A Study to Assess the Hemodynamic Effects, Safety, Tolerability, and Pharmacokinetics of Intravenous APD418 in Adult Participants With Heart Failure With Reduced Ejection Fraction
Study Details
Study Description
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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 Design
Arms and Interventions
| 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.
|
| Experimental: APD418 (Part B: Dose Group 1 and 2)
|
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.
|
Outcome Measures
Primary Outcome Measures
- Change From Baseline in Cardiac Index Measured by Right Heart Catheterization (RHC) [Baseline to end of intravenous (IV) infusion at 6 hours]
Secondary Outcome Measures
- Change From Baseline in Cardiac Output Measured by RHC [Baseline to end of IV infusion at 6 hours]
- Change From Baseline in Pulmonary Capillary Wedge Pressure Measured by RHC [Baseline to end of IV infusion at 6 hours]
- Change From Baseline in Right Atrial Pressure Measured by RHC [Baseline to end of IV infusion at 6 hours]
- Change From Baseline in Systolic and Diastolic Pulmonary Arterial Pressure Measured by RHC [Baseline to end of IV infusion at 6 hours]
- Change From Baseline in Pulmonary Artery Pulsatility Index Measured by RHC [Baseline to end of IV infusion at 6 hours]
- Change From Baseline in Systemic Vascular Resistance and Systemic Vascular Resistance Index Measured by RHC [Baseline to end of IV infusion at 6 hours]
- Change From Baseline in Pulmonary Vascular Resistance Measured by RHC [Baseline to end of IV infusion at 6 hours]
- Change From Baseline in Systolic Blood Pressure [Baseline to end of IV infusion at 6 hours]
- Change From Baseline in Diastolic Blood Pressure [Baseline to end of IV infusion at 6 hours]
- Change From Baseline in Mean Arterial Pressure [Baseline to end of IV infusion at 6 hours]
- Change From Baseline in Heart Rate [Baseline to end of IV infusion at 6 hours]
- Change From Baseline in Stroke Volume Measured by Echocardiogram (ECHO) [Baseline to end of IV infusion at 6 hours]
- Change From Baseline in Stroke Volume Index Measured by ECHO [Baseline to end of IV infusion at 6 hours]
- Change From Baseline in Left Ventricular Ejection Fraction Measured by ECHO [Baseline to end of IV infusion at 6 hours]
- Change From Baseline in Fractional Shortening Measured by ECHO [Baseline to end of IV infusion at 6 hours]
- Change From Baseline in Left Ventricular End-Systolic and Left Ventricular End-Diastolic Volume Measured by ECHO [Baseline to end of IV infusion at 6 hours]
- Change From Baseline in Left Ventricular End-Systolic and Left Ventricular End-Diastolic Diameter Measured by ECHO [Baseline to end of IV infusion at 6 hours]
- Change From Baseline in Left Ventricular Global Longitudinal Strain Measured by ECHO [Baseline to end of IV infusion at 6 hours]
- Change From Baseline in Left Ventricular Global Circumferential Strain Measured by ECHO [Baseline to end of IV infusion at 6 hours]
- Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of APD418 [Intermediate timepoints during 6-hour infusion]
- Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Plasma Concentration (AUClast) of APD418 [Intermediate timepoints during 6-hour infusion]
- Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-∞) of APD418 [Intermediate timepoints during 6-hour infusion]
- Maximum Observed Plasma Concentration (Cmax) of APD418 [Intermediate timepoints during 6-hour infusion]
- Terminal Elimination Half-life (t1/2) of APD418 [Intermediate timepoints during 6-hour infusion]
- Distribution Half-life (t1/2α) of APD418 [Intermediate timepoints during 6-hour infusion]
- Time to Maximum Observed Plasma Concentration (tmax) of APD418 [Intermediate timepoints during 6-hour infusion]
- Total Clearance (CL) of APD418 [Intermediate timepoints during 6-hour infusion]
- Volume of Distribution Based on the Terminal Phase (Vdz) of APD418 [Intermediate timepoints during 6-hour infusion]
- Volume of Distribution at Steady State (Vdss) of APD418 [Intermediate timepoints during 6-hour infusion]
- Mean Residence Time From Time 0 to Time of Last Quantifiable Plasma Concentration (MRTlast) of APD418 [Intermediate timepoints during 6-hour infusion]
- Average Plasma Concentration During the Dosing Interval (Cave) of APD418 [Intermediate timepoints during 6-hour infusion]
- Amount of Unchanged Drug Excreted in Urine During Each Collection Interval From t1 to t2 (Aet1-t2) [Intermediate timepoints during 6-hour infusion]
- Total Amount of Unchanged Drug Excreted in Urine Over the Collection Period (Amount Excreted [Ae]) [Intermediate timepoints during 6-hour infusion]
- Renal Clearance (CLr) of APD418 [Intermediate timepoints during 6-hour infusion]
- Fraction of Drug Excreted Unchanged in Urine, Expressed as a Percentage of Total Dose (Fraction Excreted [Fe]) [Intermediate timepoints during 6-hour infusion]
- Number and Severity of Adverse Events [Up to Study Day 9]
Safety will be assessed by monitoring adverse events and clinically relevant changes in vital signs and clinical laboratory results.
Eligibility Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | James A. Haley Veterans' Hospital | Tampa | Florida | United States | 33612 |
| 2 | UnityPoint Health - Methodist Hospital | Peoria | Illinois | United States | 61606 |
| 3 | UTHealth | Houston | Texas | United States | 77030 |
| 4 | Health Science Center Utah | Salt Lake City | Utah | United States | 84132 |
| 5 | University of Wisconsin | Madison | Wisconsin | United States | 53792 |
| 6 | Immanuel Hospital Bernau Brandenburg Heart Center | Bernau bei Berlin | Brandenburg | Germany | 16321 |
| 7 | Kerckhoff-Klinik Forschungsgesellschaft GmbH | Bad Nauheim | Germany | 61231 | |
| 8 | Universitatsmedizin Greifwald | Greifswald | Germany | 17475 | |
| 9 | Konstantinopouleio General Hospital of Nea Ionia - Patision ''Agia Olga'' | Nea Ionia | Athens | Greece | 14233 |
| 10 | Interbalkan European Medical Center | Pylaia | Thessaloniki | Greece | 55535 |
| 11 | General University Hospital of Larissa | Larissa | Greece | 41110 | |
| 12 | American Heart of Poland S.A. | Gniezno | Poland | 62-200 | |
| 13 | Krakowski Szpital Specjalistyczny im. Jana Pawla II | Krakow | Poland | 31-202 | |
| 14 | Uniwersytecki Szpital Kliniczny im Jana Mikulicza-Radeckiego | Wroclaw | Poland | 50-556 | |
| 15 | Clinical Hospital Centre Zemun | Belgrade | Serbia | 11 070 | |
| 16 | University Clinical Centre of Serbia | Belgrade | Serbia | 11000 | |
| 17 | Institute for Cardiovascular Diseases Dedinje | Belgrade | Serbia | 11040 | |
| 18 | Clinical Hospital Center Bezanijska Kosa | Belgrade | Serbia | 11080 | |
| 19 | Clinical Center of Kragujevac | Kragujevac | Serbia | 34000 | |
| 20 | Institute for Cardiovascular Diseases of Vojvodina | Sremska Kamenica | Serbia | 21204 | |
| 21 | Healthcare Center Uzice | Užice | Serbia | 31000 |
Sponsors and Collaborators
- Arena Pharmaceuticals
Investigators
- Study Director: Arena CT.gov Administrator, Arena Pharmaceuticals
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- APD418-201