Clinical trial NCT05139615: A Study to Assess the Hemodynamic Effects, Safety, Tolerability, and Pharmacokinetics of Intravenous APD418 in Adult Participants With Heart Failure With Reduced Ejection Fraction
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Acute Heart Failure With Reduced Ejection Fraction
Keywords: Heart failure with reduced ejection fraction
HFrEF
APD418
Acute Heart Failure (AHF)
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
Collaborators: name: Arena is a wholly owned subsidiary of Pfizer
First posted: 2021-12-01
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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).

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Part A: Change in Cardiac Index (CI) Measured by Right Heart Catheterization (RHC) From Baseline to End of Intravenous (IV) Infusion at 6 Hours
timeFrame: Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
Secondary outcomes:
measure: 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
timeFrame: Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
measure: Part A: Change in Stroke Volume Index (SVI) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours
timeFrame: Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
measure: Part A: Change in Left Ventricular Ejection Fraction (LVEF) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours
timeFrame: Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
measure: Part A: Change in Fractional Shortening (FS) Measured by ECHO From Baseline to End of IV Infusion at 6 Hours
timeFrame: Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
measure: 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
timeFrame: Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
measure: 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
timeFrame: Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
measure: Part A: Change in CI Measured by RHC at 0.5, 1, 2, 3, 4 and 5 Hours During 6 Hour IV Infusion
timeFrame: Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4 and 5 hours of IV infusion
measure: Part A: Change in Cardiac Output (CO) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours
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
measure: 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
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
measure: Part A: Change in Pulmonary Artery Pulsatility Index (PAPi) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours
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
measure: Part A: Change in Systemic Vascular Resistance Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours
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
measure: Part A: Change in Systemic Vascular Resistance Index (SVRI) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours
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
measure: Part A: Change in Pulmonary Vascular Resistance (PVR) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours
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
measure: 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
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
measure: Part A: Change in Heart Rate at 0.5, 1, 2, 3, 4, 5 and 6 Hours
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
measure: Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: From start of study treatment on Day 1 up to Day 9
measure: Part A: Area Under the Plasma Concentration Time Curve From Time Zero to 6 Hours (AUC[0-6]) of APD418
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6 hours post infusion start
measure: Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Last Quantifiable Plasma Concentration (AUCLast) of APD418
timeFrame: 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
measure: Part A: Area Under the Plasma Concentration Time Curve From Time Zero up to Infinity (AUC[0-Infinity]) of APD418
timeFrame: 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
measure: Part A: Maximum Observed Plasma Concentration (Cmax) of APD418
timeFrame: 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
measure: Part A: Terminal Elimination Half-Life (t1/2) for APD418
timeFrame: 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
measure: Part A: Distributional Half-Life (t1/2a) for APD418
timeFrame: 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
measure: Part A: Time to Maximum Observed Plasma Concentration (Tmax) for APD418
timeFrame: 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
measure: Part A: Total Clearance (CL) for APD418
timeFrame: 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
measure: Part A: Total Volume of Distribution Based on the Terminal Phase (Vdz) for APD418
timeFrame: 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
measure: Part A: Volume of Distribution at Steady State (Vdss) for APD418
timeFrame: 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
measure: Part A: Mean Residence Time From Time Zero to Time of Last Quantifiable Plasma Concentration (MRTlast) for APD418
timeFrame: 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
measure: Part A: Average Plasma Concentration During Dosing Interval (Cave) for ADP418
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6 hours post infusion start
measure: Part A: Renal Clearance (CLr) for ADP418
timeFrame: 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:
measure: Part A: Amount of Unchanged Drug Excreted in Urine During Each Collection Interval From t1 to t2 (Aet1-t2)
timeFrame: Anytime between 0 to 6 hours, 6 to 10 hours and 10 to 24 hours post infusion start
measure: Part A: Total Amount of Unchanged Drug Excreted in Urine Over the Collection Period (Amount Excreted [Ae])
timeFrame: 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
measure: Part A: Fraction of Drug Excreted Unchanged (Fe) in Urine
timeFrame: 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
Locations:
city: Tampa
country: United States
facility: James A. Haley Veterans' Hospital
state: Florida
city: Peoria
country: United States
facility: UnityPoint Health - Methodist Hospital
state: Illinois
city: Houston
country: United States
facility: UTHealth
state: Texas
city: Salt Lake City
country: United States
facility: Health Science Center Utah
state: Utah
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Bernau bei Berlin
country: Germany
facility: Immanuel Hospital Bernau Brandenburg Heart Center
state: Brandenburg
city: Bad Nauheim
country: Germany
facility: Kerckhoff-Klinik Forschungsgesellschaft GmbH
city: Greifswald
country: Germany
facility: Universitatsmedizin Greifwald
city: Nea Ionia
country: Greece
facility: Konstantinopouleio General Hospital of Nea Ionia - Patision ''Agia Olga''
state: Athens
city: Pylaia
country: Greece
facility: Interbalkan European Medical Center
state: Thessaloniki
city: Larissa
country: Greece
facility: General University Hospital of Larissa
city: Gniezno
country: Poland
facility: American Heart of Poland S.A.
city: Krakow
country: Poland
facility: Krakowski Szpital Specjalistyczny im. Jana Pawla II
city: Wroclaw
country: Poland
facility: Uniwersytecki Szpital Kliniczny im Jana Mikulicza-Radeckiego
city: Belgrade
country: Serbia
facility: Clinical Hospital Centre Zemun
city: Belgrade
country: Serbia
facility: University Clinical Centre of Serbia
city: Belgrade
country: Serbia
facility: Institute for Cardiovascular Diseases Dedinje
city: Belgrade
country: Serbia
facility: Clinical Hospital Center Bezanijska Kosa
city: Kragujevac
country: Serbia
facility: Clinical Center of Kragujevac
city: Sremska Kamenica
country: Serbia
facility: Institute for Cardiovascular Diseases of Vojvodina
city: Užice
country: Serbia
facility: Healthcare Center Uzice
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: