ClinicalTrials.gg
Sign In
TerminatedNCT05139615Updated Nov 9, 2023Results posted

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

A Phase 2 interventional study of APD418 and APD418 in Acute Heart Failure With Reduced Ejection Fraction, sponsored by Pfizer. Terminated at 21 sites in 5 countries. Open to participants aged 18 Years to 85 Years. Per ClinicalTrials.gov, last updated 2023-11-09.

Sponsored by Pfizer · Phase 2, Interventional, and Treatment

Why this study was terminated
Business decision
Phase
Phase 2
Study type
Interventional
Enrollment
22
Allocation
Randomized
Ages
18 Years to 85 Years
Sex
All
01

Study summary

The purpose of this study is to evaluate the safety, pharmacokinetics, and effect on cardiac function of intravenous APD418 in adult participants with heart failure with reduced ejection fraction (HFrEF).

Read the detailed description

This study has an adaptive design, in which dose escalation in Part A will inform dose expansion in Part B. Part A is a single-ascending dose, placebo-controlled study planned to consist of 5 cohorts evaluating 5 doses of APD418. Part B is a parallel-treatment group study planned to evaluate 2 doses of APD418 and placebo. Participants in Part A cannot participate in Part B.

02

Conditions studied

  • Acute Heart Failure With Reduced Ejection Fraction

Keywords

  • Heart failure with reduced ejection fraction
  • HFrEF
  • APD418
  • Acute Heart Failure (AHF)
03

In context

Lead sponsor

Pfizer is the lead sponsor of 3,323 studies on the registry; 145 are open to participants now.

Of its 597 completed or terminated interventional studies of FDA-regulated products, 391 (65%) have results posted.

Browse Pfizer studies →

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 85 Years
Sexes eligible
All
Accepts healthy volunteers
No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

  • Advanced chronic Heart Failure with Reduced Ejection Fraction (HFrEF), defined as left ventricular ejection fraction (LVEF) less than or equal to (≤) 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, and body weight \< 150 kg at Screening and Day 1

Exclusion criteria

Exclusion Criteria:

  • Hemodynamically unstable at Day 1 or in the opinion of the Investigator likely to progress to becoming hemodynamically unstable during the course of the study
  • Treated with carvedilol or at a dose higher than a total of 25 milligrams per day any time within 72 hours of Day 1 through the end of the in-clinic observation Post-dose Period.
  • Receiving any mechanical (respiratory or circulatory) or renal support therapy at Screening or Day 1
  • Systolic Blood Pressure ≤ 90 millimeter of mercury (mm Hg) or ≥ 160 mm Hg, or Heart Rate \< 50 beats per minute (bpm) or > 110 bpm, at Screening or Day 1
  • Recently treated with inotropic, intravenous (IV) vasoactive or IV diuretic therapy, or expected to require such therapy with these drugs any time from Day 1 through the end of study conduct.
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Double (Participant, Investigator)
Enrollment
22 participants (actual)

Study arms

  • Experimental
    APD418 (Part A: Dose Cohort 1-5)

    Drug: APD418

  • Experimental
    APD418 (Part B: Dose Group 1 and 2)

    Drug: APD418

  • Placebo comparator
    Placebo (Part A: Cohort 1-5 and Part B)

    Drug: Placebo

Interventions

  • DrugAPD418

    Participants will receive a single dose of APD418 as an intravenous (IV) infusion.

  • DrugAPD418

    Participants will receive a single dose of APD418 as an IV infusion.

  • DrugPlacebo

    Participants will receive a single dose of APD418 matching placebo as an IV infusion.

06

What researchers measure

Primary outcomes

  1. Part A: Change in Cardiac Index (CI) Measured by Right Heart Catheterization (RHC) From Baseline to End of Intravenous (IV) Infusion at 6 Hours

    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.

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

Secondary outcomes

  1. 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

    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.

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

  2. Part A: Change in Stroke Volume Index (SVI) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours

    SVI was calculated as stroke volume divided by BSA. 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)

  3. Part A: Change in Left Ventricular Ejection Fraction (LVEF) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours

    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.

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

  4. 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)

  5. 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)

  6. 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)

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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

  29. 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

Other outcomes

  1. Part A: Amount of Unchanged Drug Excreted in Urine During Each Collection Interval From t1 to t2 (Aet1-t2)

    Amount of unchanged drug excreted in urine during each collection interval from t1 to t2 was reported in this outcome measure.

