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
Phase: PHASE2
Conditions: Acute Heart Failure With Reduced Ejection Fraction
Sponsor: Pfizer

CLINICAL STUDY PROTOCOL 
Protocol 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 
Protocol number: 
APD418-201 
Version: 
Amendment 3.0, dated 26 April 2022 
Compound name or 
number: 
APD418 
Study phase: 
2 
EudraCT number: 
2020-006131-10 
Indication: 
Treatment of acute heart failure with reduced ejection fraction (HFrEF) 
Sponsor name: 
Arena Pharmaceuticals, Inc. 
Legal registered 
address: 
6154 Nancy Ridge Drive 
San Diego, California 92121 
USA 
Sponsor’s Responsible 
Medical Officer: 
, MD, MBA 
 
Sponsor’s Authorized 
Signatory 
, MD 
Vice President, Therapeutic Area Head Cardiovascular 
Clinical Lead: 
, PhD 
 
Arena Pharmaceuticals, Inc. 
Tel: 
 
E-mail: 
SAE reporting: 
IQVIA Pharmacovigilance 
Tel: +1-866-599-1341 
Fax: +1-866-599-1342 
E-mail: ArenaSafety@iqvia.com
Sponsor approval: 
This protocol was approved by the Sponsor’s Responsible Medical Officer or 
delegate. The electronic signature manifest is appended. 
Confidentiality Statement 
This document contains confidential information of Arena Pharmaceuticals, Inc. Unauthorized distribution, 
copying, or disclosure is strictly prohibited unless required by applicable law. Persons receiving this 
information must be notified that it is confidential and may not be further distributed, copied, or disclosed. 
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Clinical Study Protocol 
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PROTOCOL HISTORY  
Document 
Amendment Type 
Date 
Amendment 3.0 
Global 
26 April 2022 
Amendment 2.0 
Global 
19 October 2021 
Amendment 1.3 
Country-specific (Greece) 
06 October 2021 
Amendment 1.2 
Country-specific (Serbia) 
23 July 2021 
Amendment 1.1 
Country-specific (Germany) 
14 July 2021 
Amendment 1.0 
Global 
09 March 2021 
Original Protocol 
Not applicable 
16 December 2020 
 

Clinical Study Protocol 
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PROTOCOL SYNOPSIS  
 
Sponsor: Arena Pharmaceuticals, Inc. 
Name of investigational study drug: APD418 
Protocol 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 
Protocol number: APD418-201 
Phase: 2 
Country(ies)/region(s) (planned): United States and Europe 
Objectives:  
Primary Objective 
• 
To assess the effect of intravenous (IV) infusion of APD418 on hemodynamic status based 
on cardiac index (CI) in subjects with heart failure with reduced ejection fraction (HFrEF) 
Secondary Objectives 
• 
To assess the effect of IV infusion of APD418 on additional hemodynamic, vital sign, and 
systolic function parameters in subjects with HFrEF 
• 
To assess the pharmacokinetics (PK) of IV infusion of APD418 in subjects with HFrEF 
• 
To assess the safety and tolerability of IV infusion of APD418 in subjects with HFrEF 
Exploratory Objectives 
• 
To assess select exposure-response (PK/pharmacodynamic [PD]) relationships in subjects 
with HFrEF 
• 
To assess the relationships between select subject/disease characteristics and select PD 
measures in subjects with HFrEF 
• 
To assess the effect of IV infusion of APD418 on markers of renal function in subjects 
with HFrEF 
• 
To assess the effect of IV infusion of APD418 on cardiac biomarkers in subjects with 
HFrEF 
• 
To assess the effect of IV infusion of APD418 on additional systolic and diastolic function 
parameters in subjects with HFrEF 
• 
To assess the effect of IV infusion of APD418 on urine output in subjects with HFrEF 
• 
To assess the effect of IV infusion of APD418 on body weight in subjects with HFrEF 
• 
To assess the OATP genotype 
Study Design: 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, single-dose study 
assessing the hemodynamic effects, safety, tolerability, and PK of APD418 in subjects with HFrEF to 
be conducted in 2 parts. Each part consists of a Screening Period (up to 21 days for Part A and up to 

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14 days for Part B), a single dose of randomized study treatment (APD418 or placebo) as a 6-hour IV 
infusion on Day 1 (Dosing Period) followed by an 18- to 24-hour in-clinic observation period 
(Postdose Period), and a Follow-Up phone call 7 days (± 2 days) after discharge. Subjects participating 
in Part A cannot participate in Part B. 
On Day 1, potential eligible subjects (per initial Screening criteria) will undergo additional eligibility 
assessments during the Predose Period. Hemodynamic eligibility criteria based on right heart 
catheterization (RHC) will be assessed at Baseline for final confirmation of eligibility and 
randomization. Hemodynamic parameters based on RHC will be assessed at the end of Baseline (after 
at least a 2-hour stabilization period), during the Dosing Period throughout the study treatment 
administration (6-hour IV infusion), and for an additional 1 hour after cessation of study treatment 
administration. Subjects will continue to be observed during the Postdose Period for a minimum of 
18 hours after the end of study treatment administration for PD, PK, and safety assessments prior to 
discharge on Day 2. Subjects will be contacted by phone call for follow-up 7 days (± 2 days) after 
discharge. 
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 (SAD) study planned to consist of 5 cohorts. In each cohort, 
subjects will be randomized to APD418:placebo in a 5:2 ratio. Randomization will be stratified by 
Screening LVEF (> 25%, ≤ 25%). Following completion of all planned cohorts in Part A, 2 APD418 
doses studied in Part A will be selected for expansion in Part B. Part B is a parallel-treatment group 
study planned to consist of a placebo group and 2 APD418 treatment groups by randomizing additional 
subjects in 1:1:1 ratio (15 subjects are planned in the placebo group and each APD418 treatment 
group). Randomization will be stratified by Screening LVEF (> 25%, ≤ 25%) and baseline carvedilol 
use (yes, no).  
Each subject will receive a single dose of study treatment as an IV infusion over a duration of 6 hours. 
The initial APD418 dose to be studied in the first cohort of Part A will be 0.17 mg/kg/h (total dose 
1 mg/kg). After 7 subjects have completed treatment in each cohort in Part A, an assessment of the 
safety/tolerability and PK data will be conducted by the dose escalation committee (blinded data 
review by the Sponsor and Investigator representatives) to determine whether dose escalation to the 
next dose level in Part A can occur. Doses for each subsequent cohort in Part A may be adjusted 
depending on the safety, tolerability, and PK results of previous cohort(s). The maximum dose in the 
study will not exceed 2 mg/kg/h (12 mg/kg) without a protocol amendment. At the conclusion of 
Part A, the dose selection committee will perform safety/tolerability and PD data assessment to identify 
2 APD418 doses to be expanded in Part B (unblinded review of Part A data by the Sponsor 
representatives who are not directly involved in study conduct; site staff and sponsor representatives 
involved in study conduct will remain blinded throughout the study). Additional details about the dose 
escalation and the dose selection process are described in Sections 10.6.2 and 11.9. Additional subjects 
and/or cohorts may be enrolled in the study as described in Sections 6.4 and 11.9. The sample size will 
not increase by more than approximately 15% without a protocol amendment. 
Number of subjects (planned): 
Approximately 80 subjects (25 placebo; 55 APD418) are planned to be enrolled in the study. In Part A, 
5 cohorts are planned and 7 subjects are planned to be enrolled in each cohort (5 APD418:2 placebo 
per cohort; total N = 35). In Part B, 2 APD418 doses assessed in Part A will be expanded by enrolling 
45 additional subjects (15 subjects are planned in the placebo group and each APD418 treatment group; 
total N = 45). 
Eligibility criteria: 
Inclusion criteria: 
Subjects must meet all of the following key inclusion criteria to be eligible for enrollment into the 
study: 

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• 
Advanced chronic HFrEF, defined as left ventricular ejection fraction (LVEF) ≤ 35% at 
Screening, including documented history of HFrEF (LVEF ≤ 35%) for at least 4 months prior 
to Screening 
• 
New York Heart Association (NYHA) Class II-IV 
• 
CI ≤ 2.5 L/min/m2 and pulmonary capillary wedge pressure (PCWP) ≥ 15 mm Hg at Day 1 
• 
Males and females 18 to 85 years of age inclusive, at time of informed consent 
• 
Body mass index 18.0 to 37.0 kg/m2, inclusive, and body weight < 150 kg at Screening and 
Day 1 
Additional inclusion criteria are listed in Section 4.1. 
Exclusion criteria: 
Subjects will be excluded from the study if they meet any of the following key 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 inotropes such as dobutamine, dopamine, or milrinone within 72 hours of Day 1 
or with levosimendan within 21 days of Day 1, or expected to require therapy with these drugs 
any time from Day 1 through the end of study conduct 
• 
Treated with IV vasoactive therapy other than inotropic agents listed in Exclusion Criterion 2 
or IV diuretic therapy within 24 hours of Day 1, or expected to require IV therapy any time 
from Day 1 through the end of the in-clinic observation Postdose Period 
• 
Treated with carvedilol at a dose higher than total of 25 mg per day any time within 72 hours 
of Day 1 through the end of the in-clinic observation Postdose Period  
• 
Use of any other therapy directly acting on the beta-3 adrenergic receptor (β3-AdrR; eg, 
mirabegron) any time within 14 days of Day 1 through the end of the in-clinic observation 
Postdose Period 
• 
Use of a phosphodiesterase-5 (PDE5) inhibitor any time within 4 days of Day 1 through the 
end of the in-clinic observation Postdose Period 
• 
Receiving any mechanical (respiratory or circulatory) or renal support therapy at Screening or 
Day 1 
• 
Systolic blood pressure (SBP) ≤ 90 mm Hg or ≥ 160 mm Hg at Screening or Day 1 
• 
Heart rate (HR) < 50 beats per minute (bpm) or > 110 bpm at Screening or Day 1 
• 
Patients suffering from current infection or patients that have recovered from recent 
Coronavirus disease 2019 (COVID-19) infection that in the opinion of the Investigator would 
prevent the individual from participating in the study due to risk to the scientific validity of 
study assessments or to the patient’s personal well-being 
Additional exclusion criteria are listed in Section 4.2. 
Test product, dose, and mode of administration: 
APD418, the investigational medicinal product, is an IV formulation containing active pharmaceutical 
ingredient (APD418) provided as 15 mg/mL (adjusted free-base concentration) strength. Diluted 
APD418 IV solution will be prepared for doses less than 1800 mg. 
Subjects assigned to active treatment will receive a single dose as an IV infusion over a duration of 
6 hours. The initial APD418 dose to be studied in the Cohort 1 of Part A will be 0.17 mg/kg/h 
(1 mg/kg). Planned doses for the remaining 4 cohorts in Part A are 0.50, 1.0, 1.5, and 2.0 mg/kg/h or 
3, 6, 9, and 12 mg/kg, respectively. Doses for each subsequent cohort in Part A may be adjusted 
depending on the safety, tolerability, and PK results of previous cohort(s). The maximum dose in the 

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study will not exceed 2 mg/kg/h (12 mg/kg) without a protocol amendment. At the conclusion of 
Part A, 2 APD418 doses will be selected for expansion in Part B based on safety/tolerability and PD 
data. Additional details about the dose escalation and the dose selection process are described in 
Sections 10.6.2 and 11.9. 
Duration of treatment: 
This is a single-dose study. Study treatment will be administered only on Day 1 of the study. 
Reference therapy, dose, and mode of administration 
Placebo will be packaged to match APD418. Volume and mode of administration of placebo will 
match that of APD418 to maintain the blind. 
Endpoints: 
Primary endpoint: 
Change in CI measured by RHC from Baseline to end of IV infusion at 6 hours 
Secondary endpoints: 
• 
Change in the following hemodynamic parameters measured by RHC from Baseline to end of 
IV infusion at 6 hours: 
− 
Cardiac output (CO) 
− 
Pulmonary capillary wedge pressure (PCWP) 
− 
Right atrial pressure (RAP) 
− 
Systolic/diastolic pulmonary arterial pressure (PAS/PAD) 
− 
Pulmonary artery pulsatility index (PAPi) 
− 
Systemic vascular resistance/systemic vascular resistance index (SVR/SVRI) 
− 
Pulmonary vascular resistance (PVR) 
• 
Change in the following vital sign parameters from Baseline to end of IV infusion at 6 hours: 
− 
Systolic blood pressure (SBP) 
− 
Diastolic blood pressure (DBP) 
− 
Mean arterial pressure (MAP) 
− 
Heart rate (HR) 
• 
Change in the following hemodynamic and systolic function parameters measured by 
echocardiogram (ECHO) from Baseline to end of IV infusion at 6 hours: 
− 
Stroke volume (SV) 
− 
SV index (SVI) 
− 
Left ventricular ejection fraction (LVEF) 
− 
Fractional shortening (FS) 
− 
Left ventricular end systolic/left ventricular end-diastolic volume (LVESV/LVEDV) 
and diameter 
− 
Left ventricular global longitudinal strain (LVGLS) 
− 
Left ventricular circumferential strain (LVGCS) 
• 
Change in hemodynamic (measured by RHC) and vital sign parameters listed above at 
intermediate timepoints during 6-hour IV infusion (during Dosing Period)  
• 
Plasma and urine PK parameters of APD418 

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• 
Safety and tolerability of APD418 by incidence of all treatment-emergent adverse events 
(TEAEs) 
Exploratory endpoints: 
• 
Change in hemodynamic parameters (measured by RHC) listed above at 1 hour after end of 
6-hour IV infusion (during Postdose Period) 
• 
Change in vital sign, hemodynamic (measured by ECHO), and cardiac systolic function 
(measured by ECHO) parameters listed above for 18 hours after end of 6-hour IV infusion 
(during Postdose Period) 
• 
The relationships between select APD418 plasma exposure measures and change in select PD 
parameters 
• 
The relationships between select subject/disease characteristics (eg, Baseline LVEF, Baseline 
CI, Baseline SBP, duration of HFrEF, renal function, concomitant medications) and change in 
select PD parameters 
• 
Change in markers of renal function (estimated glomerular filtration rate [eGFR], blood urea 
nitrogren [BUN], cystatin C, urine protein/creatinine ratio, urinary sodium excretion) 
• 
Change in cardiac biomarkers (N-terminal pro b-type natriuretic peptide [NT-pro-BNP, 
high-sensitivity cardiac troponin T [hs-cTnT]) 
• 
Change in the following additional systolic and diastolic function parameters measured by 
ECHO: E, A, E', S', early/late diastolic velocities [E/A] ratio, early mitral filling velocity/early 
diastolic mitral annular velocity [E/E'] ratio), tricuspid annular plane systolic excursion 
(TAPSE), tricuspid regurgitation (TR) velocity, and left atrial (LA) volume index 
• 
Change in urine output 
• 
Change in body weight 
• 
The genotype of OATP 
Safety Assessments: 
Safety assessments will include adverse events (AEs), vital signs, clinical laboratory findings 
(including hs-cTnT), electrocardiograms (ECGs), physical examinations, and concomitant medications. 
Pharmacodynamic Assessments: 
Assessments of PD will include change in hemodynamic, vital sign, and cardiac function parameters 
obtained from RHC and ECHO, cardiac biomarkers (NT-pro-BNP and hs-cTnT), markers of renal 
function (eGFR, BUN, cystatin C, urine protein/creatinine ratio, and urinary sodium excretion), as well 
as urine output and body weight. Potential relationship between select subject/disease characteristics 
(eg, Baseline LVEF, Baseline CI, Baseline SBP, duration of HFrEF, renal function, concomitant 
medications), and select PD measures (eg, change in CI) may be explored. 
Pharmacokinetic Assessments: 
Blood samples for plasma PK analysis of APD418 will be collected at the following timepoints in 
relation to the start of the IV infusion: Baseline (within 2 hours prior to study treatment 
administration), during the Dosing Period at 0.5, 1, 2, 3, 4, 5, and 6 hours (within 10 minutes before the 
end of the IV infusion), and during the Postdose Period at 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18, and 
24 hours.  
Urine samples will be collected during the following intervals in relation to the start of the IV infusion: 
Baseline (within 2 hours prior to study treatment administration), 0 to 6 hours, 6 to 10 hours, and 
10 to 24 hours.  

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Statistical methods: 
Determination of sample size: 
Approximately 80 subjects are planned to be enrolled in this study (35 in Part A, 45 in Part B). 
It is assumed that baseline CI, as measured with RHC, is normally distributed with a mean of 2.0 and a 
standard deviation (SD) of 0.5. Sixty-five evaluable subjects (20 subjects in each of the 2 APD418 
treatment groups and 25 in placebo) is sufficient to achieve at least 80% power to detect a treatment 
effect of 0.45 in favor of APD418 (a clinically significant improvement of 22.5% from placebo) 
between each of the APD418 treatment groups and placebo by a 2-sample t-test using a 2-sided 
significance level of 0.05. 
The primary analysis will be based on pooled data from subjects in Part A and Part B. There will be 
2 APD418 treatment groups of 20 subjects each (planned to consist of 5 subjects from Part A and 
15 subjects from Part B) and 1 placebo treatment group of 25 subjects (planned to consist of 
10 subjects from Part A and 15 subjects from Part B). 
A blinded review of the data to evaluate the assumption regarding the SD of the change in CI may be 
conducted. The planned sample size will not be reduced as a result of the sample size re-estimation. 
Details will be specified in the Statistical Analysis Plan (SAP). 
Stratification: 
In Part A, randomization will be stratified by Screening LVEF (> 25%, ≤ 25%). In Part B, 
randomization will be stratified by Screening LVEF (> 25%, ≤ 25%) and baseline carvedilol use (yes, 
no). 
Testing strategy: 
No formal testing strategy or adjustments of the Type I error will be employed for secondary or 
exploratory endpoints. Estimates and confidence intervals for treatment groups and from pairwise 
comparisons will be used in an exploratory manner. 
Statistical analyses: 
The primary and secondary endpoints will be analyzed using the Full Analysis Set (FAS) and safety 
endpoints will be performed using the Safety Set. Other important statistical considerations, such as 
handling missing data imputation strategies, will be described in the SAP. 
The primary PD endpoint of the study is the change in CI measured by RHC from Baseline to end IV 
infusion at 6 hours. The primary PD analysis will be analyzed using a mixed effects model with 
repeated measures (MMRM) method. The MMRM model will include treatment group, timepoint, 
interaction of treatment-by-timepoint, and randomization stratification factors as factors, and Baseline 
CI as a covariate. An unstructured covariance matrix will be specified for the MMRM model. LS 
means at visit and LS mean differences between treatment group with p-values and corresponding 95% 
confidence intervals will be reported. 
Continuous variables measured at scheduled timepoints will be analyzed using MMRM method. The 
MMRM model will include treatment group, timepoint, interaction of treatment-by-timepoint, and 
randomization stratification factor as factors, and Baseline measure as a covariate. An unstructured 
covariance matrix will be specified for the MMRM model. LS means at visit and LS mean differences 
between treatment group with p-values and corresponding 95% confidence intervals will be reported. 
Unless otherwise specified, continuous endpoints will be analyzed using analysis of covariance 
(ANCOVA) with a model that includes treatment group and randomization stratification factors as 
factors and Baseline CI value and other Baseline values as covariates. LS means, Ses, and 95% 
confidence intervals for the treatments and their difference will be presented together with their 
p-values. 
Where statistical assumptions (eg, normality, proportional odds) are not met, alternative approaches 
will be evaluated (eg, non-parametric analysis, log transformation). 

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Details regarding the statistical analyses will be provided in the SAP. 
Pharmacokinetic analysis: 
PK parameters will be calculated using noncompartmental modeling. Calculated plasma PK parameters 
will include, but will not necessarily be limited to, area under the plasma concentration-time curve 
from time 0 to 6 hours (AUC0-6), area under the plasma concentration-time curve from time 0 to time of 
last quantifiable plasma concentration (AUClast), area under the plasma concentration-time curve from 
time 0 to infinity (AUC0-∞), maximum observed plasma concentration (Cmax), terminal elimination 
half-life (t1/2), distribution half-life (t1/2α), time to maximum observed plasma concentration (tmax), total 
clearance (CL), volume of distribution based on the terminal phase (Vdz), volume of distribution at 
steady state (VdSS), mean residence time from time 0 to time of last quantifiable plasma concentration 
(MRTlast), average plasma concentration during the dosing interval (Cave). Collected plasma PK 
samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, or to assess other actions of APD418 with plasma constituents. 
Urinary PK parameters will include, but not be limited to, the amount of unchanged drug excreted 
during each collection interval from t1 to t2 (Aet1-t2), total amount of unchanged excreted in urine over 
the collection period (amount excreted [Ae]), renal clearance (CLr) and the fraction of drug excreted 
unchanged in the urine, expressed as a percentage of total dose (fraction excreted [Fe]). 
Details regarding plasma and urine PK analysis will be provided in the SAP. 
PK/PD and subject/disease characteristics/PD analysis: 
Potential relationships may be explored between select plasma exposure measures of APD418 or 
subject/disease characteristics (eg, Baseline LVEF, Baseline CI, Baseline SBP, duration of HFrEF, 
renal function, concomitant medications) and select PD measures (eg, change in CI). 
Safety analyses: 
Aes will be listed and summarized by system organ class and preferred term, as well as according to 
severity and causality/relationship to study treatment. TEAEs will be summarized by cohort and 
treatment group. In addition, TEAEs will be pooled across treatment groups (ie, placebo, APD418). 
Observed values for clinical laboratory tests, vital signs, and safety 12-lead ECGs, will be summarized 
by cohort and treatment group. Individual data listings of clinical laboratory tests results will be 
presented for each subject. Observed values and changes from Baseline will be summarized 
descriptively. Safety 12-lead ECG data (observed values and change from Baseline) will be listed for 
each subject and timepoint. Observed values will be classified for normal, abnormality that is not 
clinically significant, and clinically significant abnormality by cohort, treatment, and timepoint of 
collection. Results of other safety assessments will be listed and summarized as appropriate. 
Interim Analysis: 
No formal interim analysis of efficacy is planned.  
Dose Escalation and Dose Selection: 
After treatment of each cohort in Part A, an assessment of the safety/tolerability and PK data will be 
performed by the dose escalation committee (blinded data review by the Sponsor and Investigator 
representatives) prior to dose escalation to the next dose level in Part A. Doses for each subsequent 
cohort in Part A may be adjusted depending on the safety, tolerability, and PK results of previous 
cohort(s).  
At the conclusion of Part A, the dose selection committee will perform a safety/tolerability and PD data 
assessment to identify 2 doses to be expanded in Part B (unblinded review of Part A data by the 
Sponsor representatives who are not directly involved in study conduct; site staff and sponsor 
representatives involved in study conduct will remain blinded throughout the study).  
Additional details about the dose escalation and the dose selection process are described in 
Sections 10.6.2 and 11.9.  

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Additional subjects and/or dose cohorts may be enrolled in the study as described in Sections 6.4 
and 11.9. 

