Conditions: Heart Failure
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 29
Healthy volunteers: no

Brief summary:
This study will be a sequential multiple-dose escalation study that will enroll (randomize and dose) approximately 28 subjects in four cohorts consisting of 3 active and 1 placebo in Cohort 1 and 6 active and 2 placebo in subsequent cohorts. Randomized subjects will receive a fixed weekly dose of study drug or placebo for a 4 week dosing period.

Detailed description:
Qualifying subjects will have a diagnosis of NYHA Class II or III heart failure with a reduced ejection fraction (HFrEF), be in stable condition, and be taking clinician-directed appropriate pharmacological therapy (e.g., angiotensin converting enzyme inhibitors, angiotensin receptor blockers or an evidence based beta blocker) for heart failure at stable doses (with the exception of diuretics) for at least 1 month prior to screening.

During the period between screening and randomization (planned first dose), the study subject will remain on stable pharmacological therapy for heart failure. Also the study subject will be in stable health with no hospitalizations or clinically significant acute illnesses between screening and randomization that would put the subject at increased risk for study participation.

Randomized subjects will receive a fixed weekly dose of study drug or placebo for a 4 week dosing period. Dose escalation in subsequent cohorts will continue if the safety and pharmacokinetic profile are deemed acceptable as assessed by the Study Review Committee.

Arms:
arm 1: Four weekly doses of PB1046 Injection, 0.2 mg/kg arm 2: Four weekly doses of PB1046 Injection, 0.4 mg/kg arm 3: Four weekly doses of PB1046 Injection, 0.6 mg/kg arm 4: Four weekly doses of PB1046 Injection, 1.2 mg/kg arm 5: Four weekly doses of Placebo (0.9% NaCl) Injection

Interventions: intervention 1: PB1046 Injection intervention 2: Placebo Injection
Intervention descriptions: intervention 1: Four weekly subcutaneous injections of PB1046. intervention 2: Four weekly subcutaneous injections of placebo.

Protocol document:
Prot_000.pdf: 
This document contains confidential information belonging to PhaseBio Pharmaceuticals, Inc. Except as 
otherwise agreed to in writing, by accepting or reviewing this document, you agree to hold this information in 
confidence and will not copy or disclose the information contained herein to others except where required by 
applicable law, or use it for unauthorized purposes. In the event of any actual or suspected breach of this 
obligation, PhaseBio Pharmaceuticals, Inc. must be promptly notified. 
 
 
 
PhaseBio Pharmaceuticals, Inc. - Confidential 
 
Page 1  
 
F-CL-0003-001.01 
PHASE 2A, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTIPLE-DOSE, 2-
PART STUDY TO ASSESS THE SAFETY, TOLERABILITY AND PHARMACOKINETIC 
RESPONSE AND EXPLORE THE PHARMACODYNAMIC RESPONSE FOLLOWING 4 WEEKS 
OF ONCE WEEKLY SUBCUTANEOUS INJECTIONS OF PB1046 IN ADULT SUBJECTS WITH 
STABLE HEART FAILURE WITH REDUCED EJECTION FRACTION (HFREF) (PART 1) AND IN 
SUBJECTS WITH CARDIAC DYSFUNCTION SECONDARY TO DUCHENNE OR BECKER 
MUSCULAR DYSTROPHY (PART 2) 
Compound: 
 PB1046 (Vasomera) Injection  
US IND Number: 
112,431 
Clinical Protocol Number: 
PB1046-PT-CL-0003-P1 
Phase: 
2a 
Version and Date: 
Version 0, 15 March 2016  
Sponsor: 
 
PhaseBio Pharmaceuticals Inc.  
1 Great Valley Parkway, Suite 30 
Malvern, PA 19355 
Medical Monitor: 
Poul Strange, MD, PhD 
Integrated Medical Development 
Windsor Business Park, Building 3B, 2th Floor  
186 Princeton-Hightstown Road 
Princeton Junction, NJ 08550 
Phone: 609-897-0505 Ext. 113 
 
Clinical Monitoring and Study 
Management: 
PhaseBio Pharmaceuticals Inc. 
1 Great Valley Parkway, Suite 30 
Malvern, PA 19355 
 
Serious Adverse Event Reporting: 
PhaseBio Pharmaceuticals, Inc.  
Phone: 610-981-6507/Mobile: 610-608-8619 
Fax: 1-484-971-5974 
 
Summary of Incorporated Protocol 
Amendments: 
 
Amendment No.  
Effective Date 
NA 
NA 
 




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AGREEMENT OF INVESTIGATOR FORM 
By signing the Agreement of Investigator Form, I the Principal Investigator agree to: 
1. Conduct the study in accordance with the protocol and as subsequently amended by the Sponsor (or 
designee), except when to protect the safety, rights or welfare of subjects; 
2. Conduct the study in accordance with applicable federal, state and local laws and regulations, and in 
accordance with Good Clinical Practice (GCP) standards; 
3. Personally conduct or supervise the study; 
4. Ensure that all associates, colleagues and employees assisting in the conduct of the study are adequately 
trained on the requirements of the protocol and informed about their obligations related to the conduct 
of the clinical study;  
 
5. Delegate only those study tasks to my associates who have appropriate training and experience and 
provide documentation on training and the tasks to be delegated in the study file; 
6. Ensure the investigational drug product is dispensed only to individuals who have signed consent, are 
enrolled in the referenced clinical study, and in accordance with the protocol; 
7. Ensure the requirements relating to obtaining informed consent and IRB review and approval meet 
federal guidelines, as stated in 21 CFR, § 50 and 56; 
8. Report to the Sponsor (or designee) any AEs that occur in the course of the study, in accordance with 
21 CFR § 312.64; 
9. Maintain adequate and accurate records in accordance with 21 CFR § 312.62 and to make those 
records available for inspection with the Sponsor (or designee) or other applicable regulatory 
authorities; 
10. Ensure that an Institutional Review Board (IRB) that complies with the requirements of 21 CFR §56 
will be responsible for initial and continuing review and approval of the clinical study; 
11. Promptly report to the IRB and the Sponsor (or designee) all changes in the research activity and all 
unanticipated problems involving risks to subjects or others (to include amendments and IND safety 
reports); 
12. Seek IRB approval before any changes are made in the research study, except when necessary to 
eliminate hazards to the patients/subjects; 
13. Comply with all other requirements regarding the obligations of clinical investigators and all other 
pertinent requirements listed in 21 CFR § 312. 
Principal Investigator Name: _________________________________ 
 
Site ID: _____ 
Signature/Date: ____________________________________________ 


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ABBREVIATIONS 
 
Abbreviations 
Definitions 
A 
Active 
ACEI 
Angiotensin-converting enzyme inhibitor 
ACS 
Acute Coronary Syndrome 
ADA 
Anti-drug antibodies 
AE 
Adverse Event 
ALT 
Alanine Amino Transferase 
ARB 
Angiotensin-receptor blocker 
AST 
Aspartate Transaminase 
AUC 
Area under the curve 
AUC(0-τ) 
Area under serum concentration-time curve to the last 
time with a concentration ≥ LOQ 
AUC(0-tmax) 
Area under the serum concentration curve concentration-
time profile from 0 to Tmax 
AUC(tmax-τ) 
Area under the curve concentration-time profile from 
Tmax to τ 
BB 
Beta blocker 
BMD 
Becker muscular dystrophy 
BMI 
Body mass index 
BP 
Blood Pressure 
BPM 
BSA 
Beats per minute 
Body surface area 
BUN 
Blood urea nitrogen 
C 
Centigrade 
CBC 
Complete Blood Count 
CCS 
Canadian Cardiovascular Society 
CD 
Compact disk 
CK 
Creatinine kinase 
CK-MB 
Creatinine kinase MB Isoenzyme 
CL/F 
Clearance uncorrected for bioavailability (F) 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 


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ABBREVIATIONS 
 
Abbreviations 
Definitions 
Cmax 
Maximum Serum Concentration 
CLIA 
Clinical Laboratory Improvement Act 
COA 
Certificate of Analysis 
cm 
Centimeter 
cm/s 
Centimeter per second 
CRU 
CT 
Clinical Research Unit 
Computed Tomography 
Da 
Dalton 
DBP 
Diastolic Blood Pressure 
dL 
Deciliter 
DLT 
Dose Limiting Toxicity 
DMD 
Duchenne Muscular Dystrophy 
ECG 
Electrocardiogram 
ECHO 
Echocardiography 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
EF 
Ejection Fraction 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme-linked immunosorbent assay 
ELP 
Elastin-like polypeptide 
ET 
Early Termination 
F 
Bioavailability 
FDA 
Food and Drug Administration 
FPG 
Fasting plasma glucose 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
GPCRs 
G-Protein Coupled Receptors 
HbsAg 
Hepatitis B surface antigen 


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ABBREVIATIONS 
 
Abbreviations 
Definitions 
HCT 
Hematocrit 
HCV 
Hepatitis C virus 
HDL 
HDL-C 
High-density lipoprotein 
High-density lipoprotein cholesterol 
HF 
Heart failure 
HFrEF 
Heart failure with reduced ejection fraction 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HR 
Heart Rate 
hs-cTnT 
High Sensitivity Cardiac Troponin T Assay 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
ICH 
International Conference on Harmonization 
ID 
Identification 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 
LDL 
LDL-C 
Low-density lipoprotein 
Low-density lipoprotein cholesterol 
LOQ 
Lower limit of the assay 
MDRD 
Modification of Diet in Renal Disease  
m 
mg 
Meter 
Milligram 
MI 
Myocardial Infarction 
mL   
Milliliter 
mM 
Millimolar 
MTD 
Maximum Tolerated Dose 


