

Outcome measures

SECONDARY outcome

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

Population: Full analysis set included all randomized participants, irrespective of whether they received any study treatment.

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

Outcome measures

Outcome measures
Measure	Cohort 1- 0.17 mg/kg/hr APD418 n=4 Participants Participants were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 1- Placebo n=3 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- 0.5 mg/kg/hr APD418 n=11 Participants Participants were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- Placebo n=4 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
Part A: Change in Heart Rate at 0.5, 1, 2, 3, 4, 5 and 6 Hours 1 hour	-2.5 Beats per minute Standard Deviation 2.65	-3.3 Beats per minute Standard Deviation 14.19	-1.6 Beats per minute Standard Deviation 4.86	-9.0 Beats per minute Standard Deviation 13.29
Part A: Change in Heart Rate at 0.5, 1, 2, 3, 4, 5 and 6 Hours 2 hours	-2.3 Beats per minute Standard Deviation 5.32	-0.7 Beats per minute Standard Deviation 9.07	-1.5 Beats per minute Standard Deviation 6.62	-7.0 Beats per minute Standard Deviation 13.49
Part A: Change in Heart Rate at 0.5, 1, 2, 3, 4, 5 and 6 Hours 3 hours	2.0 Beats per minute Standard Deviation 8.87	0.0 Beats per minute Standard Deviation 9.17	-0.6 Beats per minute Standard Deviation 8.31	-5.3 Beats per minute Standard Deviation 11.18
Part A: Change in Heart Rate at 0.5, 1, 2, 3, 4, 5 and 6 Hours 6 hours	4.5 Beats per minute Standard Deviation 9.00	1.0 Beats per minute Standard Deviation 5.57	4.2 Beats per minute Standard Deviation 9.22	-1.5 Beats per minute Standard Deviation 17.82
Part A: Change in Heart Rate at 0.5, 1, 2, 3, 4, 5 and 6 Hours 0.5 hours	-8.8 Beats per minute Standard Deviation 9.00	-7.3 Beats per minute Standard Deviation 12.66	0.0 Beats per minute Standard Deviation 5.93	3.5 Beats per minute Standard Deviation 9.11
Part A: Change in Heart Rate at 0.5, 1, 2, 3, 4, 5 and 6 Hours 4 hours	-0.5 Beats per minute Standard Deviation 6.24	0.3 Beats per minute Standard Deviation 14.22	-1.1 Beats per minute Standard Deviation 5.80	1.0 Beats per minute Standard Deviation 20.02
Part A: Change in Heart Rate at 0.5, 1, 2, 3, 4, 5 and 6 Hours 5 hours	-6.3 Beats per minute Standard Deviation 6.08	-1.7 Beats per minute Standard Deviation 5.86	-1.5 Beats per minute Standard Deviation 5.77	-5.0 Beats per minute Standard Deviation 13.49

SECONDARY outcome

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

Population: Safety set included all randomized participants who received at least one dose of study treatment.

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.

Outcome measures

Outcome measures
Measure	Cohort 1- 0.17 mg/kg/hr APD418 n=4 Participants Participants were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 1- Placebo n=3 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- 0.5 mg/kg/hr APD418 n=11 Participants Participants were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.	Cohort 2- Placebo n=4 Participants Participants were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	1 Participants	1 Participants	3 Participants	1 Participants

SECONDARY outcome

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

Population: Pharmacokinetic (PK) set included all participants in the safety set with at least 1 post-dose PK measurement.

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