    Time frame: Anytime between 0 to 6 hours, 6 to 10 hours and 10 to 24 hours post infusion start

  2. Part A: Total Amount of Unchanged Drug Excreted in Urine Over the Collection Period (Amount Excreted [Ae])

    Total amount of unchanged drug excreted in urine over the collection period 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

  3. Part A: Fraction of Drug Excreted Unchanged (Fe) in Urine

    Fraction of drug excreted in urine was reported in this outcome measure. Data is presented in terms of percentages.

    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

07

Results

Posted Nov 9, 2023
Limitations and caveats
This study was terminated early due to a business decision that was not due to any safety concerns. The number of participants was smaller than originally planned and only summary statistics were therefore generated for primary and secondary outcome measures.

Participant flow

Participant flow — Overall Study
MilestoneCohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
Started43114
Completed43114
Not completed0000

Outcome measures

PrimaryPart A: Change in Cardiac Index (CI) Measured by Right Heart Catheterization (RHC) From Baseline to End of Intravenous (IV) Infusion at 6 Hours

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.

Time frame:
Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
Reported as:
Mean · Liter per minute per meter square
Part A: Change in Cardiac Index (CI) Measured by Right Heart Catheterization (RHC) From Baseline to End of Intravenous (IV) Infusion at 6 Hours
Liter per minute per meter squareCohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
Part A: Change in Cardiac Index (CI) Measured by Right Heart Catheterization (RHC) From Baseline to End of Intravenous (IV) Infusion at 6 Hours0.33 ± 0.6600.10 ± 0.1000.25 ± 0.3720.10 ± 0.245
SecondaryPart 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

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.

Time frame:
Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
Reported as:
Mean · Milliliter
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
MilliliterCohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
Stroke Volume3.13 ± 10.623-0.80 ± NA5.94 ± 10.183-3.15 ± 7.152
LVESV-11.05 ± 22.8374.10 ± NA8.28 ± 25.6898.92 ± 29.804
LVEDV-7.92 ± 15.5313.30 ± NA14.20 ± 31.0217.30 ± 38.006
SecondaryPart A: Change in Stroke Volume Index (SVI) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours

SVI was calculated as stroke volume divided by BSA. 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)
Reported as:
Mean · Milliliter per meter square
Part A: Change in Stroke Volume Index (SVI) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours
Milliliter per meter squareCohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
Part A: Change in Stroke Volume Index (SVI) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours1.50 ± 5.518-0.30 ± NA2.62 ± 4.615-2.00 ± 4.492
SecondaryPart A: Change in Left Ventricular Ejection Fraction (LVEF) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours

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.

Time frame:
Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
Reported as:
Mean · Percentage of end diastolic volume
Part A: Change in Left Ventricular Ejection Fraction (LVEF) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours
Percentage of end diastolic volumeCohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
Part A: Change in Left Ventricular Ejection Fraction (LVEF) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours1.90 ± 6.0090.47 ± 1.4571.14 ± 3.204-1.68 ± 0.900
SecondaryPart 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)
Reported as:
Mean · Percentage
Part A: Change in Fractional Shortening (FS) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours
PercentageCohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
Part A: Change in Fractional Shortening (FS) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours-2.60 ± 7.7910.47 ± 5.710-1.55 ± 1.924-4.50 ± 7.444
SecondaryPart 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)
Reported as:
Mean · Centimeter (cm)
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
Centimeter (cm)Cohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
Left ventricular end-systolic diameter0.10 ± 0.361-0.04 ± 0.3840.22 ± 0.3210.35 ± 0.544
Left ventricular end-diastolic diameter-0.04 ± 0.087-0.02 ± 0.0980.15 ± 0.3630.16 ± 0.243
SecondaryPart 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)
Reported as:
Mean · Percentage
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
PercentageCohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
LVGLS0.30 ± NA-1.10 ± NA1.10 ± 1.337-1.29 ± 0.987
LVGCS-6.70 ± NA—0.05 ± 2.1050.00 ± 3.111
SecondaryPart 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
Reported as:
Mean · Liter per minute per meter square
Part A: Change in CI Measured by RHC at 0.5, 1, 2, 3, 4 and 5 Hours During 6 Hour IV Infusion
Liter per minute per meter squareCohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
0.5 hours-0.05 ± 0.2520.27 ± 0.3790.10 ± 0.167-0.10 ± 0.183
1 hour0.35 ± 0.2520.27 ± 0.3790.06 ± 0.1120.05 ± 0.208
2 hours0.45 ± 0.3700.13 ± 0.0580.11 ± 0.104-0.08 ± 0.126
3 hours0.68 ± 0.4270.20 ± 0.2650.20 ± 0.2790.15 ± 0.129
4 hours0.25 ± 0.1000.10 ± 0.1000.09 ± 0.2210.10 ± 0.346
5 hours0.23 ± 0.4570.17 ± 0.1530.11 ± 0.2740.08 ± 0.096
SecondaryPart 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
Reported as:
Mean · Liter per minute
Part A: Change in Cardiac Output (CO) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours
Liter per minuteCohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
0.5 hours-0.15 ± 0.4200.63 ± 0.7770.20 ± 0.329-0.15 ± 0.300
1 hour0.68 ± 0.4570.67 ± 0.9070.15 ± 0.2300.13 ± 0.340
2 hours0.90 ± 0.8760.43 ± 0.2310.21 ± 0.212-0.08 ± 0.189
3 hours1.28 ± 0.8770.47 ± 0.6430.41 ± 0.5680.33 ± 0.299
4 hours0.43 ± 0.2220.27 ± 0.2310.18 ± 0.4670.20 ± 0.560
5 hours0.43 ± 0.9110.43 ± 0.3790.25 ± 0.5590.15 ± 0.191
6 hours0.75 ± 1.4200.30 ± 0.3460.53 ± 0.7420.23 ± 0.499
SecondaryPart 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
Reported as:
Mean · Millimeters of mercury
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
Millimeters of mercuryCohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
PCWP: 0.5 hours1.50 ± 2.8870.67 ± 3.055-0.78 ± 3.456-2.67 ± 4.726
PCWP: 1 hour-0.25 ± 8.808-2.33 ± 4.041-2.00 ± 2.828-2.67 ± 8.145
PCWP: 2 hours-1.50 ± 5.000-3.33 ± 1.5281.56 ± 3.609-0.67 ± 7.506
PCWP: 3 hours-3.75 ± 3.594-0.33 ± 4.509-3.67 ± 3.464-3.67 ± 7.506
PCWP: 4 hours-2.75 ± 3.948-0.67 ± 5.033-2.90 ± 5.384-5.00 ± 9.165
PCWP: 5 hours-0.50 ± 6.137-1.33 ± 6.110-1.56 ± 2.698-3.33 ± 9.018
PCWP: 6 hours-0.75 ± 7.411-1.67 ± 5.686-1.25 ± 2.315-1.67 ± 9.504
RAP: 0.5 hours0.50 ± 1.2910.00 ± 1.7321.40 ± 3.836-1.33 ± 2.517
RAP: 1 hour2.50 ± 3.3170.33 ± 2.3090.00 ± 2.8673.33 ± 6.658
RAP: 2 hours1.00 ± 0.816-1.00 ± 1.0001.00 ± 4.3972.67 ± 7.234
RAP: 3 hours-0.25 ± 1.2580.33 ± 2.5170.40 ± 2.3663.33 ± 8.505
RAP: 4 hours-0.75 ± 4.500-0.67 ± 1.155-0.20 ± 4.3154.00 ± 6.083
RAP: 5 hours-1.50 ± 3.416-2.67 ± 1.1550.50 ± 4.3011.67 ± 8.327
RAP: 6 hours-0.67 ± 4.041-1.67 ± 1.528-0.50 ± 5.2334.00 ± 8.660
PAS: 0.5 hours1.50 ± 5.196-1.00 ± 2.6460.20 ± 6.033-0.67 ± 6.110
PAS: 1 hour4.50 ± 9.147-0.67 ± 4.041-1.50 ± 4.859-0.67 ± 6.028
PAS: 2 hours6.25 ± 4.7170.67 ± 0.5770.90 ± 6.7400.33 ± 4.933
PAS: 3 hours7.25 ± 6.1851.67 ± 5.033-1.40 ± 9.383-3.33 ± 9.292
PAS: 4 hours5.75 ± 13.5252.00 ± 4.359-1.70 ± 6.201-8.33 ± 15.631
PAS: 5 hours6.00 ± 11.1955.00 ± 1.000-1.30 ± 6.945-1.33 ± 6.658
PAS: 6 hours4.25 ± 9.1792.67 ± 2.309-0.90 ± 8.569-4.33 ± 9.609
PAD: 0.5 hours-1.25 ± 3.5000.00 ± 0.000-1.00 ± 2.7890.33 ± 4.509
PAD: 1 hour0.50 ± 2.646-1.33 ± 0.577-0.90 ± 3.872-1.67 ± 4.041
PAD: 2 hours-0.25 ± 2.217-0.67 ± 2.517-0.70 ± 3.860-1.00 ± 3.000
PAD: 3 hours-1.25 ± 4.1931.00 ± 2.646-3.60 ± 5.1680.00 ± 6.245
PAD: 4 hours-3.50 ± 8.8881.33 ± 1.155-2.40 ± 4.061-3.00 ± 7.937
PAD: 5 hours-2.50 ± 4.0411.00 ± 2.646-2.40 ± 3.6881.33 ± 5.033
PAD: 6 hours-4.00 ± 5.8311.33 ± 3.215-1.80 ± 4.9840.67 ± 5.686
SecondaryPart 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
Reported as:
Mean · Ratio
Part A: Change in Pulmonary Artery Pulsatility Index (PAPi) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours
RatioCohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
PAPi: 0.5 hours0.28 ± 0.411-0.17 ± 0.833-0.11 ± 0.7130.37 ± 1.343
PAPi: 1 hour-0.08 ± 0.5620.17 ± 0.306-0.21 ± 0.835-0.17 ± 0.603
PAPi: 2 hours0.38 ± 0.4350.33 ± 0.058-0.14 ± 1.0110.20 ± 0.900
PAPi: 3 hours0.65 ± 0.6240.43 ± 0.7770.03 ± 0.897-0.33 ± 0.611
PAPi: 4 hours1.35 ± 1.8380.83 ± 1.8340.27 ± 1.203-1.03 ± 0.907
PAPi: 5 hours0.95 ± 0.5972.33 ± 1.818-0.01 ± 0.8720.87 ± 2.639
PAPi: 6 hours0.93 ± 0.9291.27 ± 0.9290.77 ± 2.470-0.90 ± 0.173
SecondaryPart 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
Reported as:
Mean · Millimeter of mercury*minutes/milliliter
Part A: Change in Systemic Vascular Resistance Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours
Millimeter of mercury*minutes/milliliterCohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
SVR: 0.5 hours10.30 ± 74.776-71.27 ± 55.492-47.30 ± 139.87474.13 ± 198.427
SVR: 1 hour-80.50 ± 57.295-86.30 ± 80.69416.71 ± 231.657-131.93 ± 91.886
SVR: 2 hours-48.83 ± 71.811-46.23 ± 28.762-42.16 ± 205.772-49.40 ± 136.124
SVR: 3 hours-67.63 ± 56.169-8.10 ± 102.327-101.20 ± 188.863-195.77 ± 101.041
SVR: 4 hours-27.20 ± 104.35173.90 ± 136.245-33.91 ± 241.040-311.03 ± 145.094
SVR: 5 hours21.10 ± 112.824132.63 ± 171.630-92.29 ± 94.834-110.57 ± 222.498
SVR: 6 hours33.10 ± 106.65290.37 ± 137.576-70.00 ± 116.681-104.23 ± 90.537
SecondaryPart 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
Reported as:
Mean · Dynes*second*meter^2 per centimeter^5
Part A: Change in Systemic Vascular Resistance Index (SVRI) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours
Dynes*second*meter^2 per centimeter^5Cohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
SVRI: 0.5 hours5.00 ± 157.514-171.20 ± 154.962-98.41 ± 270.327107.83 ± 428.022
SVRI: 1 hour-156.58 ± 105.011-202.73 ± 185.52716.20 ± 404.144-289.57 ± 102.838
SVRI: 2 hours-115.13 ± 165.795-85.30 ± 63.286-94.82 ± 407.893-64.77 ± 281.682
SVRI: 3 hours-152.98 ± 108.934-42.57 ± 192.932-190.53 ± 315.500-403.47 ± 271.919
SVRI: 4 hours-85.05 ± 224.198201.20 ± 357.587-31.66 ± 414.786-649.80 ± 360.988
SVRI: 5 hours12.80 ± 208.554350.47 ± 458.646-172.77 ± 186.678-260.83 ± 484.601
SVRI: 6 hours61.47 ± 205.227152.63 ± 171.695-94.08 ± 306.599-227.17 ± 126.337
SecondaryPart 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
Reported as:
Mean · dynes*second per centimeter^5
Part A: Change in Pulmonary Vascular Resistance (PVR) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours
dynes*second per centimeter^5Cohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
PVR: 0.5 hours-28.98 ± 21.955-97.13 ± 134.47414.83 ± 115.97483.40 ± 80.442
PVR: 1 hour5.80 ± 108.571-37.57 ± 102.28478.37 ± 235.8846.40 ± 115.783
PVR: 2 hours37.68 ± 106.36446.43 ± 27.918-1.64 ± 290.121-0.10 ± 136.989
PVR: 3 hours29.70 ± 99.607-11.60 ± 69.29536.04 ± 171.09118.13 ± 107.316
PVR: 4 hours32.28 ± 190.27910.03 ± 72.67332.44 ± 191.341-44.03 ± 121.310
PVR: 5 hours29.08 ± 163.82544.57 ± 38.09922.61 ± 195.62653.70 ± 211.590
PVR: 6 hours2.70 ± 150.52954.57 ± 15.24538.10 ± 291.18819.53 ± 86.649
SecondaryPart 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
Reported as:
Mean · Millimeters of mercury
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
Millimeters of mercuryCohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
SBP: 0.5 hours7.3 ± 10.21-11.0 ± 10.15-2.2 ± 11.47-0.5 ± 6.35
SBP: 1 hour6.8 ± 10.56-7.3 ± 1.53-3.8 ± 9.44-0.8 ± 6.18
SBP: 2 hours8.0 ± 14.54-6.3 ± 9.81-2.6 ± 11.210.5 ± 6.14
SBP: 3 hours-1.0 ± 14.07-4.7 ± 7.77-3.9 ± 10.35-1.0 ± 10.30
SBP: 4 hours2.5 ± 15.11-2.7 ± 8.33-3.9 ± 9.660.5 ± 14.93
SBP: 6 hours9.8 ± 12.45-5.0 ± 6.00-1.4 ± 8.90-1.0 ± 12.57
DBP: 0.5 hours3.0 ± 16.06-6.7 ± 7.02-0.2 ± 4.920.0 ± 4.24
DBP: 1 hour3.0 ± 14.85-4.0 ± 5.29-2.2 ± 5.747.0 ± 18.20
DBP: 2 hours10.0 ± 16.12-7.0 ± 2.650.0 ± 7.92-1.5 ± 5.92
DBP: 3 hours-4.0 ± 12.46-3.3 ± 5.13-4.8 ± 9.26-1.0 ± 7.79
DBP: 4 hours-2.8 ± 13.100.3 ± 7.77-6.3 ± 5.76-1.0 ± 5.72
DBP: 5 hours-0.8 ± 13.67-2.0 ± 1.73-6.8 ± 6.52-1.0 ± 6.98
DBP: 6 hours1.3 ± 13.571.3 ± 2.08-0.3 ± 6.873.8 ± 7.93
MAP: 0.5 hours4.42 ± 13.723-8.11 ± 8.002-0.85 ± 4.994-0.17 ± 4.041
MAP: 1 hour4.25 ± 12.971-5.11 ± 3.097-2.73 ± 4.7184.42 ± 10.651
MAP: 2 hours9.33 ± 13.891-6.78 ± 4.623-0.88 ± 6.634-0.83 ± 5.828
MAP: 3 hours-3.00 ± 12.640-3.78 ± 5.274-4.52 ± 7.752-1.00 ± 8.551
MAP: 4 hours-1.00 ± 13.101-0.67 ± 6.960-5.48 ± 5.768-0.50 ± 8.131
MAP: 5 hours1.33 ± 13.570-1.00 ± 5.196-7.30 ± 5.742-0.17 ± 7.466
MAP: 6 hours4.08 ± 12.900-0.78 ± 1.388-0.64 ± 5.9342.17 ± 9.406
SecondaryPart 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
Reported as:
Mean · Beats per minute
Part A: Change in Heart Rate at 0.5, 1, 2, 3, 4, 5 and 6 Hours
Beats per minuteCohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
0.5 hours-8.8 ± 9.00-7.3 ± 12.660.0 ± 5.933.5 ± 9.11
1 hour-2.5 ± 2.65-3.3 ± 14.19-1.6 ± 4.86-9.0 ± 13.29
2 hours-2.3 ± 5.32-0.7 ± 9.07-1.5 ± 6.62-7.0 ± 13.49
3 hours2.0 ± 8.870.0 ± 9.17-0.6 ± 8.31-5.3 ± 11.18
4 hours-0.5 ± 6.240.3 ± 14.22-1.1 ± 5.801.0 ± 20.02
5 hours-6.3 ± 6.08-1.7 ± 5.86-1.5 ± 5.77-5.0 ± 13.49