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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
PROTOCOL HISTORY ..................................................................................................................2 
PROTOCOL SYNOPSIS ................................................................................................................3 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................16 
1. 
INTRODUCTION ......................................................................................................21 
1.1. 
Disease and Unmet Medical Need ..............................................................................21 
1.2. 
Scientific Background ................................................................................................22 
1.3. 
Nonclinical Summary .................................................................................................23 
1.4. 
Clinical Summary .......................................................................................................25 
1.5. 
Benefit-Risk Considerations .......................................................................................27 
2. 
OBJECTIVES .............................................................................................................28 
3. 
STUDY DESIGN .......................................................................................................28 
3.1. 
Overall Design ............................................................................................................28 
3.2. 
Scientific Rationale for Study Design ........................................................................30 
3.3. 
Rationale for Dose Selection ......................................................................................31 
4. 
STUDY POPULATION .............................................................................................32 
4.1. 
Inclusion Criteria ........................................................................................................32 
4.2. 
Exclusion Criteria .......................................................................................................33 
5. 
SUBJECT RESTRICTIONS ......................................................................................35 
5.1. 
Restricted Medications ...............................................................................................35 
5.2. 
Dietary Restrictions ....................................................................................................36 
5.3. 
Other Restrictions .......................................................................................................36 
6. 
STUDY TREATMENT ..............................................................................................37 
6.1. 
Study Treatment(s) Administered ...............................................................................37 
6.2. 
Identity of Study Treatments ......................................................................................37 
6.2.1. 
APD418 ......................................................................................................................37 
6.2.2. 
Placebo ........................................................................................................................38 
6.3. 
Dosage and Administration ........................................................................................38 
6.3.1. 
Dose Interruptions ......................................................................................................38 
6.4. 
Method of Assigning Subjects to Treatment ..............................................................39 

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6.5. 
Selection and Timing of Dose for Each Subject .........................................................39 
6.6. 
Blinding ......................................................................................................................40 
6.6.1. 
Procedures for Breaking the Blind Prior to Study Completion ..................................40 
6.7. 
Treatment Compliance ................................................................................................40 
6.8. 
Concomitant Therapy .................................................................................................42 
6.8.1. 
Allowed Concomitant Therapy ...................................................................................42 
7. 
STUDY TREATMENT MATERIALS MANAGEMENT ........................................42 
7.1. 
Packaging, Labeling, Storage, and Handling ..............................................................42 
7.2. 
Preparation ..................................................................................................................43 
7.3. 
Accountability, Retention, and Disposal ....................................................................43 
8. 
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT .....................44 
8.1. 
Discontinuation of Study Treatment ...........................................................................44 
8.2. 
Discontinuation from the Study ..................................................................................44 
8.3. 
Lost to Follow-Up.......................................................................................................45 
8.4. 
Premature Termination of the Study or a Study Site ..................................................45 
9. 
STUDY PERIODS .....................................................................................................46 
9.1. 
Screening ....................................................................................................................46 
9.2. 
Treatment Period ........................................................................................................46 
9.3. 
Follow-Up/End of Study.............................................................................................46 
9.4. 
Early Termination .......................................................................................................46 
9.4.1. 
Early Termination of Study Treatment .......................................................................46 
9.4.2. 
Early Termination from Study Participation ..............................................................46 
10. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................47 
10.1. 
Subject Informed Consent ..........................................................................................47 
10.2. 
Screening and Eligibility ............................................................................................47 
10.2.1. 
Rescreening .................................................................................................................47 
10.2.2. 
Demography and Other Subject Characteristics .........................................................47 
10.2.3. 
Social History .............................................................................................................47 
10.2.4. 
Prior and Ongoing Therapies ......................................................................................47 
10.2.5. 
Medical History/Cardiovascular History ....................................................................48 
10.2.6. 
Drugs of Abuse ...........................................................................................................48 
10.2.7. 
Pregnancy Testing ......................................................................................................48 
10.2.8. 
Clinical Laboratory Assessments ...............................................................................48 

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10.2.9. 
Urinalysis ....................................................................................................................48 
10.3. 
Pharmacodynamic/Hemodynamic Assessments ........................................................49 
10.3.1. 
Right Heart Catheterization Hemodynamic Assessments ..........................................49 
10.3.2. 
Vital Signs (Blood Pressure and Heart Rate) Assessments ........................................49 
10.3.3. 
Echocardiography Assessments ..................................................................................50 
10.3.4. 
Markers of Renal Function, Urine Output, and Body Weight ....................................50 
10.3.5. 
Cardiac Biomarkers ....................................................................................................50 
10.4. 
Pharmacokinetic Assessments ....................................................................................51 
10.5. 
Safety Assessments .....................................................................................................51 
10.5.1. 
Vital Signs ..................................................................................................................51 
10.5.2. 
Physical Examinations ................................................................................................52 
10.5.3. 
Electrocardiography ....................................................................................................52 
10.5.4. 
Clinical Laboratory Assessments ...............................................................................52 
10.5.4.1. 
Clinical Chemistry, Hematology, and Coagulation ....................................................54 
10.5.4.2. 
Exploratory Inflammatory and Endothelial Biomarkers ............................................54 
10.5.4.3. 
Urinalysis ....................................................................................................................54 
10.5.5. 
Adverse Events ...........................................................................................................54 
10.5.5.1. 
Definitions ..................................................................................................................54 
10.5.5.2. 
Eliciting, Recording, and Reporting Adverse Events .................................................57 
10.5.5.3. 
Reporting Serious Adverse Events .............................................................................58 
10.5.6. 
Pregnancy ...................................................................................................................59 
10.6. 
Safety-Related Stopping Criteria ................................................................................60 
10.6.1. 
Study Treatment Stopping Criteria .............................................................................60 
10.6.2. 
Dose Escalation Stopping Criteria ..............................................................................60 
10.7. 
Maximum Blood Volume ...........................................................................................61 
10.8. 
Procedures for Overdose .............................................................................................61 
10.9. 
Pharmacogenomic and Future Analyses .....................................................................61 
10.9.1. 
Pharmacogenomic Samples ........................................................................................61 
10.9.2. 
Future PK and Biomarker Research ...........................................................................62 
11. 
PLANNED STATISTICAL METHODS ...................................................................62 
11.1. 
General Considerations ...............................................................................................62 
11.2. 
Determination of Sample Size ....................................................................................63 
11.3. 
Stratification ...............................................................................................................63 

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11.4. 
Analysis Sets ...............................................................................................................63 
11.5. 
Missing Data ...............................................................................................................64 
11.6. 
Study Endpoints ..........................................................................................................64 
11.6.1. 
Primary Endpoint ........................................................................................................64 
11.6.2. 
Secondary Endpoints ..................................................................................................64 
11.6.3. 
Pharmacokinetic Endpoints ........................................................................................65 
11.6.4. 
Exploratory Endpoints ................................................................................................66 
11.6.5. 
Safety Endpoints .........................................................................................................66 
11.7. 
Testing Strategy ..........................................................................................................66 
11.8. 
Interim Analysis ..........................................................................................................66 
11.9. 
Dose Escalation and Dose Selection...........................................................................66 
11.10. 
Pharmacodynamic Analysis........................................................................................67 
11.11. 
Pharmacokinetic Analyses ..........................................................................................68 
11.12. 
Safety Analyses ..........................................................................................................68 
11.12.1. 
Adverse Events ...........................................................................................................68 
11.12.2. 
Extent of Exposure .....................................................................................................69 
11.12.3. 
Clinical Laboratory Parameters ..................................................................................69 
11.12.4. 
Electrocardiograms .....................................................................................................69 
11.12.5. 
Vital Signs ..................................................................................................................69 
11.12.6. 
Physical Examination .................................................................................................69 
12. 
ETHICAL CONSIDERATIONS................................................................................69 
12.1. 
Ethical Conduct of the Study ......................................................................................69 
12.2. 
Institutional Review Board or Independent Ethics Committee Approval ..................69 
12.3. 
Informed Consent .......................................................................................................70 
12.4. 
Confidentiality ............................................................................................................70 
12.5. 
Protocol Compliance ..................................................................................................70 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................71 
13.1. 
Training of Study Site Personnel ................................................................................71 
13.2. 
Monitoring ..................................................................................................................71 
13.3. 
Audit ...........................................................................................................................72 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................72 
14.1. 
Data Management .......................................................................................................72 
14.1.1. 
Case Report Forms .....................................................................................................72 

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14.1.2. 
Source Documents ......................................................................................................72 
14.2. 
Study Documentation and Records Retention ............................................................73 
14.3. 
Clinical Study Report .................................................................................................73 
14.4. 
Disclosure of Study Results ........................................................................................73 
15. 
RESPONSIBILITIES .................................................................................................73 
15.1. 
Investigator Responsibilities .......................................................................................73 
15.2. 
Sponsor Responsibilities .............................................................................................74 
16. 
REFERENCES ...........................................................................................................75 
 
LIST OF APPENDICES  
APPENDIX 1: SCHEDULE OF ASSESSMENTS ....................................................................80 
APPENDIX 2: INVESTIGATOR SIGNATURE .......................................................................83 
APPENDIX 3: COUNTRY-SPECIFIC REQUIREMENTS ......................................................84 
 
LIST OF TABLES  
Table 1: 
Proposed Study Treatment(s) .....................................................................................37 
Table 2: 
Clinical Laboratory Tests ...........................................................................................53 
Table 3: 
Analysis Sets ...............................................................................................................64 
Table 4: 
Study APD418-201 Schedule of Assessments: Part A and Part B .............................80 
 
LIST OF FIGURES  
Figure 1: 
Study Design Schematic .............................................................................................30 
 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation 
Explanation 
ACEI 
angiotensin-converting enzyme inhibitor 
ADR 
adverse drug reaction 
Ae 
amount excreted 
AE 
adverse event 
Aet1-t2 
amount of unchanged drug excreted during each collection interval from t1 to t2 
AHF 
acute heart failure 
ALP 
alkaline phosphatase  
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ARB 
angiotensin receptor blocker 
Arena 
Arena Pharmaceuticals, Inc. 
ARNI 
angiotensin receptor neprilysin inhibitor 
AST 
aspartate aminotransferase 
AUC0-∞ 
area under the concentration-time curve from time 0 to infinity 
AUC0-6 
area under the concentration-time curve from time 0 to 6 hours  
AUC0-24 
area under the concentration-time curve from time 0 to 24 hours 
AUClast 
area under the concentration-time curve from time 0 to time of the last 
quantifiable plasma concentration 
β-AdrR 
beta-adrenergic receptor 
β1-AdrR 
beta-1 adrenergic receptor 
β2-AdrR 
beta-2 adrenergic receptor 
β3-AdrR 
beta-3 adrenergic receptor 
β-hCG 
beta-human chorionic gonadotropin 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
cAMP 
cyclic adenosine monophosphate 
Cave 
average plasma concentration during dosing interval 
CFR 
Code of Federal Regulations 
CI 
cardiac index 
CKD-Epi 
Chronic Kidney Disease-Epidemiology Collaboration 

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Abbreviation 
Explanation 
CL 
total clearance 
CLr 
renal clearance 
Cmax 
maximum observed plasma concentration 
CMP 
Clinical Monitoring Plan 
CMR 
cardiac magnetic resonance 
CNS 
central nervous system 
CO 
cardiac output 
COVID-19 
Coronavirus disease 2019 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
cTnI 
cardiac troponin I 
cTnT 
cardiac troponin T 
CVA 
cerebrovascular accident 
CYP 
cytochrome P450 
D5W 
5% dextrose in water 
DBP 
diastolic blood pressure 
DDI 
drug-drug interaction 
DNA 
deoxyribonucleic acid 
E/A 
early/late diastolic velocities 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
eCRF 
electronic case report form 
E/E’ 
early mitral filling velocity/early diastolic mitral annular velocity 
eGFR 
estimated glomerular filtration rate 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
Fe 
fraction excreted 
FS 
fractional shortening 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 

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Abbreviation 
Explanation 
HF 
heart failure 
HFrEF 
heart failure with reduced ejection fraction 
HIV 
human immunodeficiency virus 
HOA 
healthy older adult 
HR 
heart rate 
hs-cTnI 
high-sensitivity cardiac troponin I 
hs-cTnT 
high-sensitivity cardiac troponin T 
HYA 
healthy young adult 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICD 
implantable cardioverter-defibrillator 
ICF 
informed consent form 
ICH 
International Conference for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous 
LA 
left atrial 
LS 
least square 
LVAD 
left ventricular assist device 
LVEDV 
left ventricular end-diastolic volume 
LVEF 
left ventricular ejection fraction 
LVESV 
left ventricular end-systolic volume 
LVGCS 
left ventricular global circumferential strain 
LVGLS 
left ventricular global longitudinal strain 
MAP 
mean arterial pressure 
MATE 
multidrug and toxin extrusion transporter 
MedDRA 
medical dictionary for regulatory activities 
mFAS 
modified Full Analysis Set 

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Abbreviation 
Explanation 
MMRM 
mixed-effects model repeated measures 
MRA 
mineralocorticoid receptor antagonist 
MRT 
mean residence time 
MRTlast 
mean residence time from time 0 to time of last quantifiable plasma concentration 
NOAEL 
no-observed-adverse-effect level 
NSTEMI 
non-ST-segment elevation myocardial infarction 
NT-pro-BNP 
N-terminal pro b-type natriuretic peptide 
NYHA 
New York Heart Association 
OAT3 
organic anion transporter 3 
OATP 
organic-anion-transporting polypeptide 
PAD 
diastolic pulmonary arterial pressure 
PAPi 
pulmonary artery pulsatility index 
PAS 
systolic pulmonary arterial pressure 
PCWP 
pulmonary capillary wedge pressure 
PD 
pharmacodynamic(s) 
PDE5 
phosphodiesterase-5 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PVR 
pulmonary vascular resistance 
QTc 
corrected QT interval 
QTcB 
corrected QT interval using Bazett’s formula 
QTcF 
corrected QT interval using Fridericia’s formula 
RAP 
right atrial pressure 
RHC 
right heart catheterization  
RNA 
ribonucleic acid 
RSI 
Reference Safety Information 
SAD 
single-ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SC 
subcutaneous 
SD 
standard deviation 

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Abbreviation 
Explanation 
SE 
standard error 
SOPs 
standard operating procedures 
STEMI 
ST-segment-elevation myocardial infarction 
SV 
stroke volume 
SVI 
stroke volume index 
SVR 
systemic vascular resistance 
SVRI 
systemic vascular resistance index 
t1/2 
terminal elimination half-life 
t1/2α 
distribution half-life 
TAPSE 
tricuspid annular plane systolic excursion 
TBIL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TIA 
transient ischemic attack 
TK 
toxicokinetic 
tmax 
time to maximum observed plasma concentration 
TMF 
Trial Master File 
TR 
tricuspid regurgitation 
UA 
unstable angina 
ULN 
upper limit of normal 
US 
United States 
UV 
ultraviolet 
Vdss 
volume of distribution at steady state 
Vdz 
volume of distribution based on the terminal phase 
WHF 
worsening of heart failure 
w/v 
weight per volume 
 

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1. 
INTRODUCTION  
1.1. 
Disease and Unmet Medical Need  
Heart failure (HF) is a clinical syndrome characterized by symptoms (eg, breathlessness, ankle 
swelling, and fatigue) that may be accompanied by signs (eg, elevated jugular venous pressure, 
pulmonary crackles, and peripheral edema) caused by structural and/or functional cardiac 
abnormalities (Ponikowski 2016). HF can result from a number of underlying conditions that 
damage, weaken, or stiffen the heart leading to compromised cardiac function, including 
coronary artery disease, myocardial infarction, hypertension, defects in cardiac valves, 
cardiomyopathies, myocarditis, arrhythmias, or other congenital and chronic conditions (Metra 
2017, Ponikowski 2016). Acute heart failure (AHF), a life-threatening clinical condition 
requiring hospitalization (Ponikowski 2016, Teerlink 2015) is of particular concern in HF 
patients. In the United States (US) alone, HF is responsible for approximately one million 
hospitalizations annually and it is the leading cause of hospitalization in the population above the 
age of 65 (Benjamin 2017, Gheorghiade 2013). Decompensation of chronic HF, characterized by 
(rapid or gradual) worsening of HF symptoms and signs, accounts for approximately 80% of HF 
hospitalizations, with a minority of remaining cases presenting as de novo (15%) or end stage 
(5%) HF (Gheorghiade 2013). Hospitalization for AHF can be caused by the onset or worsening 
of pathological cardiovascular processes such as myocardial infarction, abnormal heart rhythm or 
hypertension, or it can be triggered by low treatment adherence or intercurrent illness 
(Ponikowski 2016, Teerlink 2015). Although in-hospital mortality for patients hospitalized for 
AHF has improved, post-discharge risk of death continues to be significantly high; in addition, 
up to 30% of patients are re-hospitalized within 30 days and up to 70% within the first year 
(Abraham 2008, Chioncel 2017, Crespo-Leiro 2016, Dharmarajan 2015, Gheorghiade 2013, 
Levy 2002). With each event of decompensation leading to hospitalization, there is associated 
myocardial and/or renal damage leading to further progression of the disease and resulting in 
substantially increased risk of death (Gheorghiade 2005, Setoguchi 2007, Solomon 2007). Over 
50% of patients hospitalized for AHF have reduced systolic function (ie, heart failure with 
reduced ejection fraction [HFrEF], defined as left ventricular ejection fraction [LVEF] < 40%) 
(Adams 2005, Chioncel 2017, Owan 2006, Packer 2017) and these patients exhibit mortality 
rates of up to 30% in the first year (Choi 2018, Owan 2006). 
Patients hospitalized for AHF differ in clinical presentation, with clinical signs/symptoms of 
congestion (wet or dry) and peripheral hypoperfusion (cold or warm), as well as differences in 
systolic blood pressure (SBP), guiding the therapeutic approach (Ponikowski 2016). Current 
first-line management of patients hospitalized due to AHF is focused on identification and 
treatment of potential co-existing clinical conditions and precipitating factors, immediate 
stabilization, and symptom relief, as progressive cardiac decompensation can lead to respiratory 
and/or kidney failure, cardiogenic shock, or death (Metra 2017, Ponikowski 2016, Teerlink 
2015). Patients hospitalized for AHF resulting from decompensation of HFrEF can present with 
decreased cardiac output (CO), causing hypoperfusion, and/or accumulation of fluids 
(congestion) in the lungs and/or peripheral tissues (Damman 2015, Mebazaa 2015, Ponikowski 
2016, Teerlink 2015). Despite advancements in management of chronic HF, options for 
stabilization of acutely decompensated HFrEF patients are limited. Diuretics are used as first-line 
therapy to treat volume overload including congestion; vasodilators are also used as first-line 
therapy for symptom relief in hypertensive patients as well as in non-hypotensive patients who 

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fail to respond adequately to diuretics (Collins 2015, Mebazaa 2015, Ponikowski 2016). For 
patients presenting as hypotensive, who are at the highest risk of mortality, treatment options are 
particularly limited (Nohria 2003, Ponikowski 2016). Improvement of CO in patients with 
systolic dysfunction presenting with hypotension may require the use of inotropic agents, and 
currently available inotropic agents that alter intracellular calcium are associated with significant 
risk of unwanted hemodynamic effects, arrhythmias, and cardiotoxicity, leading to adverse 
outcomes and increased mortality (Francis 2014, Maack 2019, Mebazaa 2011, Nielsen 2014, 
Teerlink 2009). Despite their limitations, these agents are often the only available option for 
these patients (Metra 2017). Furthermore, a large proportion of hospitalized patients do not 
respond adequately to common therapies such as diuretics (ie, diuretic-resistant) (Felker 2012, 
Jardim 2019, Shah 2017), which may lead to in-hospital worsening of HF (WHF), requiring 
additional therapy to adequately recover from an AHF episode. Events of WHF are associated 
with longer length of hospitalization and significantly greater post-discharge mortality and 
readmission rates (Butler 2015, Cotter 2014, Cotter 2010, Davison 2015, Kelly 2015, Mentz 
2015, Torre-Amione 2009, Weatherley 2009). Given the seriousness of this condition and the 
lack of targeted therapies with an acceptable safety profile that can be used to improve cardiac 
performance and provide hemodynamic stabilization, development of new treatment options is of 
high importance. 
APD418 is a new chemical entity in development by Arena Pharmaceuticals, Inc. (Arena) for the 
treatment of AHF in patients with HFrEF. As a potential first-in-class beta-3 adrenergic receptor 
(β3-AdrR) antagonist and cardiac myotrope, APD418 is designed to prevent β3-AdrR-mediated 
repression of cardiac contractility and increase CO while avoiding known adverse events (AEs) 
associated with currently available inotropes (ie, hemodynamic instability, arrhythmias, and 
cardiotoxicity). Considering its cardioselective and disease specific mechanism of action, based 
on targeting the overexpressed β3-AdrR in the failing heart, APD418 represents a promising 
novel therapeutic approach to improve cardiac performance and provide hemodynamic 
stabilization in patients with AHF. Study APD418-201 is a Phase 2, multicenter, randomized, 
double-blind, placebo-controlled study assessing the hemodynamic effects, safety, tolerability, 
and pharmacokinetics (PK) of APD418 in subjects with HFrEF. The study will be conducted in 
compliance with the International Conference for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines for Good Clinical Practice (GCP) and 
applicable regulatory requirements, the study protocol, and where applicable, sponsor and/or 
contract research organization (CRO) standard operating procedures (SOPs). 
1.2. 
Scientific Background  
Beta-adrenergic receptors (β-AdrRs) play a pivotal role in regulating the function of the 
cardiovascular system, including both the myocardium and the vasculature where they regulate 
cardiac contractility and vascular tone, respectively (Dessy 2004, Emorine 1989, Gauthier 2000, 
Simard 1994). In the setting of HF, increased sympathetic activity and circulating levels of 
catecholamines stimulate beta-1/beta-2 adrenergic receptors (β1/β2-AdrRs) to mediate positive 
inotropic effects and preserve CO; however, long-term overstimulation of this pathway can 
negatively influence cardiac function and promote progression of HF (Anker 1998, Bristow 
1990, Cohn 1984, Engelhardt 1999, Kaye 1995, Thomas 1978, Viquerat 1985). Unlike 
β1/β2-AdrRs, β3-AdrR activation exerts a repressive effect on cardiac contractility (Gauthier 
1996). Furthermore, in contrast to β1/β2-AdrRs, β3-AdrR is expressed at much lower levels in 

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non-failing hearts but becomes upregulated in HF and is more resistant to desensitization 
(Gauthier 1996, Liggett 1993, Moniotte 2001). Owing to its differential expression pattern and 
resistance to desensitization, β3-AdrR potentially plays a crucial role in the regulation of cardiac 
function, especially in the setting of HF. In chronic HF, β3-AdrR upregulation and activation 
serves as a protective mechanism in response to excessive β1/β2-AdrR-mediated positive 
inotropy by acting as a physiological “brake” to compensate for the sustained sympathetic 
overstimulation of the adrenergic system caused by elevated levels of circulating catecholamines. 
However, during events of AHF, the β3-AdrR-mediated negative inotropic effect can be 
considered maladaptive and promotes unwanted contractile repression that impedes 
hemodynamic recovery and exacerbates systolic dysfunction (Balligand 2016, Moniotte 2001, 
Morimoto 2004, Napp 2009, Rozec 2006). In line with this, studies using a selective β3-AdrR 
antagonist, L-748,337, have demonstrated improved cardiac function in a dog model of 
ventricular pacing-induced HF (Masutani 2013, Morimoto 2004). Considering the growing 
evidence supporting the importance of β3-AdrR in modulating cardiac function in patients with 
HF, β3-AdrR antagonism has been proposed as a potential therapeutic approach in HF (Moniotte 
2002). In particular, antagonism of β3-AdrR in the setting of AHF with systolic dysfunction may 
lead to improved contractility and restored CO, without the unwanted hemodynamic effects and 
cardiotoxic/arrhythmic potential of existing inotropic agents. 
APD418 is a potential first-in-class, highly potent, and selective β3-AdrR antagonist and cardiac 
myotrope designed to improve myocardial contractility by regulating the activity of troponin I 
and remediating myofilament calcium sensitivity, without affecting intracellular cyclic adenosine 
monophosphate (cAMP) and calcium levels associated with stimulation of β1/β2-AdrR 
pathways, thereby avoiding unwanted effects on myocardial oxygen consumption, heart rate 
(HR) or blood pressure (Psotka 2019). 
1.3. 
Nonclinical Summary  
APD418 is a novel selective β3-AdrR antagonist with high affinity for the human β3-AdrR (over 
400-fold greater affinity than for β1- and β2-AdrRs). Functional cAMP assays with 
recombinantly expressed dog and rat β3-AdrR have demonstrated similar potency and selectivity 
of APD418 to human β3-AdrR. Primary pharmacology studies indicate that acute intravenous 
(IV) infusion of APD418 improves cardiac contractile function and increases CO in a canine 
model of systolic heart failure (HFrEF) induced by sequential coronary microembolization, 
without any effects on myocardial oxygen consumption, and minimal effect on HR and mean 
aortic pressure (Sabbah 2019a, Sabbah 2019b). Moreover, APD418 showed improvement in 
additional measures of systolic functions, as well as diastolic function in the failing heart, and 
was well tolerated during and after infusion (Sabbah 2019a, Sabbah 2019b). APD418 was also 
tested on electrically paced human cardiac tissue from HF donors and enhanced the contractile 
response to catecholamine stimulation (Nguyen 2020). 
 