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ABBREVIATIONS 
 
Abbreviations 
Definitions 
ms 
NaCl 
millisecond 
Sodium Chloride 
NT-Pro-BNP 
N-terminal fragment of the prohormone brain natriuretic 
peptide 
NYHA 
New York Heart Association 
OOP 
Out of Protocol 
PB1046 
Vasomera 
P 
Placebo 
PCP 
Phencyclidine 
PD 
Pharmacodynamic 
PIF 
Protocol Inquiry Form 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
PRN 
As needed 
QTcB 
QT interval corrected for heart rate 
QTcF 
QT corrected by Fredericia's formula 
r2 
Coefficient of Determination 
RBC 
Red blood cells 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SC 
SD 
SMBP 
Subcutaneous 
Standard Deviation 
Self-monitored blood pressure 
SRC 
Study Review Committee 
t½ 
Elimination half-life 
TC 
Total cholesterol 
TG 
Triglycerides  
Tmax 
Time to Maximum Concentration 
UA 
Urinalysis 
ULN 
Upper limit of normal 


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ABBREVIATIONS 
 
Abbreviations 
Definitions 
US 
United States 
USP 
United States Pharmacopeia 
USDD 
Unblinded study drug dispenser 
V 
Visit 
VIP 
Vasoactive intestinal peptide 
Vz/F 
Volume of distribution uncorrected for bioavailability (F) 
WBC 
White Blood Cells 
XL-dCMP 
X-Linked Dilated Cardiomyopathy 
λz 
Elimination rate constant 


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PROTOCOL SYNOPSIS 
 
Study Title 
Phase 2a, Randomized, Double-blind, Placebo-controlled, Multiple-dose, 2-Part Study to Assess the 
Safety, Tolerability and Pharmacokinetic Response and Explore the Pharmacodynamic Response 
Following 4 Weeks of Once Weekly Subcutaneous Injections of PB1046 in Adult Subjects with Stable 
Heart Failure with Reduced Ejection Fraction (HFrEF) (Part 1) and in Subjects with Cardiac 
Dysfunction Secondary to Duchenne or Becker Muscular Dystrophy (Part 2) 
Study Number 
Part 1: PB1046-PT-CL-0003-P1 
Study 
Objectives 
Primary objective:  
 
To evaluate the safety and tolerability of escalating doses of PB1046 administered once weekly for 4 
weeks in adult subjects with stable NYHA Class II/III heart failure with a reduced ejection fraction 
(HFrEF). 
 
Secondary objectives:  
• 
Characterize the pharmacokinetic profile of a subcutaneous dose of PB1046  administered once 
weekly for 4 weeks;  
• 
Evaluate the immunogenicity profile of a subcutaneous dose of PB1046 administered once weekly 
for 4 weeks. 
 
Exploratory: 
• 
Characterize the effect of escalating doses of PB1046 on cardiac function as measured by 2-D 
echocardiography with Doppler following 4 weeks of once weekly dosing with PB1046;  
• 
Characterize the effect of PB1046 on cardiac, anti-inflammatory and anti-fibrotic biomarkers. 
 
Study 
Endpoints 
Primary Safety: 
• 
Incidence and severity of AEs and their relationship to study drug; 
• 
Changes from baseline in vital signs, laboratory parameters, telemetry (e.g., occurrence and 
frequency of rhythm abnormalities), and the relationship to PB1046 compared to placebo; and  
• 
Change from baseline in key ECG parameters (QT, QTcB, QTcF, PR, RR and QRS) and presence 
or absence of rhythm abnormalities and relationship to exposure of PB1046 compared to placebo. 
 
Secondary Pharmacokinetic and Immunogenicity:  
• 
Comparison of dose exposures (pharmacokinetic profile) during once weekly administration of 
various doses of PB1046; and 
• 
Incidence of Immunogenicity.   
 
Exploratory:  
• 
Change from baseline in 2-D echocardiographic parameters following 4 weeks of dosing with 
PB1046 compared to placebo; and  
• 
Change from baseline on exploratory cardiac, anti-inflammatory, and anti-fibrotic biomarkers 
following 4 weeks of dosing with PB1046 compared to placebo. 
Study 
Population 
Part 1: Multiple Dose Escalation  
 
Adult male and female subjects 18 years of age and older in stable clinical condition diagnosed with 
chronic New York Heart Association (NYHA) Class II or III stable HFrEF.  
 
 
Study Design 
This study is a randomized, double-blind, placebo-controlled, study that will assess the safety, 
tolerability, pharmacokinetics and explore the pharmacodynamics of PB1046 following 4 weeks of once 


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weekly subcutaneous injections (refer to Figure S1). Part 1 will evaluate 4 escalating dose levels (refer 
to Figure S2).  
 
 
 
Figure S1. Study Schematic 
This study will be conducted in two parts. Part 1 will be a sequential multiple-dose escalation study that 
will enroll (randomize and dose) approximately 28 (3A:1P in Cohort 1 and 6A:2P in subsequent cohorts) 
subjects. Qualifying subjects will have a diagnosis of NYHA Class II or III heart failure with a reduced 
ejection fraction (HFrEF), be in stable condition, and be taking clinician-directed appropriate 
pharmacological therapy (e.g., angiotensin converting enzyme inhibitors, angiotensin receptor blockers or 
an evidence based beta blocker) for heart failure at stable doses (with the exception of diuretics) for at 
least 1 month prior to screening. Randomized subjects will receive a fixed dose of study drug throughout 
the 4 week dosing period (refer to Figure S2).  A starting dose of 0.2 mg/kg is selected based on the safety, 
and minimal to no pharmacodynamic response based on the single dose escalation study [PB1046-PT-CL-
0001].  A single dose of 0.2 mg/kg was well tolerated and showed minimal to no reduction in systolic and 
diastolic seated blood pressure.  Model predicted serum exposures covering the planned dose escalation 
are described in Figure S3 and T1 and are well below nonclinical exposure achieved in the 4 week repeat 
dose toxicology studies and do not exceed the maximum serum concentration  observed in subjects 
receiving a 30 minute intravenous infusion of PB1046 [PB0146-PT-CL-0002].  
 
 
Figure S2. Dose Escalation  
 


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Figure S3. Model-Predicted Serum 
Concentrations Following Once 
Weekly Subcutaneous 
administration 
 
 
 
Figure T1. Model-Predicted Pharmacokinetic 
Parameters Following Once Weekly 
Subcutaneous administration 
 
Dose escalation will continue if the safety and pharmacokinetic profile are deemed acceptable as assessed 
by the Medical Monitor, Study Investigators, Clinical/Regulatory, a representative from Preclinical/Assay 
Development, and a Pharmacokineticist (i.e., the Study Review Committee [SRC]).  The SRC may also 
recommend de-escalation or study discontinuation.  All decisions and outcomes related to SRC meetings 
will be documented and retained as part of the study file. Requested changes (not previously described) to 
the protocol will be submitted to the Food and Drug Administration (FDA) and to the Institutional Review 
Board (IRB) prior to implementation as appropriate.   
 
Dose Escalation and Stopping Rules 
• 
More than one subject may be dosed in a 24 hour period up to and including 0.8 mg/kg, which was 
the maximum dose utilized in the PB1046-PT-CL-0001 study. If dosing exceeds 0.8 mg/kg, no 
more than one subject will be dosed in a 24 hour period for the first four subjects dosed in a cohort. 
• 
At least 75% of subjects assigned to a cohort must receive at least three weekly doses (e.g., at steady 
state) with no reported dose limiting toxicities (DLTs) before escalation to the next higher dose 
level.   
• 
For a dose cohort exceeding 0.8 mg/kg, for which there is no available subcutaneous 
pharmacokinetic (PK) data, PK data through Day 31 (10 days following the last dose) will be 
required to be assessed, in addition to safety data, prior to escalating to a higher dose. 
• 
DLTs identified during the study will be assessed as potential indicators of cumulative toxicity and 
provide rationale for revision of the maximum tolerated dose (MTD).   
• 
Multiple dose escalation will continue until modelling of the PK data indicates that the human AUC 
(0-168 hours) would exceed currently available nonclinical exposure and/or previous human 
exposure (PB1046-PT-CL-0001 [SC] or -0002 [IV]), whichever is higher. 
• 
If a subject in a cohort experiences a DLT that is evaluated by the Investigator as related to study 
drug (PB1046), an additional four subjects (3A and 1P) will be dosed at that dose level.  If two or 
more subjects in a cohort experience a DLT related to PB1046, the MTD will be considered 
exceeded.  The dosing schema may be revised to dose additional subjects below this level to further 
refine the MTD. 
• 
The decision to temporarily hold or discontinue a subject from study treatment will be based on 
Investigator discretion regarding reported adverse events or other factors, which may include 
clinically significant reduction in blood pressure (i.e., hypotension). 
• 
Aggregate assessment of adverse events with specific emphasis on cardiac related events will be 
assessed on an ongoing basis and will be evaluated for trends related to dose escalation and will be 
reviewed at each Study Review Committee (SRC) meeting.  
• 
A study subject will be discontinued from study treatment if there is evidence of increased 
arrhythmia potential or marked prolongation (e.g., QT/QTc > 500 ms or > 60 ms over baseline) of 
the QT/QTc interval while on treatment.  


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• 
Aggregate evaluation of the risk for arrhythmias or QT/QTc prolongation will be evaluated for 
trends on an ongoing basis and will reviewed at each Study Review Committee (SRC) meeting. 
 
Study Registration 
Upon signing consent, a subject will be registered (status of screened) in the study. Subjects qualifying for 
participation will be registered (status update) in the study and will be assigned to the next available dosing 
slot.  No subject may participate (receive study drug) in more than one dose cohort.   
 
Run-in/Stabilization Period:  
During the period between screening and randomization (planned first dose), the study subject will remain 
on stable pharmacological therapy for heart failure. Stable therapy is defined as no change in dose or the 
addition or removal of a therapy with the exception of diuretic dosage. Also the study subject will be in 
stable health with no hospitalizations or clinically significant acute illnesses between screening and 
randomization that would put the subject at increased risk for study participation. 
 
Randomization  
Subjects will be randomly assigned via a central randomization system to receive either PB1046 or 
placebo (3:1). Only the study statistician, pharmacokineticist, and the unblinded study drug dispenser 
(USDD) at the study site will have access to the randomization assignment after enrollment in a cohort 
has been completed.   
   
Activities related to the conduct of Part 2 of the study will be reviewed and approved under a separate 
Part 2 protocol PB1046-PT-CL-0002-P2. 
 
Description of 
Study Drug, 
Dosage, and 
Storage 
Active:  Vasomera (PB1046) is a nearly isotonic sterile clear colorless to slight yellow liquid in a 2 mL 
clear glass vial (approximate fill volume 0.5 ± 0.1 mL) at a concentration of 40 mg/mL.  Vials will be 
stored long term at ≤ -70°C.  Short term storage at -20°C (± 10°C) or refrigerated (2 - 8°C) temperatures 
may be permitted based on ongoing stability analysis. Refer to Certificate of Analysis (COA) for additional 
drug storage stability information. 
Placebo: Commercially available 0.9% sodium chloride (NaCl) USP (10 mL single use vials) for injection 
is a sterile, clear, colorless liquid, that is similar in appearance to active study drug. 
 
Although the active compound and placebo are similar in appearance, the study drug will be prepared and 
administered by a member of the study team not otherwise involved in the evaluation of efficacy or safety.   
Study Centers 
Up to four (4) investigational sites in the United States (US) will participate in Part 1 of the study.  
Main Inclusion 
Criteria 
Subjects will be eligible for inclusion in the study if they meet all of the following criteria at screening 
and up to the time of randomization as indicated: 
 
1. Willing and able to sign a written informed consent and follow all study-related 
procedures; 
2. Male or female subject ≥ 18 years of age; 
3. Male subjects and female subjects of reproductive or childbearing potential must practice 
effective contraception during the study and be willing and able to continue contraception 
for 30 days after their last dose of study drug. Female subjects of non-childbearing 
potential are defined as being surgically sterile by bilateral tubal ligation, bilateral 
oophorectomy, or hysterectomy.  A female subject 45 to 60 years of age, inclusive who is 
post-menopausal for at least 1 year and has a follicle-stimulating hormone level 
confirmation indicating post-menopausal status will be considered of non-childbearing 
potential.  Female subjects > 60 years of age are considered post-menopausal and of non-
childbearing potential;  
4. Body mass index ≥ 18 kg/m2 and ≤ 45 kg/m2; 


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5. Receipt of stable (no change in dose (except diuretics) or addition or removal of a therapy) 
pharmacological therapy(ies) for heart failure for a minimum of 1 month (30 days) prior to 
screening and between screening and randomization and are in stable clinical condition; 
6. NYHA Class II or III heart failure diagnosis (ischemic or non-ischemic confirmed by 
medical history) at least (≥) 6 months (180 days) prior to screening;  
7. Stable HF defined as no hospitalizations for cardiac related issues within the previous 3  
months (90 days) prior to the screening visit or between screening and randomization; 
8. A screening Left Ventricular Ejection Fraction ≤ 40% by centralized reading of 2-D 
echocardiography.  
9. Screening hemoglobin ≥ 9.0g/dL secondary to the volume of blood to be collected during 
the study period. 
10. Willing and able to return to the study unit for specified study visits, and be able to self-
monitor blood pressure while at home. 
11. Live and work in an area with reliable cellular services (e.g., Sprint®) for real time 
transmission of telemetry data to the core laboratory. 
 
 
Main Exclusion 
Criteria 
Subjects will be excluded from the study if they meet any of the following criteria up to the time of 
randomization: 
 
1. Have previously received PB1046 or have a known allergy to the study drug or any of its 
components; 
2. Participating in any other study and have received any other investigational medication or 
device within 30 days prior to screening or are taking part in a non-medication study which, in 
the opinion of the Investigator, would interfere with study compliance or outcome assessments; 
3. Diagnosed with acute coronary syndrome (ACS) or an acute myocardial infarction (MI) within 
3 months (90 days) of screening;  
4. Canadian Cardiovascular Society (CCS) Class III or IV angina necessitating frequent use of as 
needed short acting nitroglycerin (e.g., sublingual); 
5. Cardiac surgery or valvuloplasty within 3 months (90 days) prior to screening; 
6. Cerebrovascular accident or transient ischemic attack within 3 months (90 days) prior to 
screening; 
7. Sustained systolic blood pressure (SBP) < 100 mmHg and/or diastolic blood pressure (DBP) < 
50 mmHg (confirmed by a duplicate seated reading) on at least 3 consecutive readings (self-
monitored or office) prior to randomization or overt symptomatic hypotension; 
8. Sustained resting heart rate >100 beats per minute (BPM) at screening (V1) or  prior to 
randomization (confirmed on baseline telemetry monitoring); 
9. History or evidence (documented on baseline telemetry monitoring) of clinically significant 
arrhythmias (uncontrolled by drug therapy or use of an implantable defibrillator), long QT 
syndrome or evidence of QT prolongation demonstrating QTcF > 460 ms (by ECG) prior to 
randomization;  
10. Clinically significant renal dysfunction as measured by the estimated glomerular filtration rate 
(eGFR) of < 40 mL/min/1.73m2 as calculated by the CKD-EPI creatinine-cystatin C equation: 
eGFR = 135 x min (Scr/k, 1)-a × max(Scr/k, 1)-0.601 × min(Scys/0.8, 1)-0.375 × max(Scys/0.8, 1)-
0.711 × 0.995age [× 0.969 if female ] [× 1.08 if black ] at screening, or a clinically significant 
change in renal function between screening and baseline; 
11. Clinically significant liver dysfunction as measured by: alanine aminotransferase >3.0 × the 
upper limit of normal (ULN), aspartate aminotransferase >3.0 × the ULN, or serum bilirubin ≥ 
1.6 mg/dL at screening, or a clinically significant change in liver function between screening 
and baseline; 
12. Pregnant or lactating female subjects; 


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13. Known history of or active alcohol abuse or use of illicit drugs within 1 year prior to 
randomization;  
14. Positive screening for human immunodeficiency virus antibodies, hepatitis B surface antigen, 
or hepatitis C virus antibodies; 
15. Any major surgical procedure within 1 month (30 days) prior to screening or planned surgical 
procedure during the study period;  
16. Other medical or psychiatric condition which, in the opinion of the Investigator, would place 
the subject at increased risk or would preclude obtaining voluntary consent/assent or would 
confound the secondary objectives of study.  


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Statistical 
Analysis 
Sample Size  
The sample size is not driven by inferential statistics. For sequential dose escalation, the sample size for 
each dose group is set for qualitative investigation of toxicity for which a minimal sample size of 4 (3 
active/1 placebo) is adequate at a dose that is considered non-effective, and 6 active/2 placebo for 
subsequent cohorts. An addition of 4 (3 active and 1 placebo) treated subjects may be dosed in case of 
potential PB1046 dose limiting toxicity or as otherwise deemed necessary by the Study Review Committee 
(SRC).  
 
Analysis Population 
The Safety and Intent-to-Treat (ITT) population will be the same and defined as all subjects who receive 
at least one dose of the study drug.  The Per-Protocol (PP) population will be a subset of the ITT population 
excluding subjects who have any major protocol violations. The pharmacokinetic analysis population will 
consist of all subjects that are dosed with active study drug and have sufficient data for pharmacokinetic 
analysis.  
 
Safety  
All safety parameters/data will be analyzed descriptively by the subject and by dose. Safety will be 
evaluated by analyses of the incidence and severity of treatment emergent adverse events, and change 
from baseline in vital signs, telemetry monitoring (e.g., rhythm abnormalities), and safety laboratory 
parameters. Safety parameters will be presented descriptively by treatment group.  Additionally, analysis 
of central tendency and categorical analysis of QT/QTc interval data will be assessed from 12 lead ECGs 
and relationship to exposure of PB1046 will be evaluated. 
 
Other: Pharmacokinetics 
Pharmacokinetic parameters for PB1046 will be calculated after the first and last doses using non 
compartmental analysis.  Only serum concentrations equal to or greater than the qualified lower limit of 
the assay (LOQ) will be used in the pharmacokinetic analysis. The following parameters will be 
evaluated:  
• 
Area under the curve over the dosing interval  [AUC(0-τ)] 
• 
Area under the curve concentration-time profile from 0 to Tmax [AUC(0-tmax)] and from Tmax to 
τ [AUC(tmax-τ)] 
• 
Maximum serum concentration (Cmax) 
• 
Time to Cmax (Tmax) 
• 
Elimination rate constant (λz)  
• 
Elimination half-life (t½) 
• 
Clearance (CL/F), uncorrected for bioavailability 
• 
Volume of Distribution (Vz/F), uncorrected for bioavailability (F) 
 
The parameters λz, t½, CL/F, and Vz/F will be calculated only for the last dose. 
 
Compartmental modeling will be done using all of the data from the first through the fourth dose (or last 
dose).  Additional analyses will be conducted as directed by the data.  
  
Other: Immunogenicity 
Serum samples will be screened for the presence of binding anti-drug antibodies (ADA) on an ongoing 
basis and will be available at the time of the periodic safety review meetings.  Samples found to be positive 
and specific for ADA will be further characterized to determine domain specificity including evaluating 
if the antibodies cross react with endogenous VIP.  Samples testing positive and specific will be titered 
and further evaluated to determine if the antibodies are capable of neutralizing the response in a cell based 
assay.   
 
Exploratory Endpoints 
All data will be analyzed descriptively by subject dose group. Inferential statistics may be utilized if 
driven by the data. 


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Study Duration 
Total anticipated study duration from initiation of screening to the last subject’s last visit in Part 1 will 
be approximately 8-12 months.  
Study 
Oversight 
 
Study Review Committee 
The Study Review Committee (SRC) will review data relating to safety, PK and hemodynamic response 
after 75% of the subjects in a cohort have completed their 3rd dose and have been followed for minimum 
of seven (7) days after the 3rd dose prior to dose escalation.  The committee will include the Principal 
Investigators, the Medical Monitor, Clinical/Regulatory Representative (Sponsor), Preclinical/Assay 
Development Representative (Sponsor), and Pharmacokineticist.  The SRC will review the interim safety 
summaries prepared by the Clinical Representative from safety data entered into the EDC system, safety 
laboratory data, and pharmacokinetic and immunogenicity (binding ADA) provided by PhaseBio’s Assay 
Development Department.  The data will be reviewed in a blinded manner and must be deemed acceptable 
to the SRC prior to dosing of the next higher single dose group.   Additionally, the SRC may recommend 
additional ECG evaluations or a change in timing of evaluations or additional assessments by holtor 
monitoring based on the PK profile to further elucidate the relationship of the exposure to PB1046 and the 
QT/QTc interval.  
 
In the case of a Dose Limiting Toxicity (DLT), Serious Adverse Event (SAE), or other significant AE, the 
SRC may request that the study drug assignment be unblinded. Following review of the interim safety 
summary, the SRC will decide if dose escalation should continue, recommend de-escalation, or 
recommend study discontinuation.  Provisional SRC recommendations not previously described in the 
protocol, or any recommendations to discontinue the study will be promptly reported to the IRB and the 
Food and Drug Administration (FDA).   
 
The SRC may recommend evaluation of up to two dose levels to carry forward to Part 2 of the study 
(PB1046-PT-CL-0003-P2).  Activities related to Part 2 of the study will be reviewed and approved under 
a separate protocol PB1046-PT-CL-0002-P2.  


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SCHEDULE OF ACTIVITIES 
Week/Description 
 
Screen 
 
Week -1  
 
Week 1/ 
Dose 1 
Week 1/ 
Daily 
Visits 
Week 2/ 
Dose 2 
Week 3/ 
Dose 3 
Week 4/ 
Dose 4 
Week 4/ 
 Daily Visits 
Week 5/ 
 Daily Visits 
Week 8/  
Safety 
Week 12/ 
Immuno-
genicity 
 Visit Number 
 V1 
 V2 
V3 
 V4-V7 
V8 
 V9 
 V10 
 V11-V14 
 V15-18 
V19 or ET 
 V20 
Study Day 
-60 
-7  
(-10 to -7) 
0 
1, 2, 3 
and 5 
7 
14 
21 
22, 23, 24 and 
26 
28, 29, 30, and  
31 
49 ± 3 days 
77 
 ± 3 days 
Test  
Protocol Reference 
ml/ 
test 
Number of  Tests 
Adverse Events 
Refer to Section:10.1  
 
 
1 
1 
4 
1 
1 
1 
4 
4 
1 
 
Concomitant 
Medications  
Refer to Section:6.3  
 
1 
1 
1 
4 
1 
1 
1 
4 
4 
1 
 
Consent 
Refer to Section 5.1 
 
1 
 
 
 
 
 
 
 
 
 
 
Demographics 
Refer to Section 5.2 
 
1 
 
 
 
 
 
 
 
 
 
 
Directed Physical 
Examination  
Refer to Section 5.6 
 
 
As needed only for Evaluation of Adverse Events 
Dosing (in office) 
Refer to Section 8.5.2 
 
 
 
1 
 
1 
1 
1 
 
 
 
 
Dose Preparation 
(USDD) 
Refer to Section 8.5.1  
 
 
 
1 
 
1k 
1k 
1k 
 
 
 
 
Echocardiography - 
2D with Doppler 
Refer to Section 5.12 
 
1g 
1b,d 
 
 
 
 
 
1i 
 
 
 
Electrocardiogram 
12- lead (triplicate) 
Refer to Section 5.10 
 
1 
 
1b 
3o,n 
1b 
1b 
1b 
3o,n 
1h 
1 
 
Height/Weight/BMI 
Refer to Section 5.7 
 
1 
 
 
 
 
 
 
 
 
1 
 
Blood 
Volume


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Week/Description 
 
Screen 
 
Week -1  
 
Week 1/ 
Dose 1 
Week 1/ 
Daily 
Visits 
Week 2/ 
Dose 2 
Week 3/ 
Dose 3 
Week 4/ 
Dose 4 
Week 4/ 
 Daily Visits 
Week 5/ 
 Daily Visits 
Week 8/  
Safety 
Week 12/ 
Immuno-
genicity 
 Visit Number 
 V1 
 V2 
V3 
 V4-V7 
V8 
 V9 
 V10 
 V11-V14 
 V15-18 
V19 or ET 
 V20 
Study Day 
-60 
-7  
(-10 to -7) 
0 
1, 2, 3 
and 5 
7 
14 
21 
22, 23, 24 and 
26 
28, 29, 30, and  
31 
49 ± 3 days 
77 
 ± 3 days 
Test  
Protocol Reference 
ml/ 
test 
Number of  Tests 
Histories – Medical, 
Targeted Medical, 
Surgical, Social and 
Medications 
Refer to Section 5.3 
 
1 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Refer to Sections 4, 
6.1, 6.2, 5.13.4.4, and 
5.10.3 
 
1 
1 
1b 
 
 
 
 
 
 
 
 
Injection Site 
Assessment 
Refer to section 5.9 
 
 
 
1a 
4f 
1b 
1b 
1b 
4f 
4f 
1 
 
LAB – Alcohol and 
drug screen (urine)q 
Refer to Section 
5.13.4.2 
NA 
1 
1 
1b 
 
1b 
1b 
1b 
 
 
 
 
LAB - NT-proBNP  
and hs-cTnT 
Refer to Sections 
5.13.4.6 and 5.13.4.7 
4.0 
 
 
1b 
3o 
1b 
1b 
1b 
1i 
1h 
1 
 
LAB - Exploratory 
Biomarkers: 
microRNA 
Refer to Section 
5.13.7 
2.5 
 
 
1b 
3o 
1b 
1b 
1b 
1i 
1h 
1 
 
LAB- Exploratory 
Biomarkers:Other 
Refer to Section 
5.13.7 
8 
 
 
1b 
3o 
1b 
1b 
1b 
1i 
1h 
1 
 
Blood 
Volume


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Protocol PB1046-PT-CL-0003-P1 
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Week/Description 
 
Screen 
 
Week -1  
 
Week 1/ 
Dose 1 
Week 1/ 
Daily 
Visits 
Week 2/ 
Dose 2 
Week 3/ 
Dose 3 
Week 4/ 
Dose 4 
Week 4/ 
 Daily Visits 
Week 5/ 
 Daily Visits 
Week 8/  
Safety 
Week 12/ 
Immuno-
genicity 
 Visit Number 
 V1 
 V2 
V3 
 V4-V7 
V8 
 V9 
 V10 
 V11-V14 
 V15-18 
V19 or ET 
 V20 
Study Day 
-60 
-7  
(-10 to -7) 
0 
1, 2, 3 
and 5 
7 
14 
21 
22, 23, 24 and 
26 
28, 29, 30, and  
31 
49 ± 3 days 
77 
 ± 3 days 
Test  
Protocol Reference 
ml/ 
test 
Number of  Tests 
LAB - 
Immunogenicity  
Refer to Section 
5.13.5  
3.5 
 
 
1b,s 
 
1b 
1b 
1b 
 
1h 
1 
1 
LAB – Lipids/FPG  
Refer to Sections 
5.13.4.5 and 5.13.4.8 
9 
1p 
1p 
 
 
 
 
 
 
 
1 
 
LAB - 
Pharmacokinetics  
Refer to Section 
5.13.6 
3.5 
 
 
4b,e 
4o,n 
1b 
1b 
4b,e 
4o, n 
4f 
 
 
LAB - Safety Labs 
(Hematology, 
chemistry UA, eGFR 
calculation) 
Refer to Sections 
5.13.4.8 and 5.13.4.9 
12 
1 
1 
 
 
1b 
1b 
1b 
 
1h 
1 
 
LAB - Serology  
(HIV, HepB and Hep 
C) 
Refer to Section 
5.13.4.1 
4 
1 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing 
(females of CBP) 
Refer to 5.13.4.3  
NA 
1 
1 
1q,b 
 
1b 
1b 
1b 
 
 
 
 
Physical 
Examination 
Refer to Section  5.4 
 
1 
 
1b,j 
 
 
 
 
 
 
1 
 
Registration 
Refer to Section 3.2 
 
 
1 
 
 
 
 
 
 
 
 
 
Blood 
Volume


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Protocol PB1046-PT-CL-0003-P1 
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Week/Description 
 
Screen 
 
Week -1  
 
Week 1/ 
Dose 1 
Week 1/ 
Daily 
Visits 
Week 2/ 
Dose 2 
Week 3/ 
Dose 3 
Week 4/ 
Dose 4 
Week 4/ 
 Daily Visits 
Week 5/ 
 Daily Visits 
Week 8/  
Safety 
Week 12/ 
Immuno-
genicity 
 Visit Number 
 V1 
 V2 
V3 
 V4-V7 
V8 
 V9 
 V10 
 V11-V14 
 V15-18 
V19 or ET 
 V20 
Study Day 
-60 
-7  
(-10 to -7) 
0 
1, 2, 3 
and 5 
7 
14 
21 
22, 23, 24 and 
26 
28, 29, 30, and  
31 
49 ± 3 days 
77 
 ± 3 days 
Test  
Protocol Reference 
ml/ 
test 
Number of  Tests 
Randomization 
Refer to Section 
8.13.4 
 
 
 
1 
 
 
 
 
 
 
 
 
SMBPm 
Refer to Section 6.6 
 
 
 
 
 
Telemetry - mobilel 
Refer to Section 5.11 
 
 
 
 
 
Telephone contactr 
Refer to section 5.5 
 
 
 
1 
 
1 
1 
1 
 
 
 
 
Vital Signs – 
Orthostatic 
Refer to Section 5.8.1 
 
1 
 
1b 
4f 
1b 
1b 
1b 
4f 
4f 
1 
 
Vital Signs  - Seated 
Refer to Section 5.8.2 
 
1 
 
3b,a 
4f 
1b 
1b 
1b,a 
4f 
4f 
1 
 
Weight  
Refer to Section 5.7 
 
 
 
1b 
 
1b 
1b 
1b 
 
 
1b 
 
Total Blood Volume 
365 mL 
 
25 
21 
35.5 
57.5 
33.5 
33.5 
44 
28.5 
44 
39 
3.5 
 
a 
1 and 6 hours post dose (± 15 minutes) 
b 
Prior to dosing 
c 
Day 22, 24 and 26 
d 
Can occur up to 2 weeks (14 days) prior to scheduled randomization but should be done before placement of the mobile telemetry device. 
e 
1, 3 and 6 hours (± 10 minutes) 
f 
Daily ± 2 hours from previous dose time.  
g 
If an historical (routine care) echo was within 60 days prior to screening and EF ≤ 40%, the screening echo will not need to be repeated. However, the baseline echo must be done between Day -14 and 
Day -7 to confirm final study eligibility by central reader.  
h 
Day 28 only (± 1 hour after last dose) 
i 
Day 24 only ± 1 day (collect biomarker and echo on the same days) 
j 
Abbreviated physical examination  
k 
± 2 hours from time of day of previously weekly dose 
l 
Continuous monitoring from approximately 7 days prior to dosing (baseline) through 7 days after the last dose of study drug. 
Blood 
Volume


PB1046 (Vasomera) Injection  
Protocol PB1046-PT-CL-0003-P1 
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m 
Omron Blood Pressure Monitor with ComFit™ Cuff (Model BP785N) for use of self-monitoring of blood pressure at home starting approximately 7 days prior to randomization.  Subjects will be required 
to collect blood pressure and heart rate using the same arm every morning and every evening. 
n 
120 hours (± 2 hours) after last dose from previous dose time. 
o 
Completed at 24, 48, and 72 hours (± 1 hour) after last dose. When PK and ECG are required at a given time point, the PK should be done prior to the ECG and the two procedures should be done no more 
than 30 minutes apart. 
p 
Only performed/analyzed at screening if subject was fasting for at least 8 hours otherwise they will only be reported at Visit 2 when subject was instructed to fast prior to visit. 
q 
r 
Local testing only. 
Should occur in evening (suggested time between 7 and 10 PM). 
s 
Collect 2 x 3.5mL tubes at baseline. 


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Protocol PB1046-PT-CL-0003-P1 
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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ..............................................................................................2 
AGREEMENT OF INVESTIGATOR FORM ..........................................................................3 
ABBREVIATIONS ...................................................................................................................4 
PROTOCOL SYNOPSIS ..........................................................................................................9 
SCHEDULE OF ACTIVITIES................................................................................................17 
1  INTRODUCTION ................................................................................................................27 
1.1 Background Information ..................................................................................................27 
1.2 Summary of Human Data ................................................................................................28 
1.3 Risk / Benefit Assessment ...............................................................................................29 
1.4 Justification of Starting Dose, Duration of Treatment Exposure and Dose Escalation ...29 
2  STUDY OBJECTIVES AND ENDPOINTS .......................................................................30 
2.1 Objectives ........................................................................................................................30 
2.1.1 Primary Objective ......................................................................................................30 
2.1.2 Secondary Objectives .................................................................................................30 
2.1.3 Exploratory .................................................................................................................30 
2.2 Criteria for Evaluation .....................................................................................................30 
2.2.1 Safety Endpoints ........................................................................................................30 
2.2.2 Other Endpoints ..........................................................................................................31 
2.2.2.1 Pharmacokinetic and Immunogenicity .................................................................31 
2.2.2.2 Exploratory ...........................................................................................................31 
3  STUDY DESIGN .................................................................................................................31 
3.1 General Description .........................................................................................................31 
3.2 Study Registration ...........................................................................................................32 
3.3 Run-in/Stabilization Period .............................................................................................32 
3.4 Randomization .................................................................................................................32 
3.5 Planned Dose Escalation..................................................................................................33 
3.5.1 Dose Escalation Rules ................................................................................................33 
3.6 Safety Oversight ..............................................................................................................34 
3.6.1 Study Review Committee ..........................................................................................34 
3.6.2 Investigator .................................................................................................................35 
3.6.3 Definitions ..................................................................................................................35 
3.6.3.1 Dose Limiting Toxicity (DLT) .............................................................................35 
3.6.3.2 Maximum Tolerated Dose (MTD) ........................................................................36 
4  SUBJECT SELECTION ......................................................................................................37 
4.1 Inclusion Criteria .............................................................................................................37 
4.2 Exclusion Criteria ............................................................................................................38 
5  DESCRIPTION OF STUDY PROCEDURES ....................................................................39 


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5.1 Informed Consent ............................................................................................................39 
5.2 Demographics ..................................................................................................................39 
5.3 Histories ...........................................................................................................................40 
5.3.1 General Medical/Surgical and Social History ............................................................40 
5.3.2 Targeted Medical History ..........................................................................................40 
5.3.3 Medications ................................................................................................................40 
5.4 Physical Examination ......................................................................................................40 
5.5 Telephone Contact ...........................................................................................................40 
5.6 Directed Physical Exam ..................................................................................................41 
5.7 Height/Weight and Calculation of BMI and BSA ...........................................................41 
5.8 Vital Signs - General .......................................................................................................41 
5.8.1 Orthostatic Blood Pressure .........................................................................................41 
5.8.2 Seated Blood Pressure ................................................................................................42 
5.9 Injection Site Assessment ................................................................................................42 
5.10 12 Lead Electrocardiogram ...........................................................................................42 
5.10.1 Subject Preparation Procedure .................................................................................42 
5.10.2 ECG Measurement and Printouts .............................................................................43 
5.10.2.1 Electrode Placement............................................................................................43 
5.10.3 Verification of Qualifying QTcF at Randomization ................................................44 
5.11 Remote 24/7 Mobile Telemetry Monitoring .................................................................44 
5.11.1 Device ......................................................................................................................44 
5.11.2 Notifications and Reporting .....................................................................................45 
5.11.2.1 Notifications ........................................................................................................45 
5.11.2.2 Reporting ............................................................................................................45 
5.12 2-D Echocardiography with Doppler ............................................................................46 
5.12.1 System Requirements ...............................................................................................47 
5.13 Laboratory Testing.........................................................................................................47 
5.13.1 Testing Facilities ......................................................................................................47 
5.13.2 Blood Volumes ........................................................................................................47 
5.13.3 Sample Identification and Sample Banking .............................................................48 
5.13.4 Screening and Safety Laboratory Testing ................................................................48 
5.13.4.1 Serology for HIV, Hepatitis B, and Hepatitis C .................................................48 
5.13.4.2 Drug and Alcohol Testing ...................................................................................48 
5.13.4.3 Pregnancy Test ....................................................................................................48 
5.13.4.4 Follicle-Stimulating Hormone Level ..................................................................49 
5.13.4.5 Lipid Profile ........................................................................................................49 
5.13.4.6 N-terminal Pro-B Type Natriuretic Peptide (NT-ProBNP) ................................49 
5.13.4.7 High Sensitivity Cardiac Troponin T Assay (hs-cTnT) ......................................49 


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5.13.4.8 Routine Safety Laboratory Testing .....................................................................49 
5.13.4.9 Calculation of Estimated Glomerular Filtration Rate .........................................50 
5.13.5 Immunogenicity (Antibody) Testing........................................................................51 
5.13.6 Pharmacokinetic Testing ..........................................................................................51 
5.13.7 Exploratory Biomarkers ...........................................................................................51 
6  STUDY GUIDELINES ........................................................................................................53 
6.1 New York Heart Association (NYHA) Classification for Heart Failure Symptoms .......53 
6.2 Canadian Cardiovascular Society (CCS) Classification for Angina ...............................53 
6.3 Concomitant Medications ................................................................................................54 
6.3.1 General .......................................................................................................................54 
6.3.2 Concomitant Heart Failure Medications ....................................................................54 
6.3.3 Medication Restrictions .............................................................................................54 
6.4 Prevention of Pregnancy during the Study ......................................................................54 
6.4.1 Instructions for Female Subjects ................................................................................54 
6.4.2 Instructions for Male Subjects ...................................................................................55 
6.5 Diet and Exercise .............................................................................................................55 
6.6 Self-Monitored Blood Pressure (SBMP) .........................................................................55 
7  STUDY VISITS ...................................................................................................................56 
7.1 Screening (Visit 1) ...........................................................................................................56 
7.2 Run In Period (Visit 2, Day -10 to Day -7) .....................................................................58 
7.2.1 Scheduling the Visit and Baseline Echocardiogram ..................................................58 
7.2.2 Visit 2 .........................................................................................................................58 
7.3 Visit 3 (Day 0) .................................................................................................................59 
7.4 Visit 4 through 7 (Days 1, 2, 3 and 5) .............................................................................62 
7.5 Visit 8 (Day 7), Visit 9 (Day 14) and Visit 10 (Day 21) .................................................63 
7.6 Visit 11 through 14 (Days 22, 23, 24 and 26) .................................................................65 
7.7 Visit 15 through 18 (Days 28, 29, 30 and 31) .................................................................66 
7.8 Visit 19 (Day 49 +/- 3 days) or Early Termination [ET] .................................................68 
7.9 Visit 20 (Day 77 +/- 3 days) ............................................................................................69 
7.9.1 Final Immunogenicity Visit .......................................................................................69 
7.10 Unscheduled Visit(s) .....................................................................................................69 
7.11 Unscheduled Procedures ................................................................................................69 
7.12 Subject Withdrawal and Early Termination (ET) ..........................................................69 
7.12.1 General .....................................................................................................................69 
7.12.2 Discontinuation from Treatment ..............................................................................70 
7.12.3 Discontinuation from the Study ...............................................................................70 
8  STUDY TREATMENT .......................................................................................................71 
8.1 Method for Assigning Treatment/Randomization ...........................................................71 


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8.1.1 Study Coordinator (or designee) ................................................................................71 
8.1.2 Unblinded Study Drug Dispenser (USDD) ................................................................71 
8.2 Drug Supplies ..................................................................................................................71 
8.3 Formulation, Packaging and Labelling of Vasomera (PB1046) Injection ......................71 
8.3.1 Formulation and Packaging of Placebo......................................................................72 
8.4 Study Drug Storage..........................................................................................................72 
8.5 Preparation and Dispensing .............................................................................................72 
8.5.1 Dose Preparation ........................................................................................................72 
8.5.2 Administration ............................................................................................................73 
8.6 Restricted Use of Cold or Heat Applications to Site of Injection ...................................74 
8.7 Compliance ......................................................................................................................74 
8.8 Study Drug Accountability ..............................................................................................74 
8.9 Blinding ...........................................................................................................................74 
8.10 Breaking the Study Blind...............................................................................................75 
8.11 Replacement of Subjects................................................................................................75 
9  PROTOCOL VIOLATIONS................................................................................................75 
10  ADVERSE EVENTS .........................................................................................................76 
10.1 Adverse Events ..............................................................................................................76 
10.2 Reporting Period ............................................................................................................76 
10.3 Definition of an Adverse Event .....................................................................................76 
10.4 Assessment of Severity ..................................................................................................77 
10.5 Assessment of Toxicity .................................................................................................77 
10.6 Causality Assessment ....................................................................................................77 
10.6.1 Suspected Adverse Reaction ....................................................................................78 
10.7 Unexpected Adverse Events ..........................................................................................78 
10.8 Serious Adverse Event Definition .................................................................................78 
10.9 Reporting .......................................................................................................................79 
10.9.1 Serious Adverse Event Reporting Requirements .....................................................80 
10.9.2 Non-Serious Adverse Event Reporting Requirements and Ongoing Safety 
Review .................................................................................................................80 
10.10 Pregnancy Reporting ...................................................................................................81 
11  DATA ANALYSIS AND STATISTICAL METHODS ....................................................82 
11.1 Sample Size Determination ...........................................................................................82 
11.2 Analysis Populations .....................................................................................................82 
11.3 Statistical Analysis ........................................................................................................82 
11.3.1 Safety........................................................................................................................82 
11.3.2 Pharmacokinetic and Pharmacokinetic Analyses.....................................................82 
11.3.2.1 Pharmacokinetic Parameters — Non-Compartmental Analysis .........................82 
11.3.2.2 Pharmacokinetic Parameters — Compartmental Modeling ...............................83 


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11.3.2.3 Pharmacokinetic/Pharmacodynamic Analysis ....................................................84 
11.3.3 Immunogenicity (Antibody) Analysis ......................................................................84 
11.3.4 Exploratory ...............................................................................................................84 
11.3.4.1 2-D Echocardiography ........................................................................................84 
11.3.4.2 Biomarkers ..........................................................................................................85 
11.4 Interim (cohort) Safety Analysis for Dose Escalation ...................................................85 
12  DATA COLLECTION, RETENTION AND MONITORING ..........................................86 
12.1 Data Collection Instruments ..........................................................................................86 
12.2 Data Management Procedures .......................................................................................86 
12.2.1 Data Quality Control and Reporting ........................................................................86 
12.2.2 Data Entry ................................................................................................................86 
12.2.3 Medical Information Coding ....................................................................................87 
12.2.4 Data Validation ........................................................................................................87 
12.3 Archival of Data ............................................................................................................87 
12.4 Availability and Retention of Investigational Records ..................................................87 
12.5 Monitoring .....................................................................................................................88 
12.6 Subject Confidentiality ..................................................................................................88 
12.7 Retained Blood Samples ................................................................................................88 
13  ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ......................89 
13.1 Protocol Amendments ...................................................................................................89 
13.2 Institutional Review Boards and Independent Ethics Committees ...............................89 
13.3 Informed Consent Form ................................................................................................90 
13.4 Publications ...................................................................................................................90 
14  SPONSOR DISCONTINUATION CRITERIA ................................................................90 
15  REFERENCES ...................................................................................................................91 
APPENDIX A:  ADVERSE EVENTS OF SPECIAL INTEREST ......................................92 
APPENDIX B:  IMMUNOGENICITY (ANTIBODY) AND PHARMACOKINETIC 
SAMPLE HANDLING, LABELING, AND SHIPMENT INSTRUCTIONS ...........103 
APPENDIX C: 
RESPONSIBILITIES OF THE UNBLINDED STUDY DRUG 
DISPENSER (USDD) .................................................................................................105 
APPENDIX D 
SELF-MONITORED BLOOD PRESSURE DIARY ..............................106 


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Protocol PB1046-PT-CL-0003-P1 
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1 
INTRODUCTION 
1.1 
Background Information 
PB1046 (Vasomera) is an investigational compound that comprises the neuropeptide, 
Vasoactive Intestinal Peptide (VIP) genetically fused to an elastin-like biopolymer (ELP).  
PB1046 is being developed as an adjunctive therapy for the treatment of heart failure, and 
cardiomyopathy associated with dystrophinopathies; Duchenne Muscular Dystrophy (DMD), 
Becker Muscular Dystrophy (BMD), and X-linked dilated cardiomyopathy (XL-dCMP). 
VIP is a 28 amino acid neuropeptide and its biological effects are mediated by two receptors, 
VPAC1 and VPAC2, belonging to the family B of G protein-coupled receptors (GPCRs). VIP 
positive fibers are distributed throughout the heart and coronary vasculature and VPAC 
receptors are found on vascular smooth muscle cells within the systemic circulation as well as 
coronary and myocardial arteries, cardiac myocytes and various immune cells. Since the 
discovery of VIP almost 50 years ago, the understanding of the function of VIP in human 
disease has undergone radical transformation from one of vasodilatory and smooth muscle 
relaxation and inhibitor of smooth muscle proliferation, to new anti-inflammatory and 
immune-protective properties including upregulation of anti-inflammatory cytokine IL-10 and 
induction of protective T cells (Szema & Hamidi, 2014).  
Several cardiovascular diseases, such as myocardial fibrosis, heart failure, cardiomyopathy and 
pulmonary hypertension, have been found to be associated with changes in myocardial VIP 
concentration or with alteration of affinity, density and physiological responsiveness of the 
VIP receptors (Dvoráková, 2005).  Furthermore, a vast body of literature exists that support 
the therapeutic potential of VIP for cardiopulmonary disease, but the poor stability after 
systemic administration (half-life of approximately 48 seconds in circulation) has limited its 
clinical application.  
PB1046 is a recombinant fusion protein expressed in Escherichia coli (E. coli) with a total 
molecular mass of 50,945 Da.  PB1046 is a 634 amino acid polypeptide with vasoactive 
intestinal peptide (VIP) at the N-terminus and a physiologically inert repeating polymeric 
elastin-like polypeptide (ELP) at the C-terminus, which results in extended circulatory half-
life of the VIP, and provides protection from enzymatic degradation. The VIP moiety 
comprises mature human VIP with an additional methionine at the N-terminus that reduces 
activation at the VPAC1 receptor in comparison to activity at the VPAC2 receptor. This profile 
allows dosing in a range that can elicit the desired therapeutic effects but minimize the potential 
for negative gastrointestinal effects (GI) associated with over activation of VPAC1 (e.g. 
profuse watery diarrhea; (Tsutsumi, M., Claus, T. H., Liang, Y., Li, Y., Yang, L., Zhu, J., 
…Pan, C., 2002)).  
Attributes of PB1046 include positive lusitropy (early diastolic relaxation); improved inotropy 
secondary to changes in intracellular calcium mobilization; peripheral vasorelaxation, which 
is thought to be due to enhanced nitric oxide synthase activity; and attenuation of inflammation 
and fibrosis, likely due to modulation of inflammatory cell activity, based on the known 
mechanisms of VIP. These beneficial effects have been confirmed in several preclinical heart 
failure (HF) models evaluated with PB1046 (doxorubicin-induced HF model in rats, diastolic 