6 hours4.5 ± 9.001.0 ± 5.574.2 ± 9.22-1.5 ± 17.82
SecondaryPart 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
Reported as:
Count of participants · Participants
Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
ParticipantsCohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)1131
SecondaryPart 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
Reported as:
Geometric mean · Hours*nanogram per milliliter
Part A: Area Under the Plasma Concentration Time Curve From Time Zero to 6 Hours (AUC[0-6]) of APD418
Hours*nanogram per milliliterCohort 1- 0.17 mg/kg/hr APD418Cohort 2- 0.5 mg/kg/hr APD418
Part A: Area Under the Plasma Concentration Time Curve From Time Zero to 6 Hours (AUC[0-6]) of APD4186620 ± 68.75970 ± 268
SecondaryPart 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
Reported as:
Geometric mean · Hours*nanogram per milliliter
Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Last Quantifiable Plasma Concentration (AUCLast) of APD418
Hours*nanogram per milliliterCohort 1- 0.17 mg/kg/hr APD418Cohort 2- 0.5 mg/kg/hr APD418
Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Last Quantifiable Plasma Concentration (AUCLast) of APD4189410 ± 84.39230 ± 164
SecondaryPart 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
Reported as:
Geometric mean · Hours*nanogram per milliliter
Part A: Area Under the Plasma Concentration Time Curve From Time Zero up to Infinity (AUC[0-Infinity]) of APD418
Hours*nanogram per milliliterCohort 1- 0.17 mg/kg/hr APD418Cohort 2- 0.5 mg/kg/hr APD418
Part A: Area Under the Plasma Concentration Time Curve From Time Zero up to Infinity (AUC[0-Infinity]) of APD4189660 ± 87.013400 ± 34.5
SecondaryPart 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
Reported as:
Geometric mean · Nanogram per milliliter
Part A: Maximum Observed Plasma Concentration (Cmax) of APD418
Nanogram per milliliterCohort 1- 0.17 mg/kg/hr APD418Cohort 2- 0.5 mg/kg/hr APD418
Part A: Maximum Observed Plasma Concentration (Cmax) of APD4181540 ± 88.81480 ± 277
SecondaryPart 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
Reported as:
Mean · Hours
Part A: Terminal Elimination Half-Life (t1/2) for APD418
HoursCohort 1- 0.17 mg/kg/hr APD418Cohort 2- 0.5 mg/kg/hr APD418
Part A: Terminal Elimination Half-Life (t1/2) for APD4185.26 ± 0.9605.26 ± 0.998
SecondaryPart 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
Reported as:
Mean · Hours
Part A: Distributional Half-Life (t1/2a) for APD418
HoursCohort 1- 0.17 mg/kg/hr APD418Cohort 2- 0.5 mg/kg/hr APD418
Part A: Distributional Half-Life (t1/2a) for APD4180.579 ± 0.3810.381 ± 0.119
SecondaryPart 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
Reported as:
Median · Hours
Part A: Time to Maximum Observed Plasma Concentration (Tmax) for APD418
HoursCohort 1- 0.17 mg/kg/hr APD418Cohort 2- 0.5 mg/kg/hr APD418
Part A: Time to Maximum Observed Plasma Concentration (Tmax) for APD4185.42 (4.00 to 6.08)5.00 (0.500 to 6.18)
SecondaryPart 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
Reported as:
Geometric mean · Liter per hour
Part A: Total Clearance (CL) for APD418
Liter per hourCohort 1- 0.17 mg/kg/hr APD418Cohort 2- 0.5 mg/kg/hr APD418
Part A: Total Clearance (CL) for APD4189.16 ± 92.717.8 ± 23.2
SecondaryPart 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
Reported as:
Geometric mean · Liter
Part A: Total Volume of Distribution Based on the Terminal Phase (Vdz) for APD418
LiterCohort 1- 0.17 mg/kg/hr APD418Cohort 2- 0.5 mg/kg/hr APD418
Part A: Total Volume of Distribution Based on the Terminal Phase (Vdz) for APD41868.6 ± 74.5133 ± 28.6
SecondaryPart 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
Reported as:
Geometric mean · Liter
Part A: Volume of Distribution at Steady State (Vdss) for APD418
LiterCohort 1- 0.17 mg/kg/hr APD418Cohort 2- 0.5 mg/kg/hr APD418
Part A: Volume of Distribution at Steady State (Vdss) for APD41827.7 ± 42.246.0 ± 34.5
SecondaryPart 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
Reported as:
Geometric mean · Hours
Part A: Mean Residence Time From Time Zero to Time of Last Quantifiable Plasma Concentration (MRTlast) for APD418
HoursCohort 1- 0.17 mg/kg/hr APD418Cohort 2- 0.5 mg/kg/hr APD418
Part A: Mean Residence Time From Time Zero to Time of Last Quantifiable Plasma Concentration (MRTlast) for APD4182.44 ± 33.62.54 ± 74.3
SecondaryPart 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
Reported as:
Geometric mean · Nanogram per milliliter
Part A: Average Plasma Concentration During Dosing Interval (Cave) for ADP418
Nanogram per milliliterCohort 1- 0.17 mg/kg/hr APD418Cohort 2- 0.5 mg/kg/hr APD418
Part A: Average Plasma Concentration During Dosing Interval (Cave) for ADP4181100 ± 68.7996 ± 268
SecondaryPart 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
Reported as:
Geometric mean · Liter per hour
Part A: Renal Clearance (CLr) for ADP418
Liter per hourCohort 1- 0.17 mg/kg/hr APD418Cohort 2- 0.5 mg/kg/hr APD418
Part A: Renal Clearance (CLr) for ADP4182.14 ± 55.33.78 ± 54.8
Other pre-specifiedPart A: Amount of Unchanged Drug Excreted in Urine During Each Collection Interval From t1 to t2 (Aet1-t2)

Amount of unchanged drug excreted in urine during each collection interval from t1 to t2 was reported in this outcome measure.

Time frame:
Anytime between 0 to 6 hours, 6 to 10 hours and 10 to 24 hours post infusion start
Reported as:
Geometric mean · Milligrams
Part A: Amount of Unchanged Drug Excreted in Urine During Each Collection Interval From t1 to t2 (Aet1-t2)
MilligramsCohort 1- 0.17 mg/kg/hr APD418Cohort 2- 0.5 mg/kg/hr APD418
Ae 0-611.8 ± 26.725.6 ± 56.9
Ae 6-104.47 ± 27.37.68 ± 68.4
Ae 10-242.83 ± 1367.93 ± 172
Other pre-specifiedPart A: Total Amount of Unchanged Drug Excreted in Urine Over the Collection Period (Amount Excreted [Ae])

Total amount of unchanged drug excreted in urine over the collection period 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
Reported as:
Geometric mean · Milligrams
Part A: Total Amount of Unchanged Drug Excreted in Urine Over the Collection Period (Amount Excreted [Ae])
MilligramsCohort 1- 0.17 mg/kg/hr APD418Cohort 2- 0.5 mg/kg/hr APD418
Part A: Total Amount of Unchanged Drug Excreted in Urine Over the Collection Period (Amount Excreted [Ae])20.1 ± 28.848.5 ± 38.0
Other pre-specifiedPart A: Fraction of Drug Excreted Unchanged (Fe) in Urine