 
 
 
 
 
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Definitive Good Laboratory Practice (GLP)-compliant toxicity studies of APD418 administered 
as a 6-hour and 10-day continuous IV infusion were conducted in the Sprague Dawley rat and 
beagle dog to assess acute and delayed toxicity, reversibility, and toxicokinetics (TK) of 
APD418. 
 
  
 
 
 
 
 
 
 
 
 Exposure to APD418 at the no-observed-adverse-effect level (NOAEL; 255 mg/kg) 
corresponded to maximum observed plasma concentration (Cmax) and area under the 
concentration-time curve from time 0 to infinity (AUC0-∞) with respective values approximately 
1.6- and 1.4-fold higher than those estimated at the highest clinical dose (25 mg/kg, 
4.17 mg/kg/h) administered in Study APD418-101. 
 
 
 
 
 
 
 
 Exposure to APD418 at the NOAEL (60 mg/kg) corresponded to Cmax 
and AUC0-∞ with respective values approximately 0.55- and 0.44-fold lower compared to those 
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estimated at the highest clinical dose (25 mg/kg, 4.17 mg/kg/h) administered in 
Study APD418-101. 
 
 
 
 
 
 
 
 
 The 
mean combined sex APD418 Cmax was 13,000 ng/mL and area under the plasma 
concentration-time curve from time 0 to time of last quantifiable plasma concentration (AUClast) 
was 270,000 ng∙h/mL on Day 10 at 750 mg/kg/day, the dose at which was considered 
nonadverse from systemic toxicity findings. 
 
 
 
 
 
 
 
 
 the 
NOAEL was considered to be 30 mg/kg/day (corresponding to mean combined sex APD418 
Cmax of 620 ng/mL and AUClast of 12,500 ng∙h/mL on Day 10). The 60 mg/kg/day dose level, a 
dose level which did not result in adverse systemic toxicity liver or kidney findings, resulted in a 
corresponding mean combined sex APD418 Cmax of 1260 ng/mL and AUClast of 25,700 ng∙h/mL 
on Day 10. 
APD418 and its metabolites were not clastogenic or genotoxic. Local tolerance to APD418 and 
the vehicle was demonstrated after IV and perivenous injections to the rabbit ear. Some minor 
irritation of APD418 was observed after a subcutaneous (SC) injection. There was no erythema 
or edema observed after administration of APD418. Addition of APD418 
(0.0938 to 1.50 mg/mL) to human whole blood had no effect on hemolysis or 
flocculation/turbidity parameters. 
A complete summary of the nonclinical studies that are relevant to the investigational product 
and its study in human subjects is provided in the current edition of the Investigator’s Brochure 
(IB). 
1.4. 
Clinical Summary  
The safety, tolerability, and PK, along with exploratory PD of single-ascending IV doses of 
APD418 have been evaluated in a Phase 1 study (Study APD418-101; Part A) in heathy young 
adults (HYA; age 18 to 40) and healthy older adults (HOA; age 50 to 65). The potential for 
drug-drug interactions (DDIs), based on PK of a single IV dose of APD418 when given with a 
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single oral dose or after multiple oral doses of rifampin, was also evaluated in healthy adult 
subjects (Study APD418-101; Part B). 
In Part A of the Study APD418-101, study treatment was administered as an IV infusion over 
6 hours in 5 cohorts of HYA (0.17, 0.50, 1.67, 2.83, or 4.17 mg/kg/h APD418 or placebo) and 
2 cohorts of HOA (0.50 or 1.67 mg/kg/h APD418 or placebo). A total of 37/39 HYA and 
15/15 HOA subjects completed treatment. Of those, 30 HYA and 11 HOA subjects received 
APD418. Safety data for Part A of Study APD418-101 demonstrated an acceptable safety profile 
for both the HYA and HOA subjects. Of the HYA subjects who received APD418, a total of 
15 subjects (50%) reported at least 1 treatment-emergent adverse event (TEAE); TEAEs were 
reported in 1 (11%) placebo treated HYA subject. The most common TEAEs were related to 
infusion site events, primarily infusion site pain (8 [27%] APD418 subjects; 0% placebo) and 
infusion site erythema (4 [13%] APD418 subjects, 0%; placebo). Other common TEAEs 
included upper respiratory tract infection (2 [7%] APD418 subjects; 1 [11%] placebo), infusion 
site swelling, infusion site warmth, arthralgia, and dizziness (each event 2 [7%] APD418 
subjects; 0% placebo). In general, infusion site TEAEs were more common at higher APD418 
doses (46% of subjects across 2.83 and 4.17 mg/kg/h doses), while only 12% of subjects across 
the range of doses (ie, 0.17, 0.50, and 1.67 mg/kg/h) planned to be studied in Study APD418-201 
experienced these events (planned doses for Study APD418-201 range from 
0.17 to 2.0 mg/kg/h). Two HOA subjects, 1 subject in each HOA APD418 treatment group, 
experienced at least 1 TEAE (≤ 20%); no TEAEs were reported in HOA placebo subjects. 
Treatment was discontinued for 2 HYA subjects (1 subject each in 0.50 and 4.17 mg/kg/h 
cohorts), who experienced Grade 2 TEAEs at the infusion site, which were considered not 
related to study drug by the Investigator. No serious adverse events (SAEs) or deaths were 
reported. There were no clinically significant or concerning findings in vital signs, 
electrocardiogram (ECG), clinical laboratory (including high-sensitivity cardiac troponin T 
[hs-cTnT]), and echocardiogram (ECHO) data sets, and overall no clinically identified risks for 
APD418 in this study. 
PK data from Study APD418-101 in healthy human volunteers showed that APD418 plasma 
concentrations generally increased rapidly during the IV infusion. Visual assessment of plasma 
concentrations suggested that plasma concentrations close to steady state occurred prior to end of 
infusion, at which point APD418 demonstrated a rapid decrease in plasma concentrations. Mean 
residence time (MRT) was ≤ 4 hours and reflects a relatively short residence time of APD418 in 
the body. Consistent with the short MRT, the area under the concentration-time curve from time 
0 to 24 hours (AUC0-24) comprised > 95% of the AUC0-∞ and suggests clearance of most drug 
from the body by 24 hours postdose. Mean exposure to APD418 increased proportionately with 
dose. APD418 PK in HOA subjects was similar to HYA subjects at the 3 mg/kg dose level. The 
10 mg/kg dose administered to HOA subjects resulted in a small increase (approximately 
1.2-fold) in exposure to APD418 in HOA compared to the HYA subjects. APD418 exposures 
achieved in healthy human volunteers spanned and exceeded the range of pharmacologically 
active concentrations in the dog model of HF; no clinically identified risks were observed across 
this exposure range. Renal clearance comprised approximately 15% of total clearance in both 
HYA subjects and HOA subjects. 

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1.5. 
Benefit-Risk Considerations  
Nonclinical findings suggest that in the setting of HFrEF, APD418 improves cardiac 
performance, which in the target population of patients with decompensated HFrEF may lead to 
faster hemodynamic stabilization. An improved clinical course of recovery is expected to be 
associated with reduced in-hospital WHF events, including in-hospital death and length of 
hospitalization, and potentially improvement in clinical outcomes. 
In this Phase 2, proof-of-mechanism study, hemodynamic effects will be investigated in stable 
advanced chronic HFrEF patients (LVEF ≤ 35% for at least 4 months, New York Heart 
Association [NYHA] Class II-IV). It is anticipated that the population chosen for this study will 
exhibit elevated expression of β3-AdrR owing to their disease status and medical history 
(documented history of HFrEF; ie, LVEF ≤ 35% for at least 4 months) and as such could benefit 
from APD418-mediated improvement in CO. Thus, this population presents a suitable setting for 
the first-in-patient assessment of the safety, tolerability, and hemodynamic effects of APD418. 
As of the date of this protocol, there are no clinically identified risks for APD418. Safety data for 
Part A of Study APD418-101, in which APD418 was administered as an IV infusion over 
6 hours, demonstrated an acceptable safety profile for both the HYA and HOA subjects. 
Extended single-dose, GLP-compliant, toxicity studies of APD418 administered as a 6-hour IV 
infusion were conducted in rats and dogs to assess acute and delayed toxicity, reversibility, and 
TK. These studies identified the following potential targets of APD418 toxicity: CNS, kidney, 
liver, and infusion site that demonstrated reversibility and are monitorable in the planned clinical 
study. Human safety data collected to date in Study APD418-101 have not identified any safety 
risks (including those observed in nonclinical studies) up to the highest dose administered. 
Corresponding exposures were approximately 1.8- (Cmax) to 2.3-fold (AUC0-∞) higher than 
observed in the dog at the NOAEL. 
The safety monitoring practices employed by this protocol (ie, physical examination, vital signs, 
safety 12-lead ECG, clinical laboratory tests including hs-cTnT, concomitant medications, and 
AE monitoring) are adequate to monitor and assess subject safety. 
The risks of participation are primarily those associated with adverse reactions to the study 
treatment, although there may also be some discomfort from collection of blood samples and 
other study procedures.  
Further description of identified risks, any potential risks, and the reference safety information 
for APD418 are provided in the current edition of the IB. 

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2. 
OBJECTIVES  
Primary Objective 
• To assess the effect of IV infusion of APD418 on hemodynamic status based on 
cardiac index (CI) in subjects with HrEF 
Secondary Objectives 
• To assess the effect of IV infusion of APD418 on additional hemodynamic, vital sign, 
and systolic function parameters in subjects with HFrEF 
• To assess the PK of IV infusion of APD418 in subjects with HFrEF 
• To assess the safety and tolerability of IV infusion of APD418 in subjects with 
HFrEF 
Exploratory Objectives 
• To assess select exposure-response (PK/pharmacodynamic [PD]) relationships in 
subjects with HFrEF 
• To assess the relationships between select subject/disease characteristics and select 
PD measures in subjects with HFrEF 
• To assess the effect of IV infusion of APD418 on markers of renal function in 
subjects with HFrEF 
• To assess the effect of IV infusion of APD418 on cardiac biomarkers in subjects with 
HFrEF 
• To assess the effect of IV infusion of APD418 on additional systolic and diastolic 
function parameters in subjects with HFrEF 
• To assess the effect of IV infusion of APD418 on urine output in subjects with HFrEF 
• To assess the effect of IV infusion of APD418 on body weight in subjects with 
HFrEF 
• To assess the OATP genotype  
3. 
STUDY DESIGN  
3.1. 
Overall Design  
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, single-dose study 
assessing the hemodynamic effects, safety, tolerability, and PK of APD418 in subjects with 
HFrEF to be conducted in 2 parts (Part A and Part B). Each part consists of a Screening Period 
(up to 21 days in Part A and up to 14 days in Part B), a single dose of randomized study 
treatment (APD418 or placebo) as a 6-hour IV infusion on Day 1 (Dosing Period) followed by an 
18- to 24-hour in-clinic observation period (Postdose Period), and a Follow-Up phone call 7 days 
(± 2 days) after discharge (Figure 1). Subjects participating in Part A cannot participate in Part B. 
 

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On Day 1, potential eligible subjects (per initial Screening criteria) will undergo additional 
eligibility assessments during the Predose Period on Day 1. Hemodynamic eligibility criteria 
based on right heart catheterization (RHC) will be assessed at Baseline for final confirmation of 
eligibility and randomization. Hemodynamic parameters based on RHC will be assessed at the 
end of Baseline (after at least 2-hour stabilization period), during the Dosing Period throughout 
the study treatment administration (6-hour IV infusion), and for an additional 1 hour after 
cessation of study treatment administration. Subjects will continue to be observed during the 
Postdose Period for a minimum of 18 hours after the end of study treatment administration for 
PD, PK, and safety assessments prior to discharge on Day 2. Subjects will be contacted by phone 
call for follow-up 7 days (± 2 days) after discharge.  
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 (SAD) study planned to consist of 5 cohorts. In each 
cohort, subjects will be randomized to APD418:placebo in a 5:2 ratio. Randomization will be 
stratified by Screening LVEF (> 25%, ≤ 25%). Following completion of all planned cohorts in 
Part A, 2 APD418 doses studied in Part A will be selected for expansion in Part B. Part B is a 
parallel-treatment group study planned to consist of a placebo group and 2 APD418 treatment 
groups by randomizing additional subjects in 1:1:1 ratio (15 subjects are planned in the placebo 
group and each APD418 treatment group; Figure 1). Randomization will be stratified by 
Screening LVEF (> 25%, ≤ 25%) and baseline carvedilol use (yes, no). 
Each subject will receive a single dose of study treatment as an IV infusion over a duration of 
6 hours. The initial APD418 dose to be studied in the first cohort of Part A will be 0.17 mg/kg/h 
(total dose 1 mg/kg). After 7 subjects have completed treatment in each cohort in Part A, an 
assessment of the safety/tolerability and PK data will be conducted by the dose escalation 
committee (blinded data review by the Sponsor and Investigator representatives) to determine 
whether dose escalation to the next dose level in Part A can occur. Doses for each subsequent 
cohort in Part A may be adjusted depending on the safety, tolerability, and PK results of previous 
cohort(s). The maximum dose in the study will not exceed 2 mg/kg/h (12 mg/kg) without a 
protocol amendment. At the conclusion of Part A, the dose selection committee will perform 
safety/tolerability and PD data assessment to identify 2 APD418 doses to be expanded in Part B 
(unblinded review of Part A data by the Sponsor representatives who are not directly involved in 
study conduct; site staff, and sponsor representatives involved in study conduct will remain 
blinded throughout the study). Additional details about the dose escalation and the dose selection 
process are described in Sections 10.6.2 and 11.9. Additional subjects and/or cohorts may be 
enrolled in the study as described in Sections 6.4 and 11.9. The sample size will not increase by 
more than approximately 15% without a protocol amendment. 

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Figure 1: 
Study Design Schematic  
 
 
Note: After treatment of each cohort in Part A, an assessment of the safety/tolerability and PK data will be conducted by the dose 
escalation committee (blinded data review by the Sponsor and Investigator representatives) to determine whether dose escalation 
to the next dose level in Part A can occur. Doses for subsequent cohorts in Part A may be adjusted depending on the safety, 
tolerability, and PK results of previous cohort(s). At the conclusion of Part A, the dose selection committee will perform 
safety/tolerability and PD data assessment to identify 2 APD418 doses to be expanded in Part B (unblinded review of Part A data 
by the Sponsor representatives who are not directly involved in study conduct; site staff and sponsor representatives involved in 
study conduct will remain blinded throughout the study). Additional subjects and/or cohorts may be enrolled in the study. 
PD, pharmacodynamic; PK, pharmacokinetic 
3.2. 
Scientific Rationale for Study Design  
This is a Phase 2, proof-of-mechanism study assessing the hemodynamic effects, safety, 
tolerability, and PK of APD418 in patients with stable advanced chronic HFrEF (LVEF ≤ 35%, 
NYHA Class II-IV). Study population will include subjects stabilized following recent 
hospitalization due to AHF, as well as subjects undergoing RHC for left ventricular assist device 
(LVAD) or transplant evaluation. These subjects represent the target patient population, with the 
exception that they are not experiencing an acute decompensation event and thus offer a suitable 
setting for the first in-patient assessments of hemodynamic effects and the safety/tolerability of 
APD418. It is anticipated that these subjects will exhibit elevated expression of β3-AdrR owing 
to their disease status and medical history (documented history of HFrEF, ie, LVEF ≤ 35% for at 
least 4 months) and as such could experience APD418-mediated improvement in CO. In support 
of this, APD418 improved cardiac performance in a canine model of pacing-induced heart 
failure, an HF model that has been shown to exhibit increased β3-AdR expression (Cheng 2001), 
while minimal effect of APD418 was observed prior to inducing HF (Cheng 2018). In addition, 
APD418 enhanced contractile response to catecholamine stimulation of human cardiac tissue 
from HF donors, but did not have any effect on cardiac tissue from healthy donors (Nguyen 
2020). APD418 also did not induce any notable effects in non-invasive hemodynamic and ECHO 
assessments in healthy subjects studied in Study APD418-101. Thus, in order to describe the 
pharmacodynamic effects of APD418 in humans, it is necessary to evaluate patients who are 
expected to exhibit increased β3-AdrR expression. 

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This study has an adaptive design, in which dose escalation in Part A will inform dose expansion 
in Part B. This study has been designed as a randomized, double-blind, placebo-controlled study 
to reduce bias and account for placebo effect in the evaluation of hemodynamic effects and the 
safety/tolerability of APD418. The primary efficacy endpoint of the study will be the change in 
CI measured by RHC from Baseline to end of IV infusion at 6 hours. Additional PD assessments 
include: Other hemodynamic and cardiac function parameters assessed with RHC and ECHO, 
vital sign, cardiac biomarkers (eg, N-terminal pro b-type natriuretic peptide [NT-pro-BNP], 
hs-cTnT), markers of renal function (estimated glomerular filtration rate [eGFR], blood urea 
nitrogen [BUN], cystatin C, urine protein/creatinine ratio, and urinary sodium excretion), as well 
as urine output and body weight. The safety monitoring practices employed by this protocol (ie, 
physical examination, vital signs, safety 12-lead ECG, clinical laboratory tests including 
hs-cTnT, concomitant medications and AE monitoring) are adequate to monitor and assess 
subject safety. Based on available PK data, most (> 95%) of the administered study drug is 
expected to be eliminated by 24 hours after dosing and therefore subjects will be discharged the 
next day following all scheduled assessments. 
It is expected that the described study design will provide relevant data on hemodynamic effects, 
safety, tolerability, and PK of APD418, and inform further clinical development of APD418 for 
treatment of AHF in patients with HFrEF, including the design and dose selection for future 
clinical studies with APD418 in the AHF setting. 
3.3. 
Rationale for Dose Selection  
The initial APD418 dose to be administered in Cohort 1 of Part A will be 0.17 mg/kg/h 
administered as an IV infusion over a duration of 6 hours (1 mg/kg). Planned doses for the 
remaining 4 cohorts in Part A are 0.50, 1.0, 1.5, and 2.0 mg/kg/h or 3, 6, 9, and 12 mg/kg, 
respectively. Doses for each subsequent cohort in Part A may be adjusted depending on the 
safety, tolerability, and PK results of previous cohort(s). The maximum dose in the study will not 
exceed 2 mg/kg/h (12 mg/kg) without a protocol amendment. At the conclusion of Part A, 
2 APD418 doses will be selected for expansion in Part B based on safety/tolerability and PD 
data. Additional details about the dose escalation and the dose selection process are described in 
Sections 10.6.2 and 11.9. 
The planned starting dose in this first-in-patient study is 0.17 mg/kg/h administered as an IV 
infusion over duration of 6 hours (total dose 1 mg/kg). This is 25-fold lower than the highest 
tested dose in HYA subjects in Study APD418-101, and 10-fold lower than the highest dose 
tested in HOA subjects. Based on dog pharmacology data, this dose level has potential to 
demonstrate a low but detectable increase in cardiac function, thus potentially providing some 
benefit for these subjects. The Cmax attained with an infusion rate of 0.17 mg/kg/h over 6 hours 
(1 mg/kg) in healthy volunteers (Study APD418-101) was 407 ng/mL and approximated values 
observed during a 6-hour IV infusion in the dog model; notable improvement in CO was 
observed at APD418 at mean Cmax concentration of approximately 717 ng/mL. Considering low 
expression of the β3-AdrR in cardiac tissue in healthy subjects, there were no APD418-related 
effects observed on cardiac function in Study APD418-101. 
Estimated exposure to APD418 at the maximal planned dose of 2.0 mg/kg/h over 6 hours (total 
dose 12 mg/kg) in Study APD418-201 from PK values observed in HOA treated with 
1.7 mg/kg/h in Study APD418-101 predicts a Cmax and AUC0-∞ of approximately 5700 ng/mL 

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and 39,000 ng·h/mL, respectively. As such, subjects will not be exposed to higher APD418 
exposures than previously observed in HYA subjects and only 1.2-fold higher than previously 
observed in HOA subjects in Study APD418-101. This dose level should provide exposure to 
APD418 that is about 8-fold higher than the Cmax (ie, 717 ng/mL) resulting in improvement of 
cardiac function after 6-hour infusion in the dog pharmacology model and could provide a 
maximal therapeutic effect. There were no APD418-related safety concerns at doses up to 
4.17 mg/kg/h over 6 hours (total dose 25 mg/kg) in Study APD418-101 and corresponding to 
APD418 exposure is approximately 1.8-fold higher than that expected at the maximal planned 
dose of 2.0 mg/kg/h (total dose 12 mg/kg) in Study APD418-201. Relative to nonclinical safety 
evaluations, the estimated APD418 plasma concentrations at the highest planned dose are 
0.98-fold to 1.3-fold compared to that observed in the dog (NOAEL) during a 6-hour infusion.  
4. 
STUDY POPULATION  
4.1. 
Inclusion Criteria  
Subjects must meet ALL of the following inclusion criteria to be eligible for enrollment into the 
study: 
1. Advanced chronic HFrEF, defined as: LVEF ≤ 35% at Screening, including 
documented history of HFrEF (LVEF ≤ 35%) for at least 4 months prior to Screening 
2. NYHA Class II-IV 
3. CI ≤ 2.5 L/min/m2 and pulmonary capillary wedge pressure (PCWP) ≥ 15 mm Hg at 
Day 1 
4. Males or females 18 to 85 years of age inclusive, at the time of informed consent 
5. Body mass index 18.0 to 37.0 kg/m2, inclusive, and body weight < 150 kg at Screening 
and Day 1 
6. Females must meet either a or b of the following criteria and males must meet criterion 
c to qualify for the study: 
a. A female who is not of childbearing potential must meet 1 of the following: 
i) Postmenopausal, defined as no menses for 12 months without an alternative 
medical cause 
ii) Permanent sterilization procedure, such as hysterectomy, bilateral salpingectomy, 
bilateral tubal ligation, or bilateral oophorectomy. 
b. A female who is of childbearing potential must agree to using a highly effective 
contraception method per drug/device labels during treatment and for 30 days 
following treatment that can achieve a failure rate of less than 1% per year when used 
consistently and correctly. The following methods are considered highly effective 
birth control methods:  
i) Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation, which may be oral, intravaginal, or 
transdermal. 
ii) Progestogen-only hormonal contraception associated with inhibition of ovulation, 
which may be oral, injected, or implanted. 