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dysfunction triggered by either renoprival hypertension or diabetes in rats, pacing induced 
systolic dysfunction in dogs and chronic ischemic HF induced via a serial coronary 
microembolization in sheep as well as an mdx mouse model, a murine model of human 
Duchenne muscular dystrophy.  Refer to Investigator’s Brochure for additional information.  
1.2 
Summary of Human Data 
At the dose ranges tested (subcutaneous injection - dose range 0.05 to 0.8 mg/kg or 30 minute 
intravenous infusion - dose range 0.005 to 0.02 mg/kg), PB1046 was not arrhythmogenic nor 
did it induce QT prolongation. PB1046 tended to reduce both systolic and diastolic blood 
pressure in a dose dependent/dose exposure manner as expected from the known 
pharmacological properties of vasoactive intestinal peptide. However, the effect was less 
pronounced following IV administration compared to subcutaneous administration. None of 
the subjects exposed experienced a hypotensive episode. Compared to placebo, there was no 
clinically relevant dose/exposure dependent increases in heart rate following subcutaneous 
administration. Compared to placebo, mild dose/exposure dependent increases in heart rate 
were observed following intravenous dosing with PB1046. The mild increases observed were 
not sustained, not associated with tachycardia nor were they considered clinically relevant and 
did not result in an appreciable change in the rate pressure product during or for the 3.5 hour 
period (PB1046 average IV t½ is approximately 2 hours) following intravenous infusion.  
 
Regardless of the route of administration, the most frequent dose/exposure dependent adverse 
events associated with the use of PB1046 were nausea and headache. Nausea was reported in 
10% of patients following subcutaneous administration and 20% following intravenous 
administration. Although headache was reported (6.7%) in patients receiving subcutaneous 
dosing with PB1046, 40% of the subjects receiving an intravenous dose of PB1046 reported 
headache.  When PB1046 was administered subcutaneously, it was almost always (90%) 
associated with mild to moderate injection site erythema that occurred hours to days after 
injection.  This effect is thought to be associated with activation of the VPAC2 receptors 
around hair follicles causing a localized vasodilatory response. Additionally, the majority 
(80%) of subjects receiving a subcutaneous injection of PB1046 experienced mild pain at the 
injection site, which again, occurred hours to days after injection and was often (33%) 
associated with mild pruritus. When PB1046 was infused intravenously (IV), only about 7% 
of subjects experienced erythema and about 13% experienced pain at the infusion site which 
was not reported during the infusion but was reported when the IV site was flushed hours after 
the infusion had been completed and resolved when the IV catheter was removed.  
Furthermore, these reported events were not associated with changes in WBC counts. Only 
one (2%) of the 45 subjects exposed to PB1046 reported mild intermittent generalized pruritus, 
with an onset approximately 92 hours after infusion of PB1046, which resolved without 
treatment. The majority of adverse events associated with PB1046 were mild; none were dose 
limiting or severe. 
 
No serious adverse events or dose limiting toxicities were identified following single SC 
administration of doses ranging from 0.05mg/kg to 0.8mg/kg and there were no dose limiting 
toxicities or serious adverse events related to study drug noted following a single 30 minute 
IV infusion of 0.005mg/kg, 0.01 mg/kg and 0.02mg/kg PB1046. 


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1.3 
Risk / Benefit Assessment 
At this stage of development, the risk benefit relationship has not been established. The 
combined nonclinical and clinical safety data support continued development of PB1046 as a 
potential adjunctive therapy for heart failure, and cardiomyopathy associated with 
dystrophinopathies. 
1.4 
Justification of Starting Dose, Duration of Treatment Exposure and Dose 
Escalation 
A starting subcutaneous dose of 0.2 mg/kg is selected based on the safety, and 
pharmacodynamic response data from the single dose study [PB1046-PT-CL-0001].  A single 
dose of 0.2 mg/kg was well tolerated and showed minimal to no reduction in systolic and 
diastolic seated blood pressure.  Model predicted serum exposures covering the planned dose 
escalation are described in Figure 1 and Table 1 are well below nonclinical exposure achieved 
in the 4 week repeat dose toxicology studies and do not exceed the maximum serum 
concentration  observed in subjects receiving a 30 minute intravenous infusion of PB1046 
[PB1046-PT-CL-0002].  
 
 
 
 
Figure 1 
Model-Predicted Serum Concentrations Following Once Weekly 
Subcutaneous Administration 
 
 


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Table 1 
Model-Predicted Pharmacokinetic Parameters Following Once Weekly 
Subcutaneous administration 
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 Primary Objective 
To evaluate the safety and tolerability of escalating doses of PB1046 administered once 
weekly for 4 weeks in adult subjects with stable NYHA Class II/III heart failure with a 
reduced ejection fraction (HFrEF). 
2.1.2 Secondary Objectives 
• Characterize the pharmacokinetic profile of a subcutaneous dose of PB1046 
administered once weekly for 4 weeks;  
• Evaluate the immunogenicity profile of a subcutaneous dose of PB1046 administered 
once weekly for 4 weeks. 
2.1.3 Exploratory 
• Characterize the effect of escalating doses of PB1046 on cardiac function as measured 
by 2-D echocardiography with Doppler following 4 weeks of once weekly dosing with 
PB1046;  
• Characterize the effect of PB1046 on cardiac, anti-inflammatory and anti-fibrotic 
biomarkers. 
2.2 
Criteria for Evaluation 
2.2.1 Safety Endpoints 
• Incidence and severity of AEs and their relationship to study drug; 
• Changes from baseline in vital signs, laboratory parameters, telemetry (e.g., occurrence 
and frequency of rhythm abnormalities), and the relationship to PB1046 compared to 
placebo; and  


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• Change from baseline in key ECG parameters (QT, QTcB, QTcF, PR, RR and QRS) 
and presence or absence of rhythm abnormalities and relationship to exposure of 
PB1046 compared to placebo. 
2.2.2 Other Endpoints 
2.2.2.1 Pharmacokinetic and Immunogenicity  
• Comparison of dose exposures (pharmacokinetic profile) during once weekly 
administration of various doses of PB1046;  
• Incidence of Immunogenicity.   
2.2.2.2 Exploratory 
• Change from baseline in 2-D echocardiographic parameters following  4 weeks of 
dosing with PB1046 compared to placebo;  
• Change from baseline on exploratory cardiac, anti-inflammatory, and anti-fibrotic 
biomarkers following 4 weeks of dosing with PB1046 compared to placebo. 
3 
STUDY DESIGN 
3.1 
General Description 
This study is a randomized, double-blind, placebo-controlled study that will assess the safety, 
tolerability, pharmacokinetics and explore the pharmacodynamics of PB1046 following 4 
weeks of once weekly subcutaneous injections. Subjects will be followed for safety for 4 weeks 
following the last dose with an additional visit 8 weeks following the last dose for collection 
of an immunogenicity sample (refer to Figure 2). This study will be conducted in two parts. 
Part 1 will be a sequential multiple-dose escalation study that will enroll (randomize and dose) 
approximately 28 (3A:1P in Cohort 1 and 6A:2P in subsequent cohorts) subjects. Qualifying 
subjects will have a diagnosis of NYHA Class II or III heart failure (ischemic or non-ischemic) 
with a reduced ejection fraction (HFrEF), be in stable condition, and be taking clinician-
directed appropriate pharmacological therapy (e.g., angiotensin converting enzyme inhibitors, 
angiotensin receptor blockers or an evidenced based beta blocker) for heart failure at stable 
doses (with the exception of diuretics) for at least 1 month prior to screening. Randomized 
subjects will receive a fixed dose of study drug throughout the 4 week dosing period. The data 
from Part 1 of the study will direct the dose(s) selected for Part 2.  Part 2 of the study will be 
further described and conducted under a separate Part 2 protocol (PB1046-PT-CL-0003-P2) 
that will evaluate the safety/tolerability, pharmacokinetics and will explore the 
pharmacodynamics of PB1406 following 4 weeks of once weekly dosing in up to 21 male 
subjects with dystrophic cardiomyopathy.   
 
 
 


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Figure 2  Study Schematic 
3.2 
Study Registration 
Upon signing consent, a subject will be screened (status set to “screened” in the electronic case 
report form [eCRF]). Subjects qualifying for participation will be registered (status update to 
“registered” in the eCRF) in the study and will be assigned to the next available dosing slot.  
No subject may participate (receive study drug) in more than one dose cohort.   
3.3 
Run-in/Stabilization Period 
During the period between screening and randomization (planned first dose), the study subject 
will remain on stable pharmacological therapy for heart failure. Stable therapy is defined as no 
change in dose or the addition or removal of a therapy. Adjustment of diuretic dosage if 
applicable, will be permitted. Also the study subject will be in stable health with no 
hospitalizations or acute illness between screening and randomization that would put the 
subject at increased risk for study participation. Approximately 7 days prior (Day -10 to Day -
7) to planned randomization, subjects will return to the study unit for placement of mobile 
telemetry and collection of baseline safety laboratory tests.  Within 14 days prior to 
randomization, subjects will undergo a baseline echocardiogram. Subjects will be instructed to 
monitor their blood pressure twice daily (morning and evening) starting at least 7 days prior to 
dosing.  
3.4 
Randomization 
Qualifying subjects will be randomly assigned via a central randomization system to receive 
either PB1046 or placebo. Only the unblinded study drug dispenser (USDD) at the study site 
will have access to the randomization assignment.  However, at the completion of each dose 
cohort, the study statistician and pharmacokineticist (including PK analytical lab) will have 
access to the randomization codes for that cohort in order to prepare data summaries required 


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for the study review meetings to assist in decisions regarding dose escalation. All displays will 
be provided to the committee in a blinded manner. 
3.5 
Planned Dose Escalation 
A starting dose of 0.2 mg/kg is selected based on the safety, and minimal to no 
pharmacodynamic response in the single dose escalation study in subjects with essential 
hypertension [PB1046-PT-CL-0001].   Model predicted serum exposures covering the planned 
dose escalation are outlined in Figure 3 are described in Figure 1 and Table 1.  The model 
predicted exposures are well below nonclinical exposure (area under the curve) achieved in the 
4 week repeat dose toxicology studies (rats and monkeys) and do not exceed the maximum 
serum concentration observed in subjects receiving a 30 minute intravenous infusion of 
PB1046 [PB0146-PT-CL-0002].  
 