Fraction of drug excreted in urine was reported in this outcome measure. Data is presented in terms of percentages.

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
Reported as:
Geometric mean · Percentage of unchanged drug
Part A: Fraction of Drug Excreted Unchanged (Fe) in Urine
Percentage of unchanged drugCohort 1- 0.17 mg/kg/hr APD418Cohort 2- 0.5 mg/kg/hr APD418
Part A: Fraction of Drug Excreted Unchanged (Fe) in Urine22.7 ± 31.219.7 ± 39.8

Adverse events

Collected over From start of study treatment on Day 1 up to Day 9. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Cohort 1- 0.17 mg/kg/hr APD4180/4 (0%)0/4 (0%)1/4 (25%)
Cohort 1- Placebo0/3 (0%)0/3 (0%)1/3 (33.3%)
Cohort 2- 0.5 mg/kg/hr APD4180/11 (0%)0/11 (0%)3/11 (27.3%)
Cohort 2- Placebo0/4 (0%)0/4 (0%)1/4 (25%)
Most frequent other events
Most frequent other events
EventCohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- Placebo
Back painMusculoskeletal and connective tissue disorders0/41/30/110/4
HaematuriaRenal and urinary disorders0/40/31/111/4
Vein ruptureVascular disorders1/40/30/110/4
Ventricular extrasystolesCardiac disorders0/40/31/110/4
FatigueGeneral disorders0/40/31/110/4
N-terminal prohormone brain natriuretic peptide increasedInvestigations0/40/31/110/4
DyspnoeaRespiratory, thoracic and mediastinal disorders0/40/31/110/4