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iii) Intrauterine device (IUD) 
iv) Intrauterine hormone-releasing system (IUS) 
v) Vasectomized partner provided that partner is the sole sexual partner of the 
women of childbearing potential study participant and that the vasectomized 
partner has received medical assessment of the surgical success. 
vi) Sexual abstinence defined as refraining from heterosexual intercourse for the 
entire period of risk associated with study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical study 
and the preferred and usual lifestyle of the subject. Periodic abstinence, such as 
calendar, symptothermal, and post-ovulation methods, are not acceptable. 
c. A male must agree to using a condom with spermicide during treatment and for 
90 days following treatment. 
7. Willing to provide written informed consent and participate in the study 
4.2. 
Exclusion Criteria  
Subjects who meet ANY of the following exclusion criteria will not be eligible for enrollment 
into the study: 
1. 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 
2. Treated with inotropes such as dobutamine, dopamine, or milrinone within 72 hours of 
Day 1 or with levosimendan within 21 days of Day 1, or expected to require therapy 
with these drugs any time from Day 1 through the end of study conduct. Refer to 
Prohibited Medications List for details. 
3. Treated with IV vasoactive therapy other than inotropic agents listed in Exclusion 
Criterion 2 or IV diuretic therapy within 24 hours of Day 1, or expected to require IV 
therapy any time from Day 1 through the end of the in-clinic observation Postdose 
Period. Refer to Prohibited Medications List for details. 
4. Treated with carvedilol at a dose higher than total of 25 mg per day any time within 72 
hours of Day 1 through the end of the in-clinic observation Postdose Period  
5. Use of any other therapy directly acting on the β3-AdrR (eg, mirabegron) any time 
within 14 days of Day 1 through the end of the in-clinic observation Postdose Period 
6. Use of a phosphodiesterase-5 (PDE5) inhibitor any time within 4 days of Day 1 
through the end of the in-clinic observation Postdose Period. Refer to Prohibited 
Medications List for details. 
7. Receiving any mechanical (respiratory or circulatory) or renal support therapy at 
Screening or Day 1 

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8. SBP ≤ 90 mm Hg or ≥ 160 mm Hg at Screening or Day 1 
9. HR < 50 beats per minute (bpm) or > 110 bpm at Screening or Day 1 
10. Cardiac troponin (hs-cTnT, high-sensitivity cardiac troponin I [hs-cTnI], cardiac 
troponin T [cTnT], or cardiac troponin I [cTnI]) > 5× upper limit of normal (ULN) at 
Day 1 
11. Use of any medications or herbal products that are reported potent 
(moderate-to-strong) clinically relevant inhibitors of P-gp or OATP1B1/3 within 
30 days or 5 half-lives (whichever is longer) of Day 1 through the end of the in-clinic 
observation Postdose Period. Amiodarone is permitted if administered at doses of 
200 mg/day or less for the preceding 90 days. Refer to Prohibited Medications List for 
more details. 
Note: Topical formulations of the above clinically relevant inhibitors of P-gp or 
OATP1B1/3 are allowed.  
12. The use of MATE1 substrates, with the exception of metformin, within 5 half-lives of 
Day 1 through the end of the in-clinic observation Postdose Period. Refer to Prohibited 
Medications List for details. 
13. Hepatic dysfunction (history of cirrhosis, or abnormal ALT or AST 5-fold greater than 
the ULN) at Screening 
14. Renal insufficiency (eGFR < 25 mL/min/1.73 m2; calculated using the Chronic Kidney 
Disease Epidemiology Collaboration [CKD-Epi] equation) at Screening  
15. Any abnormal clinical laboratory (eg, chemistry, hematology), ECG, or physical 
finding at Screening that in the opinion of the Investigator is deemed clinically 
significant and that would prevent the individual from participating in the study due to 
risk to the scientific validity of study assessments or to the patient’s personal 
well-being 
16. Pacemaker or implantable cardioverter-defibrillator (ICD) implantation within 
4 months of Screening 
17. Hospitalization within 3 months of Screening for ST-segment-elevation myocardial 
infarction (STEMI) or pulmonary embolism, or within 4 weeks of Screening for 
non-ST-segment elevation myocardial infarction/unstable angina (NSTEMI/UA) or 
arrythmia 
18. Cerebrovascular accident (CVA) or transient ischemic attack (TIA) within 3 months of 
Screening 
19. Conditions that are thought in the opinion of the Investigator to:  
a. Increase risk of infusion site reactions; eg, active connective tissue disorder or 
vasculitis, significant lymphedema affecting vascular access site extremity, history of 
hyperhomocysteinemia, nephrotic syndrome, or recent history of major trauma or 
major surgery within 3 months of Screening 

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b. Compromise subject assessment of the infusion site reactions; eg, extensive tattoos or 
areas of psoriasis or eczema that impact the selection of infusion site, severe diabetic 
neuropathy, barriers in communication 
20. Any of the following diseases or conditions: Cardiogenic shock, uncorrected severe 
valvular disease; amyloid cardiomyopathy; hypertrophic obstructive cardiomyopathy; 
myocarditis; restrictive cardiomyopathy; constrictive pericardial disease; 
contraindications to pulmonary artery catheter placement (eg, bleeding diathesis, 
tricuspid or pulmonic valve replacements); endocarditis; intra-cardiac thrombus; or 
untreated severe ventricular arrhythmia  
21. Any history or clinical manifestation of any pulmonary, endocrine, allergic, 
dermatological, hepatic, renal, hematological, gastrointestinal, neurological or 
psychiatric disorder, or malignancy (with the exception of treated basal cell 
carcinomas), as determined by the Investigator, that would prevent the individual from 
participating in the study due to risk to the scientific validity of study assessments or to 
personal well-being 
22. Patients suffering from current infection or patients that have recovered from recent 
COVID-19 infection that in the opinion of the Investigator would prevent the 
individual from participating in the study due to risk to the scientific validity of study 
assessments or to the patient’s personal well-being 
23. Females who are pregnant or lactating 
24. Known human immunodeficiency virus (HIV) or hepatitis infection 
25. Known history of alcohol or substance use disorder within 6 months of Screening 
26. Previous participation in a study with APD418 
27. Subjects who have received any investigational device or investigational drug within 
30 days, or 5 half-lives of the investigational drug (whichever is greater) prior to 
Day 1 
5. 
SUBJECT RESTRICTIONS  
5.1. 
Restricted Medications  
Subjects are to follow the medication restrictions outlined in the Inclusion (Section 4.1) and 
Exclusion (Section 4.2) criteria from the time of consent through the end of study conduct (until 
the Follow-Up phone call), unless otherwise specified. A separate Prohibited Medications List 
with examples of medications that are not allowed in the study will be provided. If such 
medications are required, consider switching to another medication in the class that is not 
restricted. Investigators are also advised to refer to the local prescribing information. In addition 
to local prescribing information, refer to FDA guidance on drug development and drug 
interactions (FDA 2020).  

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5.2. 
Dietary Restrictions  
Subjects should be advised to avoid alcohol and caffeine for 12 hours prior to RHC insertion as 
well as through the completion of the in-clinic observation Postdose Period. 
Subjects will be allowed a light meal 2 hours prior to RHC insertion (at least 4 hours prior to 
Baseline hemodynamic parameters measurements). Another light meal will be provided after the 
2-hour assessments are completed. After the end of the RHC assessments, the meals can be 
provided per the site’s standard of care. Fluids will be restricted to no more than 250 mL every 
2 hours from RHC insertion through the end of the RHC assessments. The type, amount, and 
time of consumption will be documented. 
If deviations occur, the Investigator or designee in consultation with the Sponsor, if needed, will 
decide on a case-by-case basis whether the subject may continue participation in the study. 
5.3. 
Other Restrictions  
During the RHC assessments, subjects will remain supine, if possible, and awake. After the end 
of the RHC assessments and through the completion of the in-clinic observation Postdose Period, 
subjects should remain ambulatory, seated upright, or semi-reclined, except when a supine 
position is dictated by study procedures or during night rest; subjects may be allowed to rise for 
brief periods under supervision (eg, to use the toilet facilities). 

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6. 
STUDY TREATMENT  
6.1. 
Study Treatment(s) Administered  
Study treatments in this study include the pharmaceutical form of the active substance being 
tested (APD418), and the volume-matched placebo being used as a reference (reference therapy). 
Study treatment(s) are listed in Table 1. 
The subject weight recorded during Predose Period on Day 1 will be used to calculate the study 
treatment dose. 
Table 1: 
Proposed Study Treatment(s)  
Study Treatment 
Dose(s)a                      
Mode of 
Administration 
Frequency 
Formulation 
APD418 
(Part A: Cohort 1) 
0.17 mg/kg/h 
(1 mg/kg) 
IV infusion 
Single 6-hour IV 
infusion 
IV formulation 
APD418 
(Part A: Cohort 2) 
0.50 mg/kg/h  
(3 mg/kg) 
IV infusion 
Single 6-hour IV 
infusion 
IV formulation 
APD418 
(Part A: Cohort 3) 
1.0 mg/kg/h 
(6 mg/kg) 
IV infusion 
Single 6-hour IV 
infusion 
IV formulation 
APD418 
(Part A: Cohort 4) 
1.5 mg/kg/h 
(9 mg/kg) 
IV infusion 
Single 6-hour IV 
infusion 
IV formulation 
APD418 
(Part A: Cohort 5) 
2.0 mg/kg/h 
(12 mg/kg) 
IV infusion 
Single 6-hour IV 
infusion 
IV formulation 
APD418 
(Part B: Dose Group 1) 
X mg/kg/h  
IV infusion 
Single 6-hour IV 
infusion 
IV formulation 
APD418 
(Part B: Dose Group 2) 
Y mg/kg/h 
IV infusion 
Single 6-hour IV 
infusion 
IV formulation 
Placebo 
(Part A and Part B)b                  
NA 
IV infusion 
Single 6-hour IV 
infusion 
IV formulation 
a After treatment of each cohort in Part A, a blinded safety/tolerability and PK data assessment will be conducted by the dose 
escalation committee to determine whether dose escalation to the next dose level in Part A can occur. Doses for each 
subsequent cohort in Part A may be adjusted depending on the safety, tolerability, and PK results of previous cohort(s). At the 
conclusion of Part A, the dose selection committee will perform an unblinded safety/tolerability and PD data assessment to 
identify 2 APD418 doses to be expanded in Part B. Additional cohorts (to study intermediate or higher doses) and/or additional 
subjects may be enrolled in the study based upon data reviews from the prior cohorts. 
b Placebo will follow the same dilution instructions to match the volume of APD418 in the same cohort and mode of 
administration will match that of APD418. 
IV, intravenous; NA, not applicable 
6.2. 
Identity of Study Treatments  
6.2.1. 
APD418  
The active study treatment is an IV formulation containing the active pharmaceutical ingredient 
(APD418) provided as 15 mg/mL (adjusted free-base concentration) strength. Dilution with 5% 
dextrose in water (D5W) will be carried out for total doses less than 1800 mg. All subjects 
assigned to active treatment will receive a single 6-hour IV infusion. 

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6.2.2. 
Placebo  
The placebo will be diluted with D5W to match the APD418 volume administered in the same 
cohort and mode of administration will match that of APD418. 
6.3. 
Dosage and Administration  
Each subject will receive a single dose as an IV infusion (APD418 or placebo) over a duration of 
6 hours. The initial APD418 dose to be studied in Cohort 1 of Part A will be 0.17 mg/kg/h 
(1 mg/kg). Planned doses for the remaining 4 cohorts in Part A are 0.50, 1.0, 1.5, and 
2.0 mg/kg/h or 3, 6, 9, and 12 mg/kg, respectively. Doses for each subsequent cohort may be 
adjusted depending on the safety, tolerability, and PK results of previous cohort(s). The 
maximum dose in the study will not exceed 2 mg/kg/h (12 mg/kg) without a protocol 
amendment. At the conclusion of Part A, 2 APD418 doses will be selected for expansion in 
Part B based on unblinded safety/tolerability and PD data. Additional details about the dose 
escalation and the dose selection process are described in Sections 10.6.2 and 11.9. Separate 
cohorts of subjects will be used for each dose level.  
The study treatment will arrive at the site blinded and will be administered in a blinded fashion 
to the subjects. A delegated pharmacist or designee will be responsible for providing APD418 or 
placebo to the delegated qualified study personnel for administration as per the randomization 
scheme. Dilution instructions will be provided in a separate pharmacy manual. Placebo and 
APD418 treatments will be diluted based on the body mass of the subject and the assigned cohort 
dose level. Study treatment will be administered intravenously. Larger peripheral veins (ie, in the 
upper forearm) are advised for IV administration and (see Section 4.2). the infusion site will be 
noted as well as a change in the infusion site, if applicable. Selection of vascular access shall 
include assessment of the patient’s condition of the vasculature at the insertion site and proximal 
to the intended insertion site, including condition of skin at intended insertion site and history of 
previous venipunctures and access devices. Areas of flexion or pain on palpation should be 
avoided as well as veins that are compromised (ie, sclerosed, corded, infiltrated). Additionally, it 
is advised to avoid extremities with impaired circulation, such as that caused by lymphedema. 
Hour 0 will correspond to the start of the IV infusion. The exact clock time of the start and end 
of the IV infusion will be recorded.  
The location of IV infusion will be examined prior to start of infusion as well as anytime when a 
subject reports any relevant signs and symptoms such as swelling, redness, pain, tingling and/or 
burning sensation etc, which should be reported as AEs when appropriate.  
6.3.1. 
Dose Interruptions  
Dose interruptions should be avoided if possible. The IV infusion can be interrupted upon any 
sign of clinical concern or if a subject complains of pain, burning or stinging sensation at or 
around the insertion site or anywhere along the venous pathway. Prompt recognition and timely, 
appropriate action should be instituted to prevent any complication(s) and/or prolonging subject 
discomfort. If a mechanical issue (eg, occlusion or infiltration of IV lines) is identified or if the 
peripheral line is not well tolerated, the IV infusion site may be changed to another infusion site 
or a central line. The IV infusion may be interrupted to address these issues for up to 30 minutes. 
Following the interruption, the IV infusion should be resumed to complete the planned full 

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6 hours. However, in the event of an infusion site related AE, the subject may be discontinued 
from treatment at the discretion of the Investigator, as described in Section 10.6.1. 
Subjects experiencing any type of infusion site AE should be closely observed for at least 
24 hours after dosing or until symptom resolution, and should be clinically handled in 
accordance with the standard medical practice and relevant guidelines. At the conclusion of the 
Postdose in-clinic observation period, subjects who do not achieve complete symptom resolution 
but are improving and are stable for discharge should be instructed to monitor the affected area.  
6.4. 
Method of Assigning Subjects to Treatment  
Each subject will be assigned a unique identification number upon Screening. Eligible subjects 
will be centrally randomized into the study using an interactive response technology (IRT) 
system. In Part A, subjects who complete the study Screening assessments and meet all the 
eligibility criteria will be randomized to study treatment in a 5:2 ratio (APD418:placebo), 
stratified by Screening LVEF (> 25%, ≤ 25%). In Part B, subjects who complete the study 
Screening assessments and meet all the eligibility criteria will be randomized to study treatment 
in a 1:1:1 ratio (2 doses of APD418:placebo), stratified by Screening LVEF (> 25%, ≤ 25%) and 
baseline carvedilol use (yes, no). 
Subject identification numbers will be 12 characters in length, including dashes, 
201-CCSS-XXX. The first 3 digits represent the study number, the 4 digits following the first 
dash represent the combination of country code (CC) and the site number (SS), and the last 
3 digits represent the subject number (XXX). Subject numbers will be assigned strictly 
sequentially at every site as subjects become eligible for enrollment, starting from 001. If a 
subject withdraws their participation in the study, then their unique subject number cannot be 
reused. 
After the initial 7 subjects in each cohort in Part A have been randomized, subsequent subjects 
may be screened and, if possible, will not be randomized until the next dose level has been set; 
however, if it is not possible for the subject to wait for randomization into the subsequent dose 
cohort, the subject may be enrolled in the current dose cohort.   
In Part A, in the event that a subject does not complete at least 4 hours of infusion and scheduled 
RHC assessments in that period, an additional subject may be allocated within the cohort to the 
same treatment as the discontinued subject at the discretion of the Sponsor. Additional subject(s) 
will only be enrolled in cases in which discontinuation was not the result of an AE considered 
probably related or related to study drug in the opinion of the Investigator, including the 
following: 
• Technical issues resulting in incomplete study treatment administration  
• Withdrawal based on subject or Investigator decision (not associated with an AE 
considered probably related or related to study drug in the opinion of the Investigator) 
The sample size will not increase by more than approximately 15% without a protocol 
amendment. 
6.5. 
Selection and Timing of Dose for Each Subject  
This is a single-dose study. Study treatment administration will occur only on Day 1 of the study. 

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6.6. 
Blinding  
The study treatment will arrive at the site blinded and will be administered in a blinded fashion 
to the subjects. The delegated pharmacist or designee will be blinded to active/placebo treatment 
and unblinded to the dose level in Part B of the study. The delegated pharmacist or designee will 
prepare APD418 or placebo and provide the appropriate study treatment to the blinded delegated 
qualified study personnel for administration. The Investigator and other clinical staff will be 
blinded to the treatment and will not be unblinded unless needed for safety reasons. Individuals 
who are part of the Sponsor’s safety team (who are not otherwise involved with study conduct) 
may be unblinded to the treatment (eg, for the purpose of regulatory reporting). Representatives 
from the bioanalytical lab responsible for analyzing PK samples during the study will be 
unblinded to treatment assignments. These individuals will not be involved in the management of 
the study and will not access other subject data. The identity of specific treatments is not to be 
disclosed to subjects or to any other study personnel.  
After treatment of each cohort in Part A, an assessment of the safety/tolerability and PK data will 
be conducted by the dose escalation committee (blinded data review by the Sponsor and 
Investigator representatives) to determine whether dose escalation to the next dose level in 
Part A can occur. Doses for each subsequent cohort in Part A may be adjusted depending on the 
safety, tolerability, and PK results of previous cohort(s). If warranted during blinded safety 
reviews, unblinded data may be reviewed by the dose selection committee, who are not involved 
in study conduct, to determine if dose escalation can continue. At the conclusion of Part A, the 
dose selection committee will perform safety/tolerability and PD data assessment to identify 
2 APD418 doses to be expanded in Part B (unblinded review of Part A data by the Sponsor 
representatives who are not directly involved in study conduct; site staff and sponsor 
representatives involved in study conduct will remain blinded throughout the study). 
6.6.1. 
Procedures for Breaking the Blind Prior to Study Completion  
Breaking of the blind is expressly forbidden except in the event of a medical emergency where 
the identity of the study treatment must be known to properly treat the subject. 
Treatment assignments should remain blinded unless that knowledge is necessary to determine 
subject emergency medical care. In the event of a medical emergency, the Investigator has the 
sole responsibility for determining if unblinding of a subject’s treatment assignment is warranted 
to provide appropriate medical care. Subject safety must always be the first consideration in 
making such a determination. The IRT is programmed with blind-breaking instructions to guide 
the Investigator on how to obtain treatment assignment in the event of an emergency unblinding. 
If a subject’s treatment assignment is unblinded, the Sponsor must be notified within 24 hours 
after breaking the blind. The date and reason the blind was broken must be recorded in the source 
documentation and electronic case report form (eCRF), as applicable. 
6.7. 
Treatment Compliance  
Treatment compliance will be assessed based on the administration of a single IV infusion 
(APD418 or placebo). The IV infusion will be performed by a delegated qualified personnel. 
Prior to and following IV infusion, the qualified designee will visually inspect the infusion site 
and the infusion bag to ensure that the subject has received the entire dose. 

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The date, time, and duration of the IV infusion will be documented. Comments will be recorded 
if there are any deviations from the planned IV infusion procedures. In the case of an incomplete 
dosing (ie, caused by an interruption of IV infusion for longer than 30 minutes) as assessed by 
the dose administration staff, the Investigator, and/or the Sponsor, the subject will be 
discontinued from study treatment (Section 8.1). 

