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, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Hemodynamic Effects, Safety, Tolerability, and Pharmacokinetics of APD418 in Subjects With Heart Failure With Reduced Ejection Fraction

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).

Study Overview

• Status: Terminated
• Conditions: Acute Heart Failure With Reduced Ejection Fraction
• Intervention / Treatment: Drug: APD418; Drug: APD418; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 81 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: APD418 (Part A: Dose Cohort 1-5)	Drug: APD418; Participants will receive a single dose of APD418 as an intravenous (IV) infusion.; Drug: APD418; Participants will receive a single dose of APD418 as an IV infusion.
Experimental: APD418 (Part B: Dose Group 1 and 2)	Drug: APD418; Participants will receive a single dose of APD418 as an intravenous (IV) infusion.; Drug: APD418; Participants will receive a single dose of APD418 as an IV infusion.
Placebo Comparator: Placebo (Part A: Cohort 1-5 and Part B)	Drug: Placebo; Participants will receive a single dose of APD418 matching placebo as an IV infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
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.	Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
Part A: Change in Left Ventricular 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.	Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
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.	Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
Part A: Change in Left Ventricular End-Systolic and Left Ventricular End-Diastolic Diameter Measured by ECHO From Baseline to End of IV Infusion at 6 Hours	Left ventricular end-systolic diameter and left ventricular end-diastolic diameter were measured using ECHO.	Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
Part A: Change in Left Ventricular Global Longitudinal Strain (LVGLS) and Left Ventricular Global Circumferential Strain (LVGCS) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours	Left ventricular global strain is the average strain of the cardiac chamber wall, where LVGLS presents longitudinal shortening as a percentage (change in length as a proportion to baseline length). LVGCS measures the chamber deformation along the circumference of the cardiac wall in a tangential xy-direction and similarly presents the circumferential shortening as a percentage. Both the parameters were measured by ECHO.	Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
Part A: Change in CI Measured by RHC at 0.5, 1, 2, 3, 4 and 5 Hours During 6 Hour IV Infusion	CI is a hemodynamic parameter that relates the CO from left ventricle in one minute to BSA, thus relating heart performance to the body size of the participant. It was measured by RHC.	Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4 and 5 hours of IV infusion
Part A: Change in Cardiac Output (CO) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours	Change in CO measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 hours during the 6-hour IV infusion was reported in this outcome measure.	Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion
Part A: Change in Pulmonary Capillary Wedge Pressure (PCWP), Right Atrial Pressure (RAP), Systolic Pulmonary Arterial Pressure/Diastolic Pulmonary Arterial Pressure (PAS/PAD) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours	PCWP estimated the left atrial pressure and was the pressure measured by wedging a pulmonary artery catheter with an inflated balloon into a small pulmonary arterial branch. PCWP was assessed by 2 successive measurements at least 10 minutes apart. RAP is the blood pressure in the right atrium of the heart. Change in PCWP, RAP, PAS/PAD at 0.5, 1, 2, 3, 4, 5 and 6 hours during the 6-hour IV infusion was reported in this outcome measure. All the parameters were measured by RHC.	Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion
Part A: Change in Pulmonary Artery Pulsatility Index (PAPi) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours	PAPi is a hemodynamic parameter that is derived from right atrial and pulmonary artery pulse pressures. PAPi = (PAS - PAD)/right atrial pressure. Change in PAPi measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 hours during the 6-hour IV infusion was reported in this outcome measure.	Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion
Part A: Change in Systemic Vascular Resistance Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours	Systemic vascular resistance (SVR) is the amount of force exerted on circulating blood by the vasculature of the body. SVR was calculated as 80*(mean arterial pressure - mean venous pressure) divided by cardiac output. Change in SVR measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 hours during the 6-hour IV infusion was reported in this outcome measure.	Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion
Part A: Change in Systemic Vascular Resistance Index (SVRI) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours	SVRI was calculated by dividing the difference between mean arterial pressure and central venous pressure by cardiac index and multiplying by 80. Change in SVRI measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 hours during the 6 hour IV infusion was reported in this outcome measure.	Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion
Part A: Change in Pulmonary Vascular Resistance (PVR) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours	PVR is the resistance against blood flow from the pulmonary artery to the left atrium. Change in PVR measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 hours during the 6 hour IV infusion was reported in this outcome measure.	Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion
Part A: Change in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Pressure (MAP) at 0.5, 1, 2, 3, 4, 5 and 6 Hours	SBP, DBP and MAP were measured in a supine or seated position after participant had at least 5 minutes of rest. MAP is the average pressure of the blood circulating through a participant's arteries during the cardiac cycle. MAP was derived by using the following formula: DBP + 1/3(SBP-DBP).	Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion
Part A: Change in Heart Rate at 0.5, 1, 2, 3, 4, 5 and 6 Hours	Heart rate was measured in a supine or seated position after participant had at least 5 minutes of rest.	Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion
Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	An AE was any untoward medical occurrence that did not necessarily have a causal relationship with study treatment. TEAEs were defined as those AEs with onset after start date/timepoint of study drug administration.	From start of study treatment on Day 1 up to Day 9
Part A: Area Under the Plasma Concentration Time Curve From Time Zero to 6 Hours (AUC[0-6]) of APD418	AUC [0-6] was reported in this outcome measure.	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6 hours post infusion start
Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Last Quantifiable Plasma Concentration (AUCLast) of APD418	AUClast was reported in this outcome measure.	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
Part A: Area Under the Plasma Concentration Time Curve From Time Zero up to Infinity (AUC[0-Infinity]) of APD418	AUC [0-infinity] was reported in this outcome measure.	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
Part A: Maximum Observed Plasma Concentration (Cmax) of APD418	Cmax of APD418 was reported in this outcome measure.	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
Part A: Terminal Elimination Half-Life (t1/2) for APD418	Terminal t1/2 of APD418 was reported in this outcome measure.	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
Part A: Distributional Half-Life (t1/2a) for APD418	Distributional t1/2 of APD418 was reported in this outcome measure.	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
Part A: Time to Maximum Observed Plasma Concentration (Tmax) for APD418	Tmax of APD418 was reported in this outcome measure.	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
Part A: Total Clearance (CL) for APD418	IV CL of APD418 was reported in this outcome measure.	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
Part A: Total Volume of Distribution Based on the Terminal Phase (Vdz) for APD418	Vdz of APD418 was reported in this outcome measure.	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
Part A: Volume of Distribution at Steady State (Vdss) for APD418	Vdss of APD418 was reported in this outcome measure.	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
Part A: Mean Residence Time From Time Zero to Time of Last Quantifiable Plasma Concentration (MRTlast) for APD418	MRTlast of APD418 was reported in this outcome measure.	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
Part A: Average Plasma Concentration During Dosing Interval (Cave) for ADP418	Average plasma concentration calculated over the 6-hour infusion time was reported in this outcome measure.	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6 hours post infusion start
Part A: Renal Clearance (CLr) for ADP418	CLr for APD418 was reported in this outcome measure.	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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Anytime between 0 to 6 hours, 6 to 10 hours and 10 to 24 hours post infusion start
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.	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
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.	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

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Arena is a wholly owned subsidiary of Pfizer
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): December 28, 2021
• Primary Completion (Actual): September 19, 2022
• Study Completion (Actual): September 19, 2022

Study Registration Dates

• First Submitted: November 18, 2021
• First Submitted That Met QC Criteria: November 18, 2021
• First Posted (Actual): December 1, 2021

Study Record Updates

• Last Update Posted (Estimated): November 9, 2023
• Last Update Submitted That Met QC Criteria: November 6, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Heart failure with reduced ejection fraction; HFrEF; APD418; Acute Heart Failure (AHF)
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: APD418-201; C5061001 (Other Identifier: Alias Study Number); 2020-006131-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No