Baseline characteristics

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

Age, Categorical
Age, Categorical(Participants)Cohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- PlaceboTotal
<=18 years00000
Between 18 and 65 years228113
>=65 years21339
Sex: Female, Male
Sex: Female, Male(Participants)Cohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- PlaceboTotal
Female10405
Male337417
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Cohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- PlaceboTotal
Hispanic or Latino00000
Not Hispanic or Latino4311422
Unknown or Not Reported00000
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Cohort 1- 0.17 mg/kg/hr APD418Cohort 1- PlaceboCohort 2- 0.5 mg/kg/hr APD418Cohort 2- PlaceboTotal
American Indian or Alaska Native00000
Asian00000
Native Hawaiian or Other Pacific Islander00000
Black or African American00000
White4311422
More than one race00000
Unknown or Not Reported00000
08

Study locations

21 sites
  • James A. Haley Veterans' Hospital
    Tampa, Florida 33612, United States
  • UnityPoint Health - Methodist Hospital
    Peoria, Illinois 61606, United States
  • UTHealth
    Houston, Texas 77030, United States
  • Health Science Center Utah
    Salt Lake City, Utah 84132, United States
  • University of Wisconsin
    Madison, Wisconsin 53792, United States
  • Immanuel Hospital Bernau Brandenburg Heart Center
    Bernau bei Berlin, Brandenburg 16321, Germany
  • Kerckhoff-Klinik Forschungsgesellschaft GmbH
    Bad Nauheim, 61231, Germany
  • Universitatsmedizin Greifwald
    Greifswald, 17475, Germany
  • Konstantinopouleio General Hospital of Nea Ionia - Patision ''Agia Olga''
    Nea Ionia, Athens 14233, Greece
  • Interbalkan European Medical Center
    Pylaia, Thessaloniki 55535, Greece
  • General University Hospital of Larissa
    Larissa, 41110, Greece
  • American Heart of Poland S.A.
    Gniezno, 62-200, Poland
  • Krakowski Szpital Specjalistyczny im. Jana Pawla II
    Krakow, 31-202, Poland
  • Uniwersytecki Szpital Kliniczny im Jana Mikulicza-Radeckiego
    Wroclaw, 50-556, Poland
  • Clinical Hospital Centre Zemun
    Belgrade, 11 070, Serbia
  • University Clinical Centre of Serbia
    Belgrade, 11000, Serbia
  • Institute for Cardiovascular Diseases Dedinje
    Belgrade, 11040, Serbia
  • Clinical Hospital Center Bezanijska Kosa
    Belgrade, 11080, Serbia
  • Institute for Cardiovascular Diseases of Vojvodina
    Kamenitz, 21204, Serbia
  • Clinical Center of Kragujevac
    Kragujevac, 34000, Serbia
  • Healthcare Center Uzice
    Užice, 31000, Serbia
09

References and documents

Study documents

  • Protocol and statistical analysis plan · Apr 26, 2022

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Data sharing details ↗ · www.pfizer.com

10

Timeline

Tracking since Sep 25, 2026
ElapsedEstimatedEstimated, not yet reached

Ran from Dec 2021 to primary completion in Sep 2022, 8 months.

Results were first posted in Nov 2023, 1 year 1 month after primary completion.

How these figures are worked out, and which studies are left out of them.

Registered
Nov 18, 2021
First posted
Dec 1, 2021
StartActual
Dec 28, 2021
Primary completionActual
Sep 19, 2022
CompletionActual
Sep 19, 2022
Results first posted
Nov 9, 2023
Last update
Nov 9, 2023
What these dates mean
Start.
When the first participant enrolled; while estimated, when the study expects to open to recruitment.
Primary completion.
When the last participant was examined or treated to collect data for the study's main question, its primary outcome. A study that stopped early gives the date its data collection stopped.
Completion.
When the last participant's last visit took place, for every outcome, secondary ones and side effects included: the end of the study. Often later than primary completion, sometimes the same day.
Actual and Est.
Actual means the registry says the date has happened. Est. (estimated) is a date the sponsor plans or expects. It can still move, and the sponsor is expected to change it to actual once it has passed.
No changes since tracking began. The registry record was last updated on Nov 9, 2023, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT05139615
Lead sponsor
Pfizer
Collaborators
Arena is a wholly owned subsidiary of Pfizer
Responsible party
Sponsor
First posted
Dec 1, 2021
Start date
Dec 28, 2021
Primary completion
Sep 19, 2022
Completion
Sep 19, 2022
Results posted
Nov 9, 2023
Last update
Nov 9, 2023

Study contacts

Pfizer CT.gov Call Center
study director · Pfizer

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is terminated, as verified in Nov 2023. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Sign in to follow

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies from this sponsor

Pfizer →

Start the discussion