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6.8. 
Concomitant Therapy  
Any medication (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) or vaccine that a subject receives from 30 days prior to Screening through 
Follow-Up phone call must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant 
therapy. 
6.8.1. 
Allowed Concomitant Therapy  
Medications deemed by the Investigator to be appropriate and unlikely to interfere with the 
scientific validity of the study or personal well-being of the subject and which are not prohibited 
as indicated in inclusion and exclusion criteria and/or in Section 5.1 are permitted. Concomitant 
medications, including over-the-counter or prescription therapeutics, natural products, and 
vitamins, should not be changed during Screening or at any time during the duration of the study, 
unless medically necessary; such changes will be captured in the eCRF. 
Subjects should be on guideline-directed medical therapies, unless documented intolerance or 
contradiction. Subjects should be maintained on their stable guideline-directed HF therapy, 
including beta blockers, angiotensin receptor blockers (ARBs), angiotensin-converting enzyme 
inhibitors (ACEI), angiotensin receptor neprilysin inhibitor (ARNI), and/or mineralocorticoid 
receptor antagonists (MRAs), and the type of medications or the dose should not change unless 
medically indicated from the time of consent through the end of study conduct (until the 
Follow-Up phone call). Subjects should have been stabilized on their HF medications for at least 
2 weeks prior to Screening, if possible. On the morning of Day 1, subjects should take their 
morning medications no less than 2 hours prior to RHC insertion, but, if applicable, should 
withhold their morning diuretic dose. 
7. 
STUDY TREATMENT MATERIALS MANAGEMENT  
7.1. 
Packaging, Labeling, Storage, and Handling  
APD418 injectable solution is a terminally sterilized concentrated solution composed of 
15 mg/mL (adjusted free-base concentration) active pharmaceutical ingredient (APD418 
mesylate hemihydrate) in a 10 mM acetate buffered aqueous solution (pH 4.5 ± 0.7) with 
glycerin (2.1% weight per volume [w/v]) as a tonicity adjuster. APD418 injectable solution will 
be provided in clear 20 mL vials with a stopper and flip-off cap seal and packaged in a 
single-vial carton. Each 20 mL vial contains excess volume to allow withdrawal of 20 mL. The 
supplied APD418 injection solution should be stored at room temperature (15 to 30°C) and 
protected from light until use. 
The supplied APD418 injectable solution is to be used as is or appropriately diluted by the 
clinical pharmacy using D5W based on the dosage to be administered. The diluted product is to 

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be stored at room temperature (15 to 30°C), protected from light and used within 12 hours. If 
storage time of the diluted product is > 12 hours, this product should be stored refrigerated 
(2 to 8°C) and used within 24 hours. Hands should be washed with soap and water after handling 
drug product. 
Placebo injection (sterile vehicle, 20 mL fill, 20 mL clear vial) will be supplied in a clear sterile 
vial, packaged in a single-vial carton, to be stored at room temperature (15 to 30°C), protected 
from light until use. The diluted placebo is to be stored at room temperature (15 to 30°C), 
protected from light and used within 12 hours. If storage time of the diluted placebo 
is > 12 hours, this product should be stored refrigerated (2 to 8°C) and used within 24 hours. 
Hands should be washed with soap and water after handling placebo. 
7.2. 
Preparation  
A separate pharmacy manual will detail the study treatment preparation procedures to be 
followed for this study. 
7.3. 
Accountability, Retention, and Disposal  
The lot numbers and expiration dates (where available) of the study treatment materials supplied 
will be recorded in the final Clinical Study Report. 
The Investigator or qualified designee will maintain accurate records of the receipt of all study 
treatment materials. In addition, accurate records will be kept regarding when and how much 
study treatment is dispensed and used by each subject in the study. Reasons for deviation from 
the expected dispensing regimen must also be recorded. Study treatment will be reconciled by 
the Sponsor monitor or contracted designee. The Investigator or qualified designee agrees to 
provide access to study treatment and study treatment records as required for the reconciliation 
process to be completed in a timely fashion. 
At the conclusion of the study, any unused study treatments will be retained by the study site, 
returned to the Sponsor or designee, or destroyed, as per Sponsor instructions. If no supplies 
remain, this fact will be documented in the pharmacy product accountability records. Any 
remaining supplies that were purchased by study site, such as D5W, will be destroyed. If no 
supplies remain, this fact will be documented in the pharmacy product accountability records.  

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8. 
REMOVAL OF SUBJECTS FROM THERAPY OR 
ASSESSMENT  
8.1. 
Discontinuation of Study Treatment  
A subject’s study treatment may be discontinued from study treatment for any of the following 
reasons: 
• AE (details described in Section 10.6.1) 
• Death 
• Investigator decision 
• Protocol deviation 
• Dose interruption (refer to Section 6.7) 
• Withdrawal by subject 
• Other 
8.2. 
Discontinuation from the Study  
Subjects may discontinue/be discontinued from the study at any time for any of the following 
reasons: 
• AE (details described in Section 10.6.1) 
• Death 
• Lost to follow-up 
• Investigator decision 
• Protocol deviation 
• Study terminated by Sponsor 
• Withdrawal by subject 
• Other 
A subject may elect to discontinue study participation at any time for any reason without 
prejudice to their future medical care by the physician or at the institution. When possible, all 
follow-up procedures specified in protocol Section 9.3 (Follow-Up) and Section 9.4 (Early 
Termination) should be performed. 
If a subject withdraws consent, no further evaluation should be performed, and no additional data 
should be collected. The Sponsor may retain and continue to use any data collected before such 
withdrawal of consent. The Investigator should make a reasonable attempt to document the 
specific reason why consent was withdrawn. 

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8.3. 
Lost to Follow-Up  
A subject will be considered lost to follow-up if all reasonable attempts made by the Investigator 
and delegated study staff fail to complete the scheduled Follow-Up phone call with the subject. 
A minimum of 3 attempts must be made to contact the subject. Each attempt must be 
documented in the subject’s records (ie, method of communication, times and dates). If all 
3 attempts fail, site must have receipt of a registered letter sent to the subject as the last attempt 
before considering the subject lost-to-follow-up in the eCRF. 
8.4. 
Premature Termination of the Study or a Study Site  
The Sponsor has the right to terminate this study at any time.  
The Sponsor must terminate the study for the following reasons: 
• At the conclusion of Part A, if none of the evaluated doses demonstrate a favorable 
safety profile and/or meaningful PD effects, the study will be terminated prior to the 
conduct of Part B (details described in Section 11.9) 
• Upon request of Health Authorities 
Reasons for terminating the study may also include, but are not limited to, the following: 
• The incidence or severity of AEs in this or other APD418 studies indicates a health 
hazard to subjects (specific examples of AEs that may indicate a health hazard to 
subjects and will be evaluated as part of study treatment and dose escalation stopping 
criteria in this study are described in Sections 10.6.1 and 10.6.2) 
• Subject enrollment is unsatisfactory 
The Sponsor will notify the Investigator if the study is placed on hold or if the Sponsor decides 
to discontinue the study. Health authorities and (Independent Ethics Committee[s]/Institutional 
Review Board[s] [IECs/IRBs]) will be informed about the termination of the study in accordance 
with applicable regulations. 
The Sponsor has the right to replace a study site at any time. Reasons for replacing a study site 
may include, but are not limited to: 
• Excessively slow recruitment 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• Non-compliance with the ICH guidelines for GCP 

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9. 
STUDY PERIODS  
9.1. 
Screening  
The Screening Period is to occur up to 21 days prior to and including Day 1 (Days −21 to 1) for 
Part A and 14 days prior to and including Day 1 (Days −14 to 1) for Part B. Screening 
assessments will be performed as described in the Schedule of Assessments (Table 4). Subjects 
must sign the informed consent before any study-specific procedure can be performed. Eligible 
subjects meeting all inclusion/exclusion criteria requirements may be enrolled. 
9.2. 
Treatment Period  
On Day 1 during Predose Period (prior to RHC insertion), potential eligible subjects (per initial 
Screening criteria) will undergo additional assessments for confirmation of eligibility. Following 
RHC insertion, subjects will enter Baseline stabilization period of at least 2 hours prior to study 
drug administration, which will occur if the patient is deemed eligible for the study based on 
observed hemodynamic parameters, as described in Section 10.3.1. Hemodynamic parameters 
based on RHC will be assessed at the end of Baseline, during Dosing Period throughout the 
study treatment administration (6-hour IV infusion), and for an additional 1 hour after cessation 
of study treatment administration. Subjects will continue to be observed during the Postdose 
Period for a minimum of 18 hours after the end of study treatment administration for PD, PK, 
and safety assessments prior to discharge on Day 2. Subjects are discharged at the Investigator’s 
discretion based upon clinical presentation (if the patient’s clinical state allows) and after all 
scheduled assessments at Hour 24 (+ 6 hours) have been completed.  
Treatment Period (Day 1 and Day 2) assessments are presented in the Schedule of Assessments 
(Table 4). 
9.3. 
Follow-Up/End of Study  
Subjects will be contacted by phone call for follow-up 7 days (± 2 days) after discharge to assess 
for AEs and changes in concomitant medications. For each subject, study participation is 
completed once the Follow-Up phone call has been conducted. End of Study is defined as 
completion of the final Follow-Up phone call for the last subject. 
9.4. 
Early Termination  
9.4.1. 
Early Termination of Study Treatment  
Subjects who discontinue study treatment (Section 8.1) prior to the end of the full 6-hour IV 
infusion should immediately, if possible, complete the Early End of Infusion assessments 
followed by all Postdose Period/Follow-Up assessments as indicated in the Schedule of 
Assessments (Table 4). 
9.4.2. 
Early Termination from Study Participation  
Subjects who discontinue from participating in the study (Section 8.2; individual missing data 
points do not count as early discontinuation) should receive the Follow-Up phone call. Site staff 
should work with subjects who withdraw early to obtain as much follow-up data as possible. 

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10. 
STUDY ASSESSMENTS AND PROCEDURES  
10.1. 
Subject Informed Consent  
The Investigator, or a person delegated by the Investigator, will obtain written informed consent 
from each subject before any study-specific activity is performed (refer to Section 12.3). 
10.2. 
Screening and Eligibility  
Subject eligibility will be assessed based on protocol inclusion and exclusion criteria. All 
screening evaluations must be completed and reviewed to confirm that potential subjects meet all 
eligibility criteria. 
Certain Screening and eligibility assessments must be performed on Day 1 prior to 
randomization, as described in the Schedule of Assessments (Table 4). All other Screening and 
eligibility assessments must be completed any time within the Screening Period prior to 
randomization on Day 1, unless otherwise specified (Table 4). 
Individuals may qualify for study enrollment following a clinically significant abnormal 
laboratory test, vital signs, or ECG finding by having that test repeated once with acceptable 
results as judged by the Investigator (or designee). The Investigator may consult with the 
Medical Monitor as needed. If additional retests are considered, the Clinical Lead should be 
consulted, and the outcome of the conversation should be documented. 
10.2.1. 
Rescreening  
Subjects who have not been randomized and/or do not meet the remaining inclusion and 
exclusion criteria may be re-consented and re-screened with a new screening number if the 
Investigator assesses that the subject is an appropriate candidate for re-screening. The 
Investigator may consult with the Medical Monitor if there are any questions related to 
rescreening a subject. Subjects may not be rescreened more than once. 
10.2.2. 
Demography and Other Subject Characteristics  
Demographics including year of birth, sex at birth, reproductive status for female subjects, 
ethnicity, and race as described by the subject will be collected at Screening. Other subject 
characteristic information such as height and weight will also be collected. 
10.2.3. 
Social History  
At Screening, a social history including the amount and duration of tobacco, alcohol, and 
caffeine use will be collected. 
10.2.4. 
Prior and Ongoing Therapies  
All medications and procedures conducted within 30 days prior to the first dose will be recorded 
at Screening. Updates to medications or procedures prior to dosing should be made as needed. 

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10.2.5. 
Medical History/Cardiovascular History  
A complete medical history of each subject will be collected and documented at Screening to 
determine subject eligibility. The history should include baseline disease characteristics relevant 
to the study, ie, the cardiovascular history including date and details of diagnosis, associated 
interventional procedures, and/or hospitalizations; blood donations (within 30 days), illnesses, 
participation in other investigational drug studies, and participation in any medical device 
clinical investigations will also be documented. 
10.2.6. 
Drugs of Abuse  
A standard urine drug screen will be performed on Day 1; however, it is not required to result the 
urine drug screen prior to randomization. If urine samples for urine drug screen cannot be 
obtained prior to study treatment administration due to the timing of events as required by 
subject safety considerations, then it can be obtained after study treatment administration and 
prior to discharge. 
10.2.7. 
Pregnancy Testing  
A serum pregnancy test for beta-human chorionic gonadotropin (β-hCG) will be performed at 
Screening on women of childbearing potential to determine eligibility. Urine pregnancy test 
(β-hCG) will be performed, and a negative result is required to be documented, for female 
subjects of childbearing potential on Day 1 prior to randomization to confirm eligibility as 
indicated in the Schedule of Assessments (Table 4). In the case of a positive urine β-hCG test, a 
serum β-hCG test will be performed to confirm pregnancy; only in cases where the serum 
pregnancy test is negative, can the subject be enrolled in the study.  
Women who are surgically sterile or who are postmenopausal are not considered to be of 
childbearing potential. Postmenopausal is defined as 12 consecutive months with no menses 
without an alternative medical cause.  
10.2.8. 
Clinical Laboratory Assessments  
Clinical chemistry, hematology, and coagulation parameters assessed at Screening to determine 
eligibility are identified in Table 2 and in the Schedule of Assessments (Table 4). These 
assessments will be performed at the central laboratory; however, if it is not possible to obtain 
central laboratory results for Screening assessments prior to Day 1 (eg, for a subject who is 
stabilizing during hospitalization for an AHF event), local laboratory assessments may be used 
instead for determining eligibility at Screening as long as they can be used to confirm all relevant 
exclusion criteria and the local laboratory panels are comparable to those outlined in Table 2. 
Central labs should not be collected when using local labs to confirm eligibility. 
10.2.9. 
Urinalysis  
Urinalysis parameters assessed at Screening to determine eligibility are identified in Table 2 and 
in the Schedule of Assessments (Table 4). These assessments will be performed at the central 
laboratory; however, if it is not possible to obtain central laboratory results for Screening 
assessments prior to Day 1 (eg, for a subject who is stabilizing during hospitalization for an AHF 
event), local laboratory assessments may be used instead for determining eligibility at Screening 
as long as they can be used to confirm all relevant exclusion criteria and the local laboratory 

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panels are comparable to those outlined in Table 2. Central labs should not be collected when 
using local labs to confirm eligibility. 
10.3. 
Pharmacodynamic/Hemodynamic Assessments  
10.3.1. 
Right Heart Catheterization Hemodynamic Assessments  
During the RHC assessments, an experienced cardiologist or designee will measure the 
following hemodynamic parameters: CO/CI, PCWP, right atrial pressure (RAP), 
systolic/diastolic pulmonary arterial pressure (PAS/PAD), systemic vascular resistance/systemic 
vascular resistance index (SVR/SVRI), pulmonary vascular resistance (PVR), and pulmonary 
artery pulsatility index (PAPi). Additional hemodynamic parameters may be assessed, if deemed 
necessary.  
RHC measurements of hemodynamic eligibility criteria will be performed at Baseline on Day 1 
to determine subject eligibility, no less than 1 hour following RHC insertion. PCWP will be 
assessed by 2 successive measurements at least 10 minutes apart. CI measurements will be based 
on the average of 3 individual thermodilution recordings, with no delay between recordings. 
PCWP and CI measurements are required to be within 10% and 15%, respectively, of each other 
(Note: The lower value must be within 10% or 15% of the higher value, respectively).  
Baseline hemodynamic parameters measurements will be performed after at least 2 hours 
following RHC insertion and stabilization (and preferably within 1 hour of assessment of 
hemodynamic eligibility criteria), and immediately before the start of study treatment 
administration. The Baseline CI measurement will be based on the average of 3 individual 
thermodilution recordings, with no delay between recordings. Additional recordings may be 
taken as needed until the final 3 recordings are within 15% of each other (Note: The lower value 
must be within 15% of the higher value). During Dosing and Postdose Periods, CI measurements 
will also be based on triplicate thermodilution recordings performed the same way as the 
Baseline CI measurement. 
Additional details regarding the procedures for collection, transfer, and analysis of RHC data 
will be provided in a separate operation manual by the RHC core lab. Planned timepoints for 
RHC assessments are provided in the Schedule of Assessments (Table 4). 
10.3.2. 
Vital Signs (Blood Pressure and Heart Rate) Assessments  
The following vital sign parameters will be measured as a component of the following PD 
assessments: SBP, diastolic blood pressure (DBP), mean arterial pressure (MAP), and HR. 
Vital signs (SBP, DBP, HR) will be measured and MAP will be calculated. The same equipment 
should be used whenever possible through the study; however, during the RHC assessment 
period, the same equipment must be used. During RHC assessments, vital signs should be 
collected within ± 5 minutes of hemodynamic parameter measurements. For subjects with atrial 
fibrillation, HR should be assessed by pulse measurement over at least 30 seconds.  
Planned timepoints for SBP, DBP, and HR assessments are provided in the Schedule of 
Assessments (Table 4). 

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10.3.3. 
Echocardiography Assessments  
During the ECHO assessments, an experienced sonographer will measure cardiac structure and 
function, including the following hemodynamic and cardiac function parameters: Stroke volume 
(SV), SV index (SVI), LVEF, fractional shortening (FS), left ventricular global longitudinal 
strain (LVGLS), left ventricular circumferential strain (LVGCS), left ventricular end-systolic/left 
ventricular/end-diastolic volume (LVESV/LVEDV), E, A, E', S', early/late diastolic velocities 
(E/A) ratio, early mitral filling velocity/early diastolic mitral annular velocity (E/E') ratio, 
tricuspid annular plane systolic excursion (TAPSE), tricuspid regurgitation (TR) velocity, and 
left atrial (LA) volume index.  
LVEF at Screening will be assessed by ECHO to determine subject eligibility; however, 
historical LVEF can be assessed by other modalities (eg, cardiac magnetic resonance imaging 
(CMR), computed tomography (CT), nuclear imaging, catheterization). 
Additional details regarding the procedures for collection, transfer, and analysis of ECHO data 
will be provided in a separate operation manual by the ECHO core lab. Planned timepoints for 
ECHO assessments are provided in the Schedule of Assessments (Table 4). 
10.3.4. 
Markers of Renal Function, Urine Output, and Body Weight  
The following markers of renal function will be measured: eGFR (calculated using the CKD-Epi 
equation), BUN, cystatin C, urine protein/creatinine ratio, and urinary sodium excretion 
(Table 2). These assessments will be based on blood and spot urine sampling.  
Blood samples for eGFR to determine subject eligibility will be assessed centrally during the 
Screening Period; however, if it is not possible to obtain central laboratory results for Screening 
assessments prior to Day 1, local laboratory assessments may be used instead for determining 
eligibility (Section 10.2.8). At all other timepoints eGFR analysis will be performed by the 
central laboratory. Detailed instructions regarding blood and urine sample collection, processing, 
shipping, and analysis for markers of renal function will be provided in a separate laboratory 
manual. The planned timepoints for blood/urine collection are provided in the Schedule of 
Assessments (Table 4). 
Urine output will be assessed during prespecified intervals by having the subject empty his/her 
bladder and capturing the urine volume at timepoints indicated in the Schedule of Assessments 
(Table 4), beginning with Baseline (subjects will be asked to void prior to RHC insertion) 
followed by 2-hour intervals during the IV infusion (Dosing Period). During the Postdose Period, 
urine output will be measured during the following intervals in relation to the start of the IV 
infusion: 6 to 10 hours and 10 to 24 hours. Any urine collected during the spot urine sampling 
should be accounted for in the total volume of the appropriate interval. During these intervals, 
the urine samples will be pooled for assessment of both urine volume and PK assessments 
(Section 10.4). 
Body weight will be evaluated as indicated in the Schedule of Assessments (Table 4). 
10.3.5. 
Cardiac Biomarkers  
The following cardiac biomarkers will be measured: NT-pro-BNP and hs-cTnT (Table 2). 

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Blood samples for cardiac troponin (hs-cTnT, hs-cTnI, cTnT, or cTnI) to determine subject 
eligibility will be assessed locally during the Predose Period, and in certain circumstances during 
the Screening Period (Section 10.2.8). At all other timepoints hs-cTnT analysis will be 
performed by the central laboratory. Detailed instructions regarding blood sample collection, 
processing, shipping, and analysis for cardiac biomarkers will be provided in a separate 
laboratory manual. Planned timepoints for blood collection are provided in the Schedule of 
Assessments (Table 4). 
10.4. 
Pharmacokinetic Assessments  
Blood samples for plasma PK analysis of APD418 will be collected at the following timepoints 
in relation to the start of the IV infusion: At Baseline (within 2 hours prior to the start of study 
treatment administration), during the Dosing Period at 0.5, 1, 2, 3, 4, 5, and 6 hours (within 
10 minutes before the end of the IV infusion), and during the Postdose Period at 6.083, 6.167, 
6.25, 6.5, 7, 8, 10, 18, and 24 hours, as indicated by PK blood sample footnote in the Schedule of 
Assessments (Table 4). Detailed instructions regarding sample collection, processing, and 
shipping will be provided in a separate laboratory manual. 
Pooled urine samples for PK analysis of APD418 will be collected during the following intervals 
in relation to the start of the IV infusion: Baseline (within 2 hours prior to the start of study 
treatment administration), during Dosing Period (0 to 6 hours), and during Postdose Period at the 
same intervals as for urine output (6 to 10 hours and 10 to 24 hours), as indicated in 
Section 10.3.4 and the Schedule of Assessments (Table 4). Any extra urine collected during the 
spot urine sampling (Section 10.3.4) should be included in the above pools. Detailed instructions 
regarding sample collection, processing, and shipping will be provided in a separate laboratory 
manual. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel. 
10.5. 
Safety Assessments  
Safety assessments include assessment of AEs, vital signs, clinical laboratory tests (including 
hs-cTnT), ECGs, physical examinations, and concomitant medications.  
Planned timepoints for all safety assessments are provided in the Schedule of Assessments 
(Table 4). 
10.5.1. 
Vital Signs  
Resting vital signs measurements will be performed with the subject in the supine or seated 
position (rest time at least 5 minutes prior to collection of vital signs) and include HR, blood 
pressure (BP), body temperature, and respiratory rate. Vital signs will be measured prior to any 
blood draws that occur at the same study visit or overlapping timepoint. For subjects with atrial 
fibrillation, HR should be assessed by pulse measurement over at least 30 seconds.  
Planned timepoints for vital signs assessments are provided in the Schedule of Assessments 
(Table 4). 

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10.5.2. 
Physical Examinations  
A physical examination will be performed by a licensed physician or designee per the site’s 
standard of care (including examination of general appearance, skin/dermatologic, lymph nodes, 
head, eyes, ears, nose and throat, neck, chest, thorax/lungs, and the following systems: 
Cardiovascular, gastrointestinal, neurologic, hematologic, and musculoskeletal). Abbreviated 
physical examination includes examination of general appearance, thorax/lungs, cardiovascular 
system, and abdomen, as well as assessments of any changes in the subject’s health since the last 
examination.  
Planned timepoints for physical examinations are provided in the Schedule of Assessments 
(Table 4). A symptom-based physical exam may also be performed at the Investigator’s 
discretion at any time during the study. 
10.5.3. 
Electrocardiography  
All ECGs will be recorded from a 12-lead ECG machine. Every attempt should be made to 
ensure the subject ECG readings are obtained using the same machine throughout the study. 
Intervals to be provided on the confirmed read for each safety ECG are RR, PR, QRS, QT, QTc, 
corrected QT interval using Bazett’s formula (QTcB), and corrected QT interval using 
Fridericia’s formula (QTcF). All ECGs will be recorded with subjects in supine position (rest 
time at least 5 minutes prior to collection). If applicable, it is recommended to collect ECGs at 
least 30 minutes after the end of the subject’s most recent meal. 
The Investigator will be responsible for review and interpretation of ECGs on site for eligibility 
purposes and for determining if the ECG is normal, abnormal clinically insignificant, or 
abnormal clinically significant and recording any clinically relevant worsening from Baseline 
occurring during the study in the AE section of the eCRF. ECGs will also be analyzed by the 
core lab. Both local and central reports must be filed with the source documents. 
Planned timepoints for ECGs are provided in the Schedule of Assessments (Table 4). 
10.5.4. 
Clinical Laboratory Assessments  
All clinical laboratory assessments will be analyzed by a central laboratory unless otherwise 
stated. Details regarding clinical laboratory sample collection, preparation, and shipment of 
central lab samples will be provided in the laboratory manual by the central laboratory. Refer to 
Table 2 for the list of clinical laboratory tests to be performed and the Schedule of Assessments 
(Table 4) for timing and frequency for each test. 
Lab results that are invalid, or appear to be invalid, should be repeated when possible. If lab tests 
used to determine subject eligibility are invalid, the tests may be repeated to determine subject 
eligibility as judged by the Investigator (or designee) (ie, it is not required to screen-fail a subject 
prior to repeating the lab test). 
Central laboratory reports and, when applicable, local laboratory reports used for Screening and 
eligibility purposes must be filed with the source documents. The Investigator must review all 
the laboratory reports from the local and central laboratory, document the review, and record any 
clinically relevant changes on the AE section of the eCRF. Clinically significant abnormal 
laboratory findings are those that are not associated with the underlying disease, unless judged 
by the investigator to be more severe than expected for the subject’s condition. All laboratory 

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tests with values considered clinically significantly abnormal during participation in the study 
should be repeated until the values return to normal or Baseline, or are no longer considered 
clinically significant by the investigator or Medical Monitor.  
In cases when laboratory values from non-protocol-specified assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are considered 
clinically significant by the Investigator (eg, AE or dose modification), then the details must be 
documented on the AE section of the eCRF. 
Table 2: 
Clinical Laboratory Tests  
Pregnancy Testing 
Coagulation  
Serum and urine pregnancy test 
beta-human chorionic gonadotropin  
(β-hCG, female subjects only) 
Prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
International Normalized Ratio (INR) 
Thrombin time 
Fibrinogen/Fibrin 
Fibrin degradation products (FDP) 
Functional plasminogen  
Urinalysis 
Hematology 
Appearance 
Bilirubin 
Color 
Glucose 
Ketones 
Microscopic examination of sediment 
Nitrite 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
Leukocyte esterase 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration (MCHC) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count with differential 
Serum Chemistry 
Albumin 
Alkaline phosphatase (ALP) 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Bicarbonate 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Creatinine 
Creatine kinase 
Glucose 
Lactate dehydrogenase (LDH) 
Phosphorus 
Potassium 
Sodium 
Thyroid-stimulating hormone (TSH) 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
Uric acid 
Cardiac Biomarkers 
Renal Function Biomarkers 
High-sensitivity cardiac troponin T (hs-cTnT)  
N-terminal pro b-type natriuretic peptide (NT-pro-BNP) 
Estimated glomerular filtration rate (eGFR) 
Cystatin C 
Blood urea nitrogen (BUN) 
Urine protein/creatinine ratio 
Urinary sodium excretion 

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Exploratory Inflammatory and Endothelial Biomarkers 
Pro-inflammatory cytokines (tumor necrosis factor-alpha  
[TNF-α], interleukin [IL]-1β, IL-6) 
high-sensitivity C-reactive protein (hs-CRP) 
Vascular adhesion molecule 1 (VCAM-1) 
Vascular endothelial growth factor (VEGF) 
Von Willebrand factor (VWF) 
Drugs of Abuse 
Opiates 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cocaine metabolites 
Cannabinoids 
Additional Tests 
Optional organic anion transporting polypeptide (OATP) genotypic analysis  
 
10.5.4.1. 
Clinical Chemistry, Hematology, and Coagulation  
Clinical chemistry, hematology, and coagulation parameters to be assessed during the study are 
identified in Table 2. Planned timepoints for collection of samples is provided in the Schedule of 
Assessments (Table 4).  
10.5.4.2. 
Exploratory Inflammatory and Endothelial Biomarkers  
Exploratory inflammatory and endothelial biomarkers to be assessed during the study are 
identified in Table 2. Planned timepoints for collection of samples is provided in the Schedule of 
Assessments (Table 4).  
10.5.4.3. 
Urinalysis  
Urinalysis parameters to be assessed during the study are identified in Table 2. Planned 
timepoints for collection of samples is provided in the Schedule of Assessments (Table 4).  
10.5.5. 
Adverse Events  
10.5.5.1. 
Definitions  
10.5.5.1.1. 
Adverse Event  
An AE is any untoward medical occurrence that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
AEs can include, but are not limited to, any of the following: 
• Unfavorable changes in general condition 
• Subjective or objective signs/symptoms 
• Concomitant disease or accidents 
• Clinically relevant adverse changes in laboratory parameters over the course of the 
study 

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• Pre-existing conditions that worsen in severity, increase in frequency, or have new 
signs/symptoms 
10.5.5.1.2. 
Serious Adverse Event  
An AE should be classified as an SAE if it meets one of the following criteria: 
Fatal: 
The AE resulted in death. 
Life-threatening: 
The AE placed the subject at immediate risk of death. This 
classification does not apply to an adverse event that hypothetically 
might cause death if it were more severe. 
Hospitalization: 
The AE required or prolonged an existing inpatient hospitalization. 
Hospitalizations for elective medical or surgical procedures or 
treatments planned before the signing of informed consent in the study 
or routine check-ups are not SAEs by this definition. 
Disabling/ 
incapacitating: 
The AE resulted in a persistent or significant incapacity or substantial 
disruption of the subject’s ability to conduct normal life functions. 
Congenital anomaly 
or birth defect: 
An adverse outcome in a child or fetus of a subject exposed to the 
study treatment before conception or during pregnancy. 
Medically significant: The AE did not meet any of the above criteria but could have 
jeopardized the subject and might have required medical or surgical 
intervention to prevent one of the outcomes listed above or involves 
suspected transmission via a medicinal product of an infectious agent. 
10.5.5.1.3. 
Adverse Drug Reaction  
An adverse drug reaction (ADR) in the pre-approval clinical experience with a new medicinal 
product or its new usages, particularly as the therapeutic dose(s) may not be established, is any 
noxious and unintended response to a medicinal product related to any dose. The phrase 
“responses to a medicinal product” means that a causal relationship between a medicinal product 
and an adverse event is at least a reasonable possibility (ie, the relationship cannot be ruled out). 
10.5.5.1.4. 
Severity  
The severity of each AE will be assessed at the onset by a nurse/or physician. When recording 
the outcome of the adverse event the maximum severity of the AE experienced will also be 
recorded. The severity of each AE will be graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE): 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living. 

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Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, 
limiting self-care activities of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing 
money). 
Grade 4: 
Life-threatening consequences, urgent intervention indicated. 
Grade 5: 
Death related to adverse event. 

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10.5.5.1.5. 
Relationship  
The Investigator is obligated to assess the relationship (causal relationship) between the study 
treatment and each occurrence of each AE. The AE relationship (causal relationship) to study 
treatment must be characterized as one of the following categories: 
Not Related: 
The AE does not follow a reasonable temporal sequence from 
administration of the drug, does not abate upon discontinuation of the 
drug, does not follow a known or hypothesized cause-effect relationship, 
and (if applicable) does not reappear when the drug is reintroduced, 
furthermore, there may exist a clear alternative medical explanation (eg, 
underlying disease state) or association with study procedure or study 
conduct. 
Unlikely Related: 
The temporal association between the AE and the drug is such that the 
drug is not likely to have any reasonable association with the AE. 
Probably Related: 
The AE follows a reasonable temporal sequence from administration of 
the drug and cannot be reasonably explained by the known 
characteristics of the subject’s clinical state, environmental, or toxic 
factors, or other modes of therapy administered to the subject. 
Related: 
The AE follows a reasonable temporal sequence from administration of 
the drug, abates upon discontinuation of the drug, follows a known or 
hypothesized cause-effect relationship, and (if appropriate) reappears 
when the drug is reintroduced. 
The Investigator will use clinical judgment to determine the relationship. Alternative causes, 
such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to the study treatment administration should be considered and 
investigated. The Investigator should consult the IB and the Product Information of marketed 
products within the drug class, when applicable. For each AE, the Investigator must document in 
the medical notes that he/she has reviewed the adverse event and has provided an assessment of 
causality. There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to the Sponsor; however, the Investigator 
should always make an initial assessment of causality for every event before the initial 
transmission of the SAE to the Sponsor. The Investigator may change his/her opinion of 
causality based on subsequent receipt of information and send an SAE follow-up report with the 
updated causality assessment. The causality assessment is one of the criteria used when 
determining regulatory reporting requirements. 
10.5.5.2. 
Eliciting, Recording, and Reporting Adverse Events  
10.5.5.2.1. 
Eliciting Adverse Events  
Subjects will be instructed that they may report AEs at any time. An open-ended or nondirected 
method of questioning should be used at each study visit to elicit the reporting of AEs. 

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10.5.5.2.2. 
Recording Adverse Events  
The AE reporting period for safety surveillance begins when the subject is initially included in 
the study (date of first signature of informed consent) and continues up to 30 days after the last 
study treatment administration. If an AE is not resolved or stabilized by this time, the Sponsor in 
consultation with the Investigator will decide whether to continue to monitor the AE or closeout 
the event in the database if no further follow-up is necessary.  
Investigator and study personnel will record all AEs and SAEs whether received through an 
unsolicited report by a subject, elicited during subject questioning, discovered during physical 
examination, laboratory testing, and/or other means by recording them on the eCRF and SAE 
Report Form, as appropriate. The following information should be recorded on the AE eCRF: 
• Description including onset and resolution dates 
• Whether it met SAE criteria 
• Severity 
• Relationship to study treatment or other causality 
• Outcome 
Any SAE suspected to be related to the study treatment must be reported whenever it occurs, 
irrespective of the time elapsed since the last study treatment administration. 
For SAEs, events occurring secondary to the primary event should be described on the SAE 
Report Form in the narrative description of the case. 
The following should be considered when recording SAEs: 
• Death is an outcome of an event. The event that resulted in the death should be 
recorded and reported on both the SAE Report Form and eCRF. 
• For hospitalizations, surgical, or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself. The procedure should be captured in the narrative as part of the action taken in 
response to the illness. 
10.5.5.2.3. 
Diagnosis Versus Signs or Symptoms  
In general, the use of a unifying diagnosis is preferred to the listing out of individual symptoms. 
Grouping of symptoms into a diagnosis should only be done if each component sign and/or 
symptom is a medically confirmed component of a diagnosis as evidenced by standard medical 
textbooks. If any aspect of a sign or symptom does not fit into a classic pattern of the diagnosis, 
report the individual symptom as a separate adverse event. 
10.5.5.3. 
Reporting Serious Adverse Events  
All SAEs are subject to reporting requirements. 

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10.5.5.3.1. 
Serious Adverse Events  
All SAEs, whether or not considered related to study treatment, must be reported to the Sponsor 
Contact immediately, without undue delay, and under no circumstances later than 24 hours 
of becoming aware of the event. In addition, a completed report using the Sponsor’s SAE 
Report Form must be submitted within 24 hours of notification to the designated Sponsor 
Contact.  
IQVIA Pharmacovigilance 
Phone: +1-866-599-1341 
Fax: +1-866-599-1342 
Email (preferred method): ArenaSafety@iqvia.com 
If additional follow-up information is required or becomes available for a previously reported 
SAE, the new information should be reported to the designated Sponsor Contact within 
24 hours of awareness.  
Elective hospitalization and/or surgery for clearly preexisting conditions (eg, a surgery that has 
been scheduled prior to the subject’s entry into the study) will not be reported as an SAE. All 
other hospitalizations, including elective hospitalizations for any condition that was not 
preexisting, will be reported as an SAE. 
Any SAE that is ongoing when the subject completes the study or discontinues the study will be 
followed by the Investigator until the event resolves, stabilizes or returns to baseline status. 
10.5.5.3.2. 
Serious, Unexpected Adverse Drug Reactions  
All ADRs that are both serious and unexpected are subject to expedited reporting to regulatory 
agencies and will be reported in accordance with Directive 2001/20/EC or as per national 
regulatory requirements in participating countries. An unexpected ADR is one for which the 
nature or severity is not consistent with information in the relevant source documents. 
The following documents or circumstances will be used (by the Sponsor) to determine whether 
an adverse event/ADR is expected: 
1. For a medicinal product not yet approved for marketing in a country, the Reference 
Safety Information (RSI) section of a company’s IB will serve as the source document 
in that country. 
2. Reports that add significant information on specificity or severity of a known, already 
documented serious ADR constitute unexpected events. For example, an event more 
specific or more severe than described in the RSI in the IB would be considered 
“unexpected”. 
10.5.6. 
Pregnancy  
Details of all pregnancies in female subjects and female partners of male subjects will be 
collected after the start of study treatment and until 90 days after the end of study treatment. 
Pregnancy (during maternal or paternal exposure to study treatment) does not meet the definition 
of an adverse event; however, to fulfill regulatory requirements, any pregnancy and/or pregnancy 

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outcome should be reported via the Pregnancy Report Form to the designated Sponsor Contact 
within 24 hours of awareness. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and should be reported as such even if 
outside the SAE reporting period. 
10.6. 
Safety-Related Stopping Criteria  
10.6.1. 
Study Treatment Stopping Criteria  
Study treatment will be discontinued per subject and the subject will follow procedures described 
in Section 9.4.1 if the following safety-related criteria occur: 
• A subject experiences an AE of arrythmia or hemodynamic instability, which is not 
tolerated and is considered probably related or related to study drug in the opinion of 
the Investigator  
• A subject experiences a complication related to an infusion site reaction and/or the 
RHC procedure, which in the opinion of the Investigator puts subject safety at risk 
10.6.2. 
Dose Escalation Stopping Criteria  
Safety data will be monitored in a blinded manner on an ongoing basis throughout the duration 
of the study. After treatment of each cohort in Part A, an assessment of the safety/tolerability and 
PK data will be conducted by the dose escalation committee (blinded data review by the Sponsor 
and Investigator representatives) to determine whether dose escalation to the next dose level in 
Part A can occur. Doses for each subsequent cohort in Part A may be adjusted depending on the 
safety, tolerability, and PK results of previous cohort(s).  
The dose escalation committee will use the following safety-related criteria per cohort to 
preclude escalation to the next planned dose level in Part A: 
• Two or more subjects experience an SAE considered probably related or related to 
study drug in the opinion of the Investigator and the dose selection committee   
• Two or more subjects experience an AE Grade 3 or higher related to clinical 
instability associated with hemodynamic/arrhythmia events requiring intervention 
(pharmacologic or mechanical) considered probably related or related to study drug in 
the opinion of the Investigator  
• Two or more subjects experience a CNS-associated AE Grade 3 or higher considered 
probably related or related to study drug in the opinion of the Investigator  
• Three or more subjects experience an infusion site related AE Grade 3 or higher 
considered probably related or related to study drug in the opinion of the Investigator  
• Two or more subjects experience a clinically significant increase in ALT or AST, and 
TBIL, indicative of drug-induced liver injury. For subjects with values < 2× ULN 
prior to dosing, this criterion is met with ALT or AST ≥ 3 × ULN, and TBIL ≥ 2 × 
ULN, following study treatment administration. For subjects with values ≥ 2 × ULN 
prior to dosing, a 100% increase from baseline values meets the criterion 

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• Two or more subjects experience clinical worsening of renal function requiring 
intervention (pharmacologic or mechanical; eg, intensification of diuretic treatment 
due to renal function deterioration or the need for dialysis) 
• Mean cohort Cmax exceeds 5700 ng/mL and/or AUC0-∞ with the 6-hour infusion 
exceeds 39,000 ng·h/mL  
In addition to the safety-related dose escalation stopping criteria listed above, the dose escalation 
safety committee will review overall safety (including AEs, clinical laboratory, and vital 
sign/ECG data) and PK data of each cohort when deciding whether to escalate to the next 
planned dose level in Part A.  
If warranted during blinded safety reviews, unblinded data may also be reviewed by the dose 
selection committee, who are not involved in study conduct, to adjudicate relatedness of SAEs or 
assess overall subject safety and determine if dose escalation can continue.  
In the event that dose escalation cannot occur as planned, alternative (lower) dose(s) may be 
explored in the subsequent cohort(s) in Part A (details described in Section 11.9).  
10.7. 
Maximum Blood Volume  
Blood sample collection during RHC assessments must be performed via indwelling catheter. 
Standard venipuncture may be used for blood collection during other study periods. 
The maximum amount of blood collected from each subject over the duration of the study, 
including planned PK and planned clinical laboratory samples will not exceed 260 mL. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
10.8. 
Procedures for Overdose  
The current version of the IB should be referenced for overdose procedures.   
10.9. 
Pharmacogenomic and Future Analyses  
10.9.1. 
Pharmacogenomic Samples  
Participation in the genetic testing portion of the study is optional. Subjects who do not wish to 
participate in the genetic research may still participate in the study. A blood sample will be 
collected at Baseline only from the subjects who give consent to participate in the genetic 
research. The sample will be utilized to determine OATP genotype. 
The biological material will be stored at a secure laboratory designated by the Sponsor for up to 
10 years after the study is completed. In addition to analyses performed during the study, 
samples will be saved for potential future exploratory research aimed at identifying/exploring 
genetic variations and response to APD418 that may affect its PK, pharmacodynamics, safety, or 
tolerability, if warranted. The Sponsor and CRO involved in the clinical conduct, bioanalytical 
analyses, PK and/or statistical analyses of the data will have access to the samples and the data 
that result from the analysis, if performed. Samples will not be submitted to a public database. 
By signing the informed consent form (ICF), subjects agree to the possible future analysis of 
these samples. At any time, the subjects can contact the clinical staff to request destruction of 
their residual samples after the required assessments are completed.  

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Details on processes for collection, labeling, shipment, and destruction of pharmacogenomic 
samples are provided in a separate laboratory manual.  
10.9.2. 
Future PK and Biomarker Research  
Any residual plasma and/or urine from PK sample collection will be stored by the Sponsor or 
bioanalytical facility for up to 3 years (or according to local regulations) after the closing of the 
study and may be used for future drug related research such as profiling of drug binding proteins, 
bioanalytical method development and validation purposes, stability assessments, metabolite 
assessments, or to assess other actions of the drug with plasma constituents. The analyses will 
only focus on analytes and/or additional biomarkers to further study the disposition and efficacy 
of APD418 and/or its mechanism of action. No disease/conditions, deoxyribonucleic acid (DNA) 
or ribonucleic acid (RNA) will be the focus of these analyses. Samples will not be submitted to a 
public database. The Sponsor and CROs involved in the clinical conduct and analyses of the 
samples/data will have access to the samples and/or the data that result from the analyses, if 
performed. At any time, the subjects can contact the clinical staff to request destruction of their 
residual samples after the required assessments are completed. 
11. 
PLANNED STATISTICAL METHODS  
11.1. 
General Considerations  
Details regarding the statistical analyses will be provided in the Statistical Analysis Plan (SAP), 
which will be finalized prior to database lock and unblinding. 
Continuous variables will be summarized using the number of observations, mean, standard 
deviation (SD), median, minimum, and maximum. Categorical variables will be summarized 
using frequency counts and percentages. 
Continuous variables measured at scheduled timepoints will be analyzed using a mixed-effects 
model with repeated measures (MMRM) method. The MMRM model will include treatment 
group, timepoint, interaction of treatment-by-timepoint, and randomization stratification factors 
as factors, and Baseline measure as a covariate. An unstructured covariance matrix will be 
specified for the MMRM model. Least square (LS) means at visit and LS mean differences 
between treatment group with p-values and corresponding 95% confidence intervals will be 
reported. 
Unless otherwise specified, continuous endpoints will be analyzed using analysis of covariance 
(ANCOVA) with a model that includes treatment group and randomization stratification factors 
as factors, and Baseline CI value and other Baseline value as covariates. The LS means, standard 
errors (SE), and 95% confidence intervals for the treatments and their difference will be 
presented together with their p-values. 
Categorical endpoints will be analyzed by either the Cochran-Mantel-Haenszel method, Fisher’s 
exact test, or by logistic regression with a model that includes treatment group and 
randomization stratification factors as factors, and Baseline CI value and other and Baseline 
value as covariates. The odds ratio relative to placebo and percentage of difference from placebo 
will be presented together with corresponding 95% confidence intervals and the p-value. 

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Where statistical assumptions (eg, normality, proportional odds) are not met, alternative 
approaches will be evaluated (eg, non-parametric analysis, log transformation). 
Efficacy data will be analyzed by randomized treatment, while safety data will be analyzed by 
actual treatment. 
11.2. 
Determination of Sample Size  
Approximately 80 subjects are planned to be enrolled in this study (35 in Part A and 45 in 
Part B). It is assumed that CI, as measured with RHC, from Baseline to end of infusion is 
normally distributed with a mean of 2.0 and SD of 0.5. Sixty-five evaluable subjects (20 subjects 
in each of the 2 APD418 treatment groups and 25 in placebo) is sufficient to achieve at least 80% 
power to detect a treatment effect of 0.45 in favor of APD418 (a clinically significant 
improvement of 22.5% from placebo) between each of the APD418 treatment groups and 
placebo by a 2-sample t-test using a 2-sided significance level of 0.05. 
The primary endpoint analysis will be based on pooled data from subjects in Part A and Part B. 
There will be 2 APD418 treatment groups of 20 subjects each (planned to consist of 5 subjects 
from Part A and 15 subjects from Part B) and one placebo treatment group of 25 subjects 
(planned to consist of 10 subjects from Part A and 15 subjects from Part B). 
. 
11.3. 
Stratification  
In Part A, randomization will be stratified by Screening LVEF (> 25%, ≤ 25%). In Part B, 
randomization will be stratified by Screening LVEF (> 25%, ≤ 25%) and baseline carvedilol use 
(yes, no). 
11.4. 
Analysis Sets  
The primary and secondary endpoints will be analyzed using the Full Analysis Set (FAS) and 
safety endpoints will be performed using the Safety Set. For purposes of analysis, the following 
populations are defined (Table 3). 

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Table 3: 
Analysis Sets  
Analysis Set 
Description 
Full Analysis Set (FAS) 
The FAS will include all randomized subjects, irrespective of whether they 
received any study treatment. 
Modified Full Analysis Set 
(mFAS) 
The mFAS will include all randomized subjects who receive any study 
treatment and have a baseline measurement and at least 1 post-baseline 
measurement. The mFAS is endpoint specific, therefore subjects included in 
the analysis set for one endpoint may differ from another endpoint, based on 
the baseline and post-baseline data. 
Per Protocol Set  
The Per Protocol Set will include all subjects from the FAS without major 
protocol violations that might affect the evaluation of the effect of study 
treatment on the primary endpoint. 
Pharmacokinetic (PK) Set 
The Pharmacokinetic Set will include all subjects in the Safety Set with at 
least 1 postdose PK measurement. 
Safety Set 
The Safety Set will include all randomized subjects who received at least one 
dose of study treatment. 
11.5. 
Missing Data  
Imputation strategies for the handling of missing data is described in detail in the SAP. 
11.6. 
Study Endpoints  
11.6.1. 
Primary Endpoint  
Change in CI measured by RHC from Baseline to end of IV infusion at 6 hours 
11.6.2. 
Secondary Endpoints  
Secondary endpoints are: 
• Change in the following hemodynamic parameters measured by RHC from Baseline 
to end of IV infusion at 6 hours: 
− CO 
− PCWP 
− RAP 
− PAS/PAD 
− PAPi 
− SVR/SVRI 
− PVR 
• Change in the following vital sign parameters from Baseline to end of IV infusion at 
6 hours: 
− SBP 
− DBP 
− MAP 
− HR 

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• Change in the following hemodynamic and systolic function parameters measured by 
ECHO from Baseline to end of IV infusion at 6 hours: 
− SV 
− SVI 
− LVEF 
− FS 
− LVESV/LVEDV and diameter 
− LVGLS 
− LVGCS 
• Change in hemodynamic (measured by RHC) and vital sign parameters listed above 
at intermediate timepoints during 6-hour IV infusion (during Dosing Period) 
• Plasma and urine PK parameters of APD418 
• Safety and tolerability of APD418 by incidence of all TEAEs 
11.6.3. 
Pharmacokinetic Endpoints  
PK endpoints are PK profiles of APD418, including, but not limited to, the following measures:  
• Area under the concentration-time curve from time 0 to 6 hours (AUC0-6) 
• Area under the concentration-time curve from time 0 to time of the last quantifiable 
plasma concentration (AUClast) 
• AUC0-∞ 
• Cmax  
• Terminal elimination half-life (t1/2)  
• Distribution half-life (t1/2α) 
• Time to maximum observed plasma concentration (tmax) 
• CL 
• Volume of distribution based on the terminal phase (Vdz) 
• Volume of distribution at steady state (Vdss) 
• Mean residence time from time 0 to time of last quantifiable plasma concentration 
(MRTlast) 
• Average plasma concentration during dosing interval (Cave) 
• Renal clearance (CLr) 

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11.6.4. 
Exploratory Endpoints  
Exploratory endpoints are: 
• Change in hemodynamic parameters (measured by RHC) listed above at 1 hour after 
the end of 6-hour IV infusion (during Postdose Period)  
• Change in vital sign, hemodynamic (measured by ECHO), and cardiac systolic 
function (measured by ECHO) parameters listed above for 18 hours after end of 
6-hour IV infusion (during Postdose Period) 
• The relationships between select APD418 plasma exposure measures and change in 
select PD parameters 
• The relationships between select subject/disease characteristics (eg, Baseline LVEF, 
Baseline CI, Baseline SBP, duration of HFrEF, renal function, concomitant 
medications) and change in select PD parameters 
• Change in markers of renal function (eGFR, BUN, cystatin C, urine protein/creatinine 
ratio, urinary sodium excretion) 
• Change in cardiac biomarkers (NT-pro-BNP, hs-cTnT) 
• Change in the following additional systolic and diastolic function parameters 
measured by ECHO: E, A, E, S, E/A E/E ratio), TAPSE, tricuspid regurgitation 
(TR) velocity, and LA volume index 
• Change in urine output 
• Change in body weight 
• The OATP genotype  
11.6.5. 
Safety Endpoints  
• Safety and tolerability of APD418 by incidence of all TEAEs 
11.7. 
Testing Strategy  
No formal testing strategy or adjustments of the Type I error will be employed for secondary or 
exploratory endpoints. Estimates and confidence intervals for treatment groups and from 
pairwise comparisons will be used in an exploratory manner. 
11.8. 
Interim Analysis  
No formal interim analysis of efficacy is planned.. 
11.9. 
Dose Escalation and Dose Selection  
After treatment of each cohort in Part A, an assessment of the safety/tolerability and PK data will 
be performed by the dose escalation committee (blinded data review by the Sponsor and 
Investigator representatives) prior to dose escalation to the next dose level in Part A. The 
decision to escalate to the next planned dose level in Part A will be made with consideration of 

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the safety-related dose escalation stopping criteria and overall safety (including AEs, clinical 
laboratory, and vital sign/ECG data) and PK data of each cohort, as described in Section 10.6.2.  
Doses for each subsequent cohort in Part A may be adjusted depending on the safety, tolerability, 
and PK results of previous cohort(s). The maximum dose in the study will not exceed 2 mg/kg/h 
(12 mg/kg) and will not produce exposures to APD418 higher than that predicted for a 12 mg/kg 
dose (ie, Cmax of 5700 ng/mL or AUC0-∞ of 39,000 ng·h/mL) without a protocol amendment.  
The dose escalation committee may decide to evaluate an alternative dose(s) in the subsequent 
cohort(s) in Part A in the following scenarios: 
• Based on the safety profile observed, lower or higher than planned dose(s) may be 
chosen to be evaluated in the subsequent cohort(s) (not to exceed 12 mg/kg without a 
protocol amendment) 
• If large deviations from the expected PK profile are observed, adjustment to the 
planned dose escalations may occur to ensure evaluation of dose levels that will elicit 
appropriate exposure  
• If warranted based on the emerging safety and PK data, up to 1 additional or 1 fewer 
cohort may be studied than originally planned  
At the conclusion of Part A, the dose selection committee will perform a safety/tolerability and 
PD data assessment to identify 2 doses to be expanded in Part B (unblinded review of Part A data 
by the Sponsor representatives who are not directly involved in study conduct; site staff, and 
sponsor representatives involved in study conduct will remain blinded throughout the study). 
Selection of doses will be based on the criteria including, but not limited to: 
• Doses selected for expansion in Part B have shown a favorable safety profile in 
Part A as determined by the criteria described in Section 10.6.2  
• Doses selected for expansion in Part B have shown clinically relevant PD effects 
indicating a clinically meaningful benefit in cardiac function (eg, SV, CO, LVEF) 
Sample size for Part B may also be adjusted based on data review of Part A. The sample size will 
not increase by more than approximately 15% of the sample size without a protocol amendment. 
11.10. 
Pharmacodynamic Analysis  
The primary PD endpoint of the study is the change in CI measured by RHC from Baseline to 
end of infusion at 6 hours. The primary PD analysis will be analyzed be MMRM method. The 
MMRM model will include treatment group, timepoint, interaction of treatment-by-timepoint, 
and randomization stratification factor as factors, and Baseline CI as a covariate. An unstructured 
covariance matrix will be specified for the MMRM model. LS means at visit and LS mean 
differences between treatment group with p-values and corresponding 95% confidence intervals 
will be reported. 
Potential relationships may be explored between select subject/disease characteristics (eg, 
Baseline LVEF, Baseline CI, Baseline SBP, duration of HFrEF, renal function, concomitant 
medications) and select PD measures (eg, change in CI). 
Details regarding the statistical analyses will be provided in the SAP. 

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11.11. 
Pharmacokinetic Analyses  
PK parameters will be calculated using noncompartmental modeling.  
Calculated plasma PK parameters will include, but will not necessarily be limited to AUC0-6, 
AUClast, AUC0-∞, Cmax, t1/2, t1/2α, tmax, CL, Vdz, VdSS, MRTlast, and Cave. Urinary PK parameters 
will include, but not be limited to, the amount of unchanged drug excreted during each collection 
interval from t1 to t2 (Aet1-t2), total amount of unchanged excreted in urine over the collection 
period (amount excreted [Ae]), renal clearance (CLr) and the fraction of drug excreted 
unchanged in the urine, expressed as a percentage of total dose (fraction excreted [Fe]). 
Collected plasma and urine PK samples may also be used for profiling of drug binding proteins, 
bioanalytical method validation purposes, stability assessments, or to assess other actions of 
APD418 with plasma constituents.  
A detailed description of all PK analyses will be provided in the SAP. 
Potential relationships may be explored between select plasma APD418 exposure parameters and 
select PD measures (eg, change in CI).  
OATP genotyping will be analyzed and presented in the listing to allow any potential future 
analysis. 
11.12. 
Safety Analyses  
AEs will be listed and summarized by system organ class and preferred term, as well as 
according to severity and causality/relationship to study treatment. TEAEs will be summarized 
by cohort and treatment group. In addition, TEAEs will be pooled across treatment groups (ie, 
placebo, APD418). Observed values for clinical laboratory tests, vital signs, and safety 12-lead 
and ECGs will be summarized by cohort and treatment group. Individual data listings of clinical 
laboratory tests results will be presented for each subject. Observed values and changes from 
Baseline will be summarized descriptively. Safety 12-lead ECG data (observed values and 
change from Baseline) will be listed for each subject and timepoint. Observed values will be 
classified for normal, abnormality that is not clinically significant, and clinically significant 
abnormality by cohort, treatment, and timepoint of collection. Results of other safety 
assessments will be listed and summarized as appropriate.  
A detailed description of all safety analyses will be provided in the SAP. 
11.12.1. 
Adverse Events  
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
For each treatment group, the proportion of subjects with TEAEs will be summarized overall, by 
severity, and by relationship to study treatment. SAEs will also be summarized by treatment 
group. A TEAE is defined as: 
• An AE that occurs after initiation of study treatment that was not present at the time 
of treatment start. 
• An AE that increases in severity after the initiation of medication, if the event was 
present at the time of treatment start. 

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AEs occurring before the first dose of study treatment will be summarized separately. 
11.12.2. 
Extent of Exposure  
The duration of time on study and time on study treatment will be summarized for each treatment 
group using descriptive statistics.  
11.12.3. 
Clinical Laboratory Parameters  
Laboratory parameters will be summarized by treatment group at each scheduled assessment 
timepoint using descriptive statistics. 
11.12.4. 
Electrocardiograms  
Individual ECG values will be listed by cohort, treatment, and timepoint, and summarized using 
descriptive statistics. Intervals to be provided for each ECG are RR, PR, QRS, QT, QTc, QTcB, 
and QTcF. Post-Baseline ECGs for each subject will be compared with the Baseline ECG. Any 
clinically significant change from Baseline may be recorded as an AE if deemed appropriate by 
the Investigator, or Investigator in consultation with the Clinical Lead. Outlier analysis will be 
performed on all subjects with QTcF values greater than 500 ms or change from Baseline 
> 60 ms in the absence of Baseline ECG abnormalities that preclude accurate surface ECG 
assessment of ventricular repolarization (eg, bundle branch block). 
11.12.5. 
Vital Signs  
Descriptive statistics for vital signs (SBP, DBP, HR, respirations, and body temperature) will be 
presented by treatment group. 
11.12.6. 
Physical Examination  
Clinically significant physical examination abnormalities will be included in medical history or 
recorded and summarized as an AE. 
12. 
ETHICAL CONSIDERATIONS  
12.1. 
Ethical Conduct of the Study  
This study shall be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with GCP, ICH guidelines, and other 
applicable regulatory requirements (eg, local requirements). 
12.2. 
Institutional Review Board or Independent Ethics Committee 
Approval  
Before initiating a study, the Investigator must have written and dated approval from the 
IRB/IEC for the study protocol, written ICF, subject recruitment materials and procedures (eg, 
advertisements or websites), and any other written information to be provided to subjects. 
Approval from the committee must be documented in a letter to the Investigator specifying the 
protocol number, protocol version, documents reviewed, and the date on which the committee 
met and granted the approval. 

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All documents subject to review during the study, including any modifications made to the 
protocol after receipt of IRB/IEC approval, must also be submitted to the committee for approval 
prior to implementation. The Investigator must also provide periodic reports as required and 
promptly report important safety information (ie, SAEs) and protocol violations, as appropriate, 
to the IRB/IEC. 
As part of the Investigator’s written application to the IRB/IEC, the Investigator should provide 
the committee with a current copy of the IB. If the IB is updated during the study, the 
Investigator should supply an updated copy to the committee. 
12.3. 
Informed Consent  
The Investigator will fully inform the subject of all pertinent aspects of the study, including the 
approval of the study by the IRB/IEC. Before informed consent may be obtained, the 
Investigator should provide the subject ample time and opportunity to inquire about details of the 
study and to decide whether to participate. 
Prior to a subject’s participation in the study, the IRB/IEC-approved ICF must be signed and 
personally dated by the subject and by the person who conducted the informed consent 
discussion. If a subject is unable to read, an impartial witness will be present during the entire 
informed consent discussion. 
The written ICF and any other written information to be provided to subjects should be revised 
whenever important new information becomes available that may be relevant to the subject’s 
consent. Any revised written ICF or study materials to be available and/or supplied to subjects 
should receive the IRB/IEC’s approval in advance of use. The subject will be informed in a 
timely manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study. The communication of this information should 
be documented. 
12.4. 
Confidentiality  
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is provided from the sponsor. 
Prior to study participation, the Investigator shall inform the subject that the monitor(s), 
auditor(s), IRB/IEC, and the regulatory authorities will be granted direct access to the subject’s 
original medical records for verification of clinical study procedures and/or data, and that, by 
signing a written ICF, the subject is authorizing such access. 
In addition, prior to study participation, the subject must be informed that the records identifying 
the subject will not be made publicly available; if the results of the study are published, the 
subject’s identity will remain confidential. 
12.5. 
Protocol Compliance  
The Investigator/institution will conduct the study in compliance with the protocol agreed to by 
the sponsor and regulatory authorities (if applicable) and that was approved by the IRB/IEC. The 

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Investigator/institution and the sponsor should sign the protocol, or an alternative contract, to 
confirm agreement. 
The Investigator should not implement any deviation from, or changes to, the protocol without 
agreement by the sponsor and prior review and documented approval from the IRB/IEC of an 
amendment, except where necessary to eliminate immediate hazard(s) to study subjects or when 
the change involves only logistical or administrative aspects of the study (eg, change in monitor, 
change of telephone number). 
When an important deviation from the protocol is deemed necessary for an individual subject, 
the Investigator must contact the Clinical Lead for the study. Such contact must be made as soon 
as possible to permit a review by the sponsor to determine the impact of the deviation on the 
subject’s participation and/or the assessment of safety or efficacy in the study. Any significant 
protocol deviations affecting subject eligibility and/or safety must be reported by Investigator or 
site delegate to the IRB/IEC and regulatory authorities, as applicable, prior to implementation. 
The Investigator should document and explain any deviation from the approved protocol. 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE  
Quality assurance and quality control systems shall be implemented and maintained with written 
SOPs to ensure that the study is conducted and data are generated, documented (recorded), and 
reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s). 
Quality control shall be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
An agreement must be secured from all involved parties to ensure direct access to all 
study-related sites, source documents, and reports for the purpose of monitoring and auditing by 
the sponsor and inspection by regulatory authorities. 
13.1. 
Training of Study Site Personnel  
Prior to study activities being initiated at the study site, the sponsor or designee will train study 
site personnel on the protocol and applicable procedures. Training should be documented. 
Note: If new study site personnel are assigned to the study after the initial training, study sites 
should contact the study monitor to coordinate training. Qualified study personnel may conduct 
training, as appropriate. Training of new study personnel should also be documented. 
13.2. 
Monitoring  
Study site monitoring is conducted to ensure the study is progressing as expected, the rights and 
well-being of human subjects are protected, the reported study data are accurate, complete, and 
verifiable, and the conduct of the study is in compliance with the currently approved protocol, 
with GCP and with applicable regulatory requirements. Protocol deviations identified will be 
documented. 
Details of study site monitoring are documented in the study Clinical Monitoring Plan (CMP) or 
similar document. The CMP describes in detail who will conduct the monitoring, at what 
frequency monitoring will be done, at what level of detail monitoring will be performed (eg, 

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targeted and/or risk based), and the distribution of monitoring reports. Monitoring may include a 
study site selection visit, which may be conducted in person or via communication media (eg, 
teleconference, online meeting) or may be waived in accordance with policy and procedures 
being followed for the study, if appropriate. Monitoring will include a study site initiation visit, 
interim monitoring visit(s), and a study site closeout visit. An interim monitoring visit may be 
combined with a closeout visit, if applicable. 
13.3. 
Audit  
An audit of one or more participating study sites may be performed independently of, and 
separately from, routine monitoring to evaluate clinical study conduct and compliance with the 
protocol, SOPs, GCP, and the applicable regulatory requirements. 
14. 
DATA HANDLING AND RECORD KEEPING  
14.1. 
Data Management  
14.1.1. 
Case Report Forms  
An eCRF must be completed for each subject screened/enrolled in this study. These forms will 
be used to transmit information collected during the study to the sponsor and regulatory 
authorities, as applicable. 
The documentation related to the validation of the eCRFs will be maintained in the Trial Master 
File (TMF). The TMF will be maintained by the CRO and the sponsor. 
The Investigator will document subject data in his/her own subject files. These subject files will 
serve as source data for the study. All eCRF data required by this protocol will be recorded by 
study site personnel. All data entered into the eCRF will be supported by source documentation. 
The Investigator or an authorized member of the Investigator’s staff will make any necessary 
corrections to the eCRF. All changed information, including the date and person performing the 
corrections, will be available via the audit trail, which will be part of the electronic data capture 
system. For any correction, a reason for the alteration will be provided. The eCRFs will be 
reviewed periodically for completeness and acceptability by sponsor personnel (or their 
representatives). The sponsor (or their representatives) will also be allowed access to all source 
documents pertinent to the study in order to verify eCRF entries. The Investigator will review the 
eCRFs for completeness and accuracy and provide his or her electronic signature and date to the 
eCRFs as evidence thereof. 
14.1.2. 
Source Documents  
Per regulatory requirements, the Investigator or designee will maintain accurate and up-to-date 
study documentation, including source documentation for each study subject. Source documents 
are defined as original documents, data, and records. These may include, but are not limited to, 
hospital records, clinical and office charts, endoscopy reports, laboratory data/information, 
evaluation checklists, pharmacy dispensing and other records, recorded data from automated 
instruments, ECGs, X-rays, ultrasounds, RHC reports, ECHOs. Data collected during this study 
must be recorded on the appropriate source documents. 

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The Investigator(s)/institution(s) will permit study-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s) and will provide direct access to the source data. 
14.2. 
Study Documentation and Records Retention  
The Investigator and study staff have the responsibility of maintaining a comprehensive and 
centralized filing system containing all study-related documentation. These files must be 
available for inspection by the sponsor, representatives of the sponsor, the IRB/IEC, and 
regulatory authorities (ie, Food and Drug Administration [FDA] or international regulatory 
authorities) at any time, and should consist of the following elements: 
• Subject files: Containing the completed eCRFs (if applicable), supporting source 
documentation including medical records, laboratory data, and signed ICFs. 
• Regulatory files: Containing the protocol with all amendments and Investigator 
signature pages, copies of all other regulatory documentation, all correspondence 
between the study site and the IRB/IEC and sponsor, and drug accountability files, 
including a complete account of the receipt and disposition of the study treatment. 
Records will be available for 2 years after marketing application approval, or if the application is 
not approved or never submitted, 2 years after the last shipment and delivery of the study 
treatment and the appropriate competent regulatory authorities are notified. The sponsor will 
provide written notification when it is appropriate for the Investigator to discard the 
study-specific documents referenced above. 
During the record retention period, the Investigator or designee must inform the sponsor or 
designee (eg, CRO), of the following:  
• Location of study documentation 
• If the custody of documentation will be transferred or moved to another location 
• If the Investigator is unable to retain documentation for the specified period 
14.3. 
Clinical Study Report  
Whether the study is completed or prematurely terminated, a clinical study report will be 
prepared and provided to the regulatory agencies according to applicable regulatory 
requirement(s). 
14.4. 
Disclosure of Study Results  
The sponsor will post the results of the study in a publicly accessible database in accordance with 
the applicable laws and regulations. 
15. 
RESPONSIBILITIES  
15.1. 
Investigator Responsibilities  
The Investigator must comply with this protocol and the conduct of all study procedures. The 
Investigator will disclose to the sponsor sufficient, accurate, financial information to allow the 

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sponsor to submit accurate disclosure statements to the FDA per 21 Code of Federal Regulations 
(CFR) Part 54 (Financial Disclosure by Clinical Investigators) or to other regulatory authorities 
that have similar requirements. The Investigator is responsible for compliance with applicable 
sections of ICH GCP requirements. The investigator may also be responsible for compliance 
with 21 CFR Part 312, Subpart D, (Responsibilities of Investigators) and other, federal, and local 
laws, applicable to conducting drug studies. 
The Investigator is responsible for ensuring an investigation is conducted according to the signed 
Investigator statement, the investigational plan, and applicable regulations; for protecting the 
rights, safety, and welfare of subjects under the Investigator’s care; and for the control of drugs 
under investigation. An Investigator shall, in accordance with the provisions of ICH GCP 
guidelines and/or 21 CFR Part 50, obtain the informed consent of each human subject to whom 
the drug is administered. 
15.2. 
Sponsor Responsibilities  
The sponsor is responsible for compliance with applicable sections of ICH Guideline E6(R2) and 
21 CFR Part 312, Subpart D (Responsibilities of Sponsors). The sponsor is responsible for 
selecting qualified Investigators. Sponsors are also responsible for providing them with the 
information they need to conduct an investigation properly, and ensuring proper monitoring of 
the investigation(s). Sponsors are also responsible for ensuring the investigation(s) is conducted 
in accordance with the general investigational plan and protocols contained in the Investigational 
New Drug (IND) application (or equivalent), maintaining an effective IND (or equivalent) with 
respect to the investigations, and ensuring the FDA (and/or other regulatory authorities as 
applicable), and all participating Investigators are promptly informed of significant new adverse 
effects or risks with respect to the drug. 

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APD418-201 
Safety, Tolerability, PK, PD Study 
 
Amendment 3.0 
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Page 75 of 84 
16. 
REFERENCES  
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Safety, Tolerability, PK, PD Study 
 
Amendment 3.0 
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Coll Cardiol. 2012;59(24):2145-2153.  
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Gauthier C, Langin D, Balligand JL. beta3-Adrenoceptors in the cardiovascular system. Trends 
Pharmacol Sci. 2000;21(11):426-431.  

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Safety, Tolerability, PK, PD Study 
 
Amendment 3.0 
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Gauthier C, Tavernier G, Charpentier F, Langin D, Le Marec H. Functional beta3-adrenoceptor 
in the human heart. J Clin Invest. 1996;98(2):556-562.  
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Gheorghiade M, Vaduganathan M, Fonarow GC, Bonow RO. Rehospitalization for heart failure: 
Problems and perspectives. J Am Coll Cardiol. 2013;61(4):391-403.  
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failure. Rev Port Cardiol. 2019;37(11):935-945.  
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Kelly JP, Mentz RJ, Hasselblad V, et al. Worsening heart failure during hospitalization for acute 
heart failure: Insights from the Acute Study of Clinical Effectiveness of Nesiritide in 
Decompensated Heart Failure (ASCEND-HF). Am Heart J. 2015;170(2):298-305.  
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heart failure. N Engl J Med. 2002;347(18):1397-1402.  
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exercise performance in pacing-induced heart failure. Am J Physiol Heart Circ Physiol. 
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hospitalized with acute heart failure: The global ALARM-HF registry using propensity scoring 
methods. Intensive Care Med. 2011;37(2):290-301.  
Mebazaa A, Yilmaz MB, Levy P, et al. Recommendations on pre-hospital & early hospital 
management of acute heart failure: A consensus paper from the Heart Failure Association of the 
European Society of Cardiology, the European Society of Emergency Medicine and the Society 
of Academic Emergency Medicine. Eur J Heart Fail. 2015;17(6):544-558.  
Mentz RJ, Metra M, Cotter G, et al. Early vs. late worsening heart failure during acute heart 
failure hospitalization: Insights from the PROTECT trial. Eur J Heart Fail. 2015;17(7):697-706.  
Metra M, Teerlink JR. Heart failure. Lancet. 2017;390(10106):1981-1995.  

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Safety, Tolerability, PK, PD Study 
 
Amendment 3.0 
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Moniotte S, Balligand JL. Potential use of beta3-adrenoceptor antagonists in heart failure 
therapy. Cardiovasc Drug Rev. 2002;20(1):19-26.  
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adrenoceptors and altered contractile response to inotropic amines in human failing myocardium. 
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activation contributes to left ventricular and cardiomyocyte dysfunction in heart failure. Am J 
Physiol Heart Circ Physiol. 2004;286(6):H2425-2433.  
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endothelial nitric oxide synthase phosphorylation and force of contraction in human failing 
myocardium. J Card Fail. 2009;15(1):57-67.  
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blockade increases contractility of human ventricular trabeculae from HFrEF donors. European 
Society of Cardiology Congress; August 29-September 1, 2020; Virtual. On file at Arena. 
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with and without use of inotropic therapy in cardiac surgery: Results of a propensity score-
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contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129-
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pathologies. Pharmacol Ther. 2006;111(3):652-673.  

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Safety, Tolerability, PK, PD Study 
 
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Sabbah HN, Zhang K, Xu J, Gupta RC, Adams J. Intravenous infusion of the beta-3 adrenergic 
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Sabbah HNH, Zhang K, Xu J, Gupta RC, Adams J. Acute intravenous infusion of the beta-3 
adrenergic receptor antagonist APD418 improves left ventricular function in dogs with advanced 
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Fundam Clin Pharmacol. 2009;23(5):633-639.  
 

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APD418-201 
Safety, Tolerability, PK, PD Study 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 80 of 84 
APPENDIX 1: 
SCHEDULE OF ASSESSMENTS  
Table 4: 
Study APD418-201 Schedule of Assessments: Part A and Part B 
Study Day 
−21 to 1 
(Part A) 
−14 to 1 
(Part B)a     
Day 1 
Day 2 
Day 9 (± 2) 
Study Period 
Screen 
Predose 
Periodb      
Baselinec 
Dosing Periodd 
Postdose Periode and Dischargef 
Follow-Upg 
Time from Initiation of 
Study Treatment (hours) 
NA 
> −2 
−2 to 0 
0.5 
1 
2 
3 
4 
5 
6h/EEOIi     6.5 
7 
8 
10 
18 
(+ 3 h) 
24 
(+ 6 h) 
NA 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
X 
 
X 
Height and weight 
X 
Xj            
 
 
 
 
 
 
 
 
 
Xj 
 
 
 
Xj 
 
Mealsk                                                 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationl                  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital signsm                                         
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECGn                                     
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
 
ECHOo                                                 
X 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
RHC assessmentsp                         
 
 
 
 
 
 
 
 
Cardiac biomarkersq                     
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
Markers of renal functionr       
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
Urine outputs                                      
 
 
 
X 
 
DNA for genetic testing 
(optional) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Study Protocol 
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Safety, Tolerability, PK, PD Study 
 
Amendment 3.0 
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Confidential 
Page 81 of 84 
Study Day 
−21 to 1 
(Part A) 
−14 to 1 
(Part B)a     
Day 1 
Day 2 
Day 9 (± 2) 
Study Period 
Screen 
Predose 
Periodb      
Baselinec 
Dosing Periodd 
Postdose Periode and Dischargef 
Follow-Upg 
Time from Initiation of 
Study Treatment (hours) 
NA 
> −2 
−2 to 0 
0.5 
1 
2 
3 
4 
5 
6h/EEOIi     6.5 
7 
8 
10 
18 
(+ 3 h) 
24 
(+ 6 h) 
NA 
Hematology, serum 
chemistry, and coagulation 
Xt          
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Inflammation and 
endothelial biomarkers 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Serum pregnancy testu                
Xt 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testu 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
Xt 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Urine drug screenv                         
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Txw             
 
 
 
 
 
 
 
 
 
 
 
PK blood samplex                           
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK urine samplesy                          
 
 
 
 
Adverse events 
X 
 
X 
a Screening period for Part A is up to 21 days prior to (and including) Day 1. Screening period for Part B is up to 14 days prior to (and including) Day 1. 
b Predose assessments are performed on Day 1 prior to RHC insertion (Hours > −2), including certain assessments for confirmation of eligibility. 
c Baseline assessments are performed over at least 2 hours from RHC insertion to start of study treatment administration (Hours −2 to 0), including confirmation of hemodynamic 
eligibility criteria and randomization, followed by all other assessments ending with Baseline hemodynamic parameters measurements. 
d Dosing Period to occur over 6 hours from start to end of IV infusion (Hours 0 to 6). 
e Postdose Period to occur over 18 to 24 hours from end of IV infusion (Hours 6 to 24 [+ 6 hours]). 
f Subjects are discharged at the Investigator's discretion based upon clinical presentation (if the patient’s clinical state allows) and after all scheduled assessments at Hour 24 
(+ 6 hours) have been completed. 
g Follow-Up phone contact to occur on Day 9 (± 2 days) to assess for AEs and any changes to concomitant medications. Site staff will work with Early Termination subjects to 
obtain as much follow-up data as possible.  
h Assessments can occur within 60 minutes of Hour 6, with priority on the RHC assessments occurring as close as possible to 6 hours after start of IV infusion/EOI. The following 
order of assessments should be followed, if possible: 12-lead ECG, ECHO, vital signs, RHC hemodynamic parameter measurements, blood sampling, EOI, urine sampling. 

Clinical Study Protocol 
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Safety, Tolerability, PK, PD Study 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 82 of 84 
i Subjects who discontinue study treatment prior to the end of the full 6-hour IV infusion will immediately, if possible, complete the EEOI assessments followed by all Postdose 
Period/Follow-Up assessments. In such situations, order of assessments specified in footnote “h” can be modified, but the priority should be given to RHC hemodynamic 
parameter measurements, vital signs, and blood sampling occurring as close as possible to EOI.  
j Only weight. The weight collected during the Predose Period will be used to calculate the subject’s dose. 
k Subjects are allowed a light meal 2 hours prior to RHC insertion (at least 4 hours prior to Baseline hemodynamic parameters measurements). Another light meal is provided after 
the 2-hour assessments are completed. After the end of RHC measurements, the meals can be provided per the site’s SOC. 
l Physical examination is performed per the site's SOC at Screening and abbreviated physical examination is performed during the Predose Period. A symptom-based physical
examination is performed prior to Discharge.
m Vital signs include BP, HR, respiratory rate, and temperature. Temperature and respiratory rate are collected only at the following timepoints: Baseline, Hour 6, and Hour 24. 
During RHC assessments, vital signs (BP and HR) are collected within ± 5 minutes of hemodynamic parameter measurements. 
n If applicable, it is recommended to collect ECGs at least 30 minutes after the end of the subject’s most recent meal. 
o ECHO is performed at Screening to confirm eligibility (LVEF ≤ 35%).
p RHC measurements for confirmation of hemodynamic eligibility criteria (CI ≤ 2.5 L/min/m2 and PCWP ≥ 15 mm Hg) are performed at Baseline no less than 1 hour following
RHC insertion. After at least 2-hour stabilization period, Baseline hemodynamic parameters measurements are performed prior to start of study treatment administration. During 
the Dosing and Postdose Periods, hemodynamic parameters measurements are performed at specified timepoints (at 0.5, 1, 2, 3, 4, 5, and 6 hours during Dosing Period, and at 
0.5 and 1 hour during Postdose Period). 
q Cardiac biomarkers include NT-pro-BNP and hs-cTnT. Only cardiac troponin is required at Screening and Predose for eligibility purposes (hs-cTnT, hs-cTnI, cTnT, or cTnI), 
and it is collected and reported locally at Predose and at Screening if required per Section 10.3.5. 
r Renal function assessments include eGFR, BUN, cystatin C, urine protein/creatinine ratio, and urinary sodium excretion. Subjects are encouraged to provide urine sample at 
these timepoints. Only eGFR is required at Screening for eligibility purposes, and may be collected and reported locally if required per Section 10.3.4. 
s Urine output is assessed during prespecified intervals by having the subject empty his/her bladder and capturing the urine volume at indicated timepoints. Any spot urine samples 
collected during the intervals will be accounted for in the total volume for that specific interval. Urine output is assessed during the following intervals in relation to the start of 
the IV infusion: Baseline (within 2 hours prior to study treatment administration), every 2 hours during the IV infusion (at Hours 2, 4, and 6), and during the Postdose Period at 
6 to 10 hours and 10 to 24 hours intervals.  
t Local laboratory assessments may be used for determining eligibility at Screening under certain circumstances; refer to Sections 10.2.8, and 10.2.9 for clinical laboratory
assessments (and serum pregnancy) and urinalysis, respectively. 
u Serum pregnancy test is performed for female subjects of childbearing potential to determine eligibility at Screening. Urine pregnancy test is performed and a negative result is
required to be documented for female subjects of childbearing potential at Day 1 prior to randomization to confirm eligibility. In case of positive urine pregnancy test, serum
pregnancy test should be performed before the subject can be enrolled in the study.
v It is not required to result the urine drug screen prior to randomization. If a urine drug screen cannot be obtained prior to study treatment administration due to the timing of
events as required by subject safety considerations, then it can be obtained after study treatment administration and prior to discharge. 
w Continuous 6-hour IV infusion.
x Blood samples for plasma PK are collected as denoted in the table above. In addition to the timepoints denoted in the table above, blood samples for plasma PK are collected
during the Postdose Period at 6.083, 6.167, 6.25 hours. The collection at Hour 6 should be done within 10 minutes before EOI. 
y Urine samples for PK analysis are collected during the following intervals in relation to the start of the IV infusion: Baseline (within 2 hours prior to study treatment
administration), 0 to 6 hours, 6 to 10 hours, and 10 to 24 hours. 
AE, adverse event; BP, blood pressure; BUN, blood urea nitrogen; CI, cardiac index; DNA, deoxyribonucleic acid; ECHO, echocardiogram; ECG, electrocardiogram; EEOI, early 
end of infusion; eGFR, estimated glomerular filtration rate; EOI, end of infusion; HR, heart rate; hs-cTnT, high-sensitive cardiac troponin T; IV, intravenous; LVEF, left 
ventricular ejection fraction; NA, not applicable; N-pro-BNP, N-terminal pro b-type natriuretic peptide; PK, pharmacokinetic; PCWP, pulmonary capillary wedge pressure; RHC, 
right heart catheterization; SOC, standard of care; Tx, treatment

Clinical Study Protocol 
APD418-201 
Safety, Tolerability, PK, PD Study 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 83 of 84 
APPENDIX 2: 
INVESTIGATOR SIGNATURE  
 
Study 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 number: APD418-201 
 
 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol. 
 
 
 
 
 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
 
Investigator Name and Credentials - Printed 
 
 
 
 
 
 
 
 
Institution Name - Printed 
 
 
 
 
 
 
 
 
 

Clinical Study Protocol
Safcty, Tolerability, PK, PD Study
APD418-201
Amendment 3.0
APPENDIX 3:
COUNTRY-SPECIFIC REQUIREMENTS
SPONSOR SIGNATURE
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to
Study title:
Assessthe Hemodynamic Effects, Safety, Tolerability, and Pharmacokinetics of APD418 in
Subjects with Heart Failure with Reduced Ejection Fraction
Study number:
APD418-201
This document is signed electronically; the electronic signature is the signature of record in
countries and regions that recognize electronic signature. This signature page is provided to meet
signature requirements in countries that do not recognize electronic signature; the hand-written
signature on this page is the signature of record in countries and regions that do not recognize
electronic signature.
, MD, MBA
Sponsor Signature
Date
Arena Pharmaceuticals, Inc.
Confidential
Page 84 of 84
PPD
PPD
PPD
PPD

Name: Clinical Study Protocol: APD418-201 Amendment 3.0
Description: A Phase 2, Multicenter, Randomized, Double‑Blind, Placebo‑Controlle
User Nam
Capacity: 
Meaning: Approval Task
Date: 26-Apr-2022 15:48:26 GMT+0000
PPD
PPD

APD418-Pharmacokinetic NTF, 30 December 2022
Note to File Template Version 1.0, 28Aug2020
Page 1 of 3
Note to File, Addendum
Date:
13 January 2023
To:
TMF
From:
 
Protocol No.:
APD418-201
Subject:
Addendum to APD418-201 NTF to document the status of select post-database 
lock outline plan for pharmacokinetic analyses
Background:
On 25 August 2022, the decision was made to discontinue development of the 
Arena cardiovascular programs, which includes APD418. 
As a result of the immediate termination, the biostatistics aspects related to 
finalizing documents (e.g., statistical analysis plan [SAP]) and other downstream 
activities pertaining to pharmacokinetic analyses were either draft and/or have not 
been established. These tasks would have taken significant time and resources by 
both the Arena and Medpace team to finalize, which was not feasible given the 
accelerated study close-out timeline, including the database lock (DBL) which 
occurred on 24 October 2022. The document here serves as the addendum to 
APD418-201 NTF (approved on 21 October 2022) to outline the plans for select 
post-database lock pharmacokinetic analyses.
Final Status:
Pharmacokinetic (PK) Analysis 
As per draft statistical analysis plan (SAP) v0.3
Final pharmacokinetic analysis completed on Nov 14
Pharmacokinetics-Pharmacodynamics Analysis 
Development has not begun
OATP1B Analysis 
Raw genotyping data received on 25 October 2022
Development has not begun
Deliverables & 
Analyses:
Alternative solutions were utilized to provide post-DBL pharmacokinetic analyses. 
PK parameters were estimated as per stated in SAP (v0.3) by Medpace clinical 
pharmacologists. Following DBL, the raw datasets, both eCRF (EDC) and external 
non-CRF, were made available to Medpace for production of unblinded 
pharmacokinetic outputs. PK TLFs were produced as presented in Appendix I of 
this Note to File, Addendum. Arena utilized this existing report structure in place of 
SAP-based TLFs for the final report. 
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APD418-Pharmacokinetic NTF, 30 December 2022
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Signatures:
 
_____________________
Distribution:
  TMF or applicable document repository
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APD418-Pharmacokinetic NTF, 30 December 2022
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Appendix A – Table of Contents of Pharmacokinetic Analysis Final Report
Figure 14.3.1.1
Plot of Mean (+/-SD) Plasma APD418 Concentrations by Treatment on Linear and 
Semi-log Scale
Figure 14.3.1.2
Plot of Mean (+/-SD) Urine APD418 Concentrations by Treatment on Linear and 
Semi- log Scale
Table 14.2.6.1.1 Listing and Summary of Plasma APD418 Concentrations (ng/mL) by Treatment and 
Timepoint
Table 14.2.6.1.2 Listing and Summary of Urine APD418 Concentrations (ng/mL) by Treatment and 
Timepoint
Table 14.2.6.2.1 Individual Values and Summary of Plasma APD418 Pharmacokinetic Parameters by 
Treatment
Table 14.2.6.2.2 Individual Values and Summary of Urine APD418 Pharmacokinetic Parameters by 
Treatment
Listing 16.2.5.1 Plasma APD418 Concentration-Time Listing
Listing 16.2.5.2 Urine APD418 Concentration-Time Listing
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APD418-201 Biostatistics NTF, Addendum, 13 Jan 2023
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Page 1 of 3
 
 
 
Note to File, Addendum 
 
 
Date: 
13 Jan 2023 
To: 
TMF 
From: 
 
 
Protocol No.: 
APD418-201 
Subject:
Addendum to APD418-201 NTF to document the status of biometrics-related
documents/processes and outline plan for select post-database lock safety and 
efficacy analyses
 
 
 
Background: 
On 25 August 2022, the decision was made to discontinue development of the 
Arena cardiovascular programs, which includes APD418. Enrollment into the 
ongoing clinical trial APD418-201 was terminated and study team activities were 
reprioritized to focus and accelerate study close-out activities. For this study, the 
biostatistics, data management, and statistical programming deliverables and 
activities are outsourced to the clinical research organization (CRO) Medpace. 
 
As a result of the immediate termination, the biostatistics aspects related to 
finalizing documents (e.g., statistical analysis plan [SAP]) and other downstream 
activities are either immature and/or have not been established. These tasks would 
take significant time and resources by both the Arena and Medpace team to finalize, 
which is not feasible given the accelerated study close-out timeline, which includes 
the database lock (DBL) which occurred on 24 October 2022. The original note to 
file (date: 21 October 2022), is amended here to re-number the outputs included in 
the appendix to be ICH consistent for CSR reporting and added Table 14.3.3.6. 
 
Final Status: 
Statistical Analysis Plan 
 
Draft SAP (v0.4) 
 
Statistical Analysis Plan: Table, Listing, and Figure (TLF) Shells 
 
Development has not begun.
 
CDISC Specifications and Datasets (aCRF/SDTM/ADaM) 
 
aCRF (dbCRF; based on protocol amendment v3.0) 
 
SDTM: Specifications and datasets by 18 November 2022 
 
ADaM: Draft specifications (Development not yet begun)
 
Statistical Analysis Plan: Table, Listing, and Figure (TLF) Programming 
 
Development has not begun for output programming 
 
Define.xml 
 
Development has not begun for either SDTM or ADaM Defines 
 
 
 
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Guide (SDTM/ADaM)
Development has not begun for either SDTM or ADaM
Guides
Unblinding
Procedure:
Following completion of the DBL sign-off form, the Medpace project statistician
will circulate the Unblinding form for signature by Arena (Lead Study Statistician,
Head of Biostatistics and Data Management) and by appropriate Medpace team
members. The Medpace project statistician will then present both the signed DBL
and Unblinding forms to the IRT group to document that the unblinded treatment
assignments could be shared with the Biostatistics team for incorporation into the
final database. The signed DBL and Unblinding forms will be included in TMF.
Deliverables &
Analyses:
Since the SAP, CDISC ADaM data development, and statistical programming (e.g.,
dataset level, table level) will not be finalized, alternative solutions are being
utilized to provide post-DBL safety and efficacy analyses.
As outlined in the Study APD418-201 protocol (Section 11.9), a Dose Escalation
Committee is utilized. The Dose Escalation Charter outlines a list of outputs
(presented in Appendix I of this Note to File) produced following each cohort in
Part A of the study. Arena will be utilizing this existing report structure in place of
SAP-based TLFs for the final report.
Following DBL, the raw datasets, both eCRF (EDC) and external non-CRF, will be
made available to Medpace for production of unblinded safety and efficacy outputs
for Part A Cohort 1 (N = 7; reproduction for data completeness) and Part A Cohort
2 (N = 15). A pooled placebo treatment group (Cohort 1 + Cohort 2 will also be
presented in tables and figures).
Signatures:
Distribution:
TMF or applicable document repository
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Appendix A  Table of Contents of Final Report 
Disposition
Table 14.1.1 Subject Disposition 
Listing 16.2.1.1 Disposition
 
Demographics 
Table 14.1.2: Demographics and Baseline Characteristics 
Listing 16.2.4.1 Demographic and Baseline Characteristics 
 
Concomitant Medications 
Listing 16.2.4.2 Concomitant Medications 
 
Medical History 
Listing 16.2.4.3 Medical History 
 
Adverse Events 
Table 14.3.1.1 Overview Summary of Treatment Emergent Adverse Events (TEAE) 
Table 14.3.1.2 Treatment Emergent Adverse Events (TEAE) by System Organ Class and Preferred Term 
Table 14.3.1.3 Serious Treatment Emergent Adverse Events (TEAE) by System Organ Class and Preferred Term 
Table 14.3.1.4 Grade 3 or Higher Treatment Emergent Adverse Events (TEAE) by System Organ Class and Preferred Term 
Table 14.3.1.5 Treatment Emergent Adverse Events (TEAE) Related or Probably Related to Study Drug by System Organ Class and Preferred Term 
Table 14.3.1.6 Cardiovascular-related Treatment Emergent Adverse Events (TEAE) by System Organ Class and Preferred Term 
Table 14.3.1.7 Treatment Emergent Adverse Events (TEAE) leading to Death by System Organ Class and Preferred Term 
Listing 16.2.7.1 Adverse Events 
 
Vital Signs 
Table 14.3.3.1: Summary of Observed and Change from Baseline in Vital Signs  
Figures 14.3.3.1.1-14.3.3.1.6 Plots of Individual Subject Vital Signs 
Listing 16.2.8.5 Vital Signs 
 
Electrocardiograms (ECGs) 
Table 14.3.3.2.1 Summary of Observed and Change from Baseline in 12-Lead Electrocardiogram Intervals  
Table 14.3.3.2.2 Post-Baseline 12-Lead ECG Analyses 
Listing 16.2.8.6 12-Lead Electrocardiogram Intervals 
 
Liver Function and Other Chemistry Measures 
Table 14.3.3.4.1 Summary of Observed and Change from Baseline in Laboratory - Chemistry (Liver Function)  
Table 14.3.3.4.2 Summary of Liver Function Tests 
Figures 14.3.3.4.1.1-14.3.3.4.1.4 Plots of Individual Subject Laboratory values - Chemistry (Liver Function)  
Listing 16.2.8.1 Laboratory values - Chemistry 
 
Renal Function Biomarkers 
Table 14.3.3.5 Summary of Observed and Change from Baseline in Laboratory - Renal Function Biomarkers  
Figures 14.3.3.5.1-14.3.3.5.4 Plots of Individual Subject Laboratory values: Renal Function Biomarkers 
Listing 16.2.8.2 Laboratory values  Renal Function Biomarkers
 
Coagulation 
Table 14.3.3.6 Summary of Observed and Change from Baseline in Laboratory - Coagulation 
Listing 16.2.8.3 Laboratory values  Coagulation 
 
Cardiac Biomarkers 
Table 14.3.3.7 Summary of Observed and Change from Baseline in Laboratory - Cardiac Biomarkers 
Figures 14.3.3.7.1-14.3.3.7.2 Plots of Individual Subject Laboratory values - Cardiac Biomarkers 
Listing 16.2.8.4 Laboratory values  Cardiac Biomarkers 
 
Hemodynamics by RHC 
Figures 14.3.6.1.1-14.3.6.1.10 Plots of Individual Subject Hemodynamics  Right Heart Catheterization (RHC)  
Listing 16.2.6.1 Hemodynamic Parameters by RHC 
 
Hemodynamics by ECHO
Figures 14.3.7.1.1-14.3.7.1.11 Plots of Individual Subject Hemodynamics  ECHO  
Listing 16.2.6.2 Hemodynamic - ECHO 
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