 
 
Figure 3 
Dose Escalation  
3.5.1 Dose Escalation Rules 
• More than one subject may be dosed in a 24 hour period up to and including 0.8 mg/kg, 
which was the maximum dose utilized in the PB1046-PT-CL-0001. If dosing exceeds 
0.8 mg/kg, no more than one subject will be dosed in a 24 hour period for the four three 
subjects dosed in a cohort. 
• At least 75% of subjects assigned to a cohort must receive at least three weekly doses 
(e.g., at steady state) with no reported dose limiting toxicities (DLTs) before escalation 
to the next higher dose level.   
• For a dose cohort exceeding 0.8 mg/kg, for which there is no available subcutaneous 
pharmacokinetic (PK) data, PK data through Day 31 (10 days following the last dose) 
will be required to be assessed in addition to safety data prior to escalating to a higher 
dose. 
• DLTs identified during the study will be assessed as potential indicators of cumulative 
toxicity and provide rationale for revision of the maximum tolerated dose (MTD).   


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• Multiple dose escalation will continue until modelling of the PK data indicates that the 
human AUC (0-168 hours) would exceed currently available nonclinical exposure 
and/or previous human exposure (PB1046-PT-CL-0001 [SC] or -0002 [IV]), 
whichever is higher. 
• If a subject in a cohort experiences a DLT that is evaluated by the Investigator as related 
to study drug (PB1046), an additional four subjects (3A and 1P) will be dosed at that 
dose level.  If two or more subjects in a cohort experience a DLT related to PB1046, 
the MTD will be considered exceeded.  The dosing schema may be revised to dose 
additional subjects below this level to further refine the MTD. 
• The decision to temporarily hold or discontinue a subject from study treatment will be 
based on Investigator discretion regarding reported adverse events or other factors, 
which may include clinically significant reduction in blood pressure (i.e., hypotension). 
• Aggregate assessment of adverse events with specific emphasis on cardiac related 
events will be assessed on an ongoing basis and will be evaluated for trends related to 
dose escalation and will be reviewed at each Study Review Committee (SRC) meeting.  
• A study subject will be discontinued from study treatment if there is evidence of 
increased arrhythmia potential or marked prolongation (e.g., QT/QTc > 500 ms or > 60 
ms over baseline) of the QT/QTc interval while on treatment.  
• Aggregate evaluation of the risk for arrhythmias or QT/QTc prolongation will be 
evaluated for trends on an ongoing basis and will reviewed at each Study Review 
Committee (SRC) meeting. 
Dose escalation will continue if the safety and pharmacokinetic profile are deemed acceptable 
as assessed by the Medical Monitor, Principal Investigators, Clinical/Regulatory and a 
representative from Preclinical/Assay Development (i.e., the Study Review Committee 
[SRC]).  The SRC may also recommend de-escalation or study discontinuation.  All decisions 
and outcomes related to SRC meeting will be documented and retained as part of the study file. 
Updates will be made to the Food and Drug Administration (FDA) and to the Institutional 
Review Board (IRB) as appropriate.   
3.6 
Safety Oversight 
3.6.1 Study Review Committee 
The Study Review Committee (SRC) will review data relating to safety, PK and hemodynamic 
response after 75% of the subjects in a cohort have completed their 3rd dose and have been 
followed for seven (7) days after the 3rd dose prior to dose escalation.  The committee will 
include the Principal Investigators, the Medical Monitor, Clinical/Regulatory Representative 
(Sponsor), 
Preclinical/Assay 
Development 
Representative 
(Sponsor) 
and 
a 
Pharmacokineticist.  The SRC will review the interim safety summaries prepared by the 
Clinical Representative from safety data entered into the EDC system, safety laboratory data, 
and pharmacokinetic and immunogenicity (binding ADA) data provided by PhaseBio’s Assay 


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Development Department, as applicable.  The safety data will be reviewed in a blinded manner 
and must will be deemed acceptable to the SRC prior to dosing of the next higher dose group.   
The SRC may recommend additional ECG evaluations or a change to the scheduled 
evaluations based on the PK profile, to further elucidate the relation of exposure to PB1046 
and the QT/QTc interval.  
In the case of a Dose Limiting Toxicity (DLT), Serious Adverse Event (SAE), or other 
significant AE, the SRC may request that the study drug assignment be unblinded. Following 
review of the interim safety summary, the SRC will decide if dose escalation should continue, 
recommend de-escalation, or recommend study discontinuation.  SRC recommendations not 
previously described in the protocol, or any recommendations to discontinue the study will be 
promptly reported to the IRB and the Food and Drug Administration (FDA).     
The SRC amy recommend up to two dose levels to carry forward to Part 2 of the study 
(PB1046-PT-CL-0003-P2).  Activities related to Part 2 of the study will be reviewed and 
approved under a separate protocol PB1046-PT-CL-0002-P2.  
3.6.2 Investigator 
The Investigator (Principal or physician Sub-Investigator) must have access and be available 
to promptly review the results of all safety assessments (i.e., clinical laboratory testing), 
electrocardiogram (ECG) results, vital signs and adverse events (AEs) including injection site 
assessment information throughout the study. Safety assessments must be promptly (should be 
within 48 hours of notification of event) entered into the Electronic Data Capture (EDC) 
system and clinical laboratory data should be available within about 48 hours from date of 
receipt of samples at the central laboratory.   
Clinical laboratory data will be evaluated by the Investigator (Principal or physician Sub 
investigator) and clinical relevance will be assessed for abnormal values and the assessment 
will be documented on the laboratory report. A copy of the reports will be maintained as part 
of the source documentation.   
3.6.3 Definitions 
3.6.3.1 Dose Limiting Toxicity (DLT)  
A dose limiting toxicity is defined as any Grade 3 or greater toxicity excluding injection site 
reactions as further described, that is evaluated by the Investigator as related to study drug. For 
injection site reactions a DLT is defined as a Grade 3 toxicity in 2 or more injection site 
assessment categories (e.g., pain, tenderness, erythema/redness, and/or induration/swelling; 
refer to Appendix A),  or a Grade 4 injection site reaction in any one assessment category and 
is evaluated by the Investigator as related to study drug. The treatment assignment will be 
unblinded to confirm relationship to PB1046.  An additional four subjects (3A and 1P) may be 
dosed with PB1046 at that dose level if deemed appropriate by the Study Review Committee 
(SRC).    
 


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3.6.3.2 Maximum Tolerated Dose (MTD)   
Although this study is not designed to dose to a MTD, the MTD may be reached if two or more 
subjects in a cohort experience a DLT as defined in section  3.6.3.1.  No further dosing will 
occur above the MTD. 
 
 
 
 
 
GRADE 
Clinical Description of Severity 
1 
MILD Adverse Event 
2 
MODERATE Adverse Event 
3 
SEVERE Adverse Event 
4 
LIFE-THREATENING OR DISABLING Adverse Event 
5 
DEATH RELATED TO Adverse Event 


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4 
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
Subjects will be eligible for inclusion in the study if they meet all of the following criteria: 
 
1. Willing and able to sign a written informed consent and follow all study-related 
procedures; 
2. Male or female subject ≥ 18 years of age; 
3. Male subjects and female subjects of reproductive or childbearing potential must 
practice effective contraception during the study and be willing and able to continue 
contraception for 30 days after their last dose of study drug. Female subjects of non-
childbearing potential are defined as being surgically sterile by bilateral tubal ligation, 
bilateral oophorectomy, or hysterectomy.  A female subject 45 to 60 years of age, 
inclusive who is post-menopausal for at least 1 year and has a follicle-stimulating 
hormone level confirmation indicating post-menopausal status will be considered of 
non-childbearing potential.  Female subjects > 60 years of age are considered post-
menopausal and of non-childbearing potential;  
4. Body mass index ≥ 18 kg/m2 and ≤ 45 kg/m2; 
5. Receipt of stable (no change in dose (except diuretics) or addition or removal of a 
therapy) pharmacological therapy(ies) for heart failure for a minimum of 1 month (30 
days) prior to screening and between screening and randomization and are in stable 
clinical condition; 
6. NYHA Class II or III heart failure diagnosis (ischemic or non-ischemic confirmed by 
medical history) at least (≥) 6 months (180 days) prior to screening;  
7. Stable HF defined as no hospitalizations for cardiac related issues within the previous 
3  months (90 days) prior to the screening visit or between screening and 
randomization; 
8. A screening Left Ventricular Ejection Fraction ≤ 40% by centralized reading of 2-D 
echocardiography.  
9. Screening hemoglobin ≥ 9.0g/dL secondary to the volume of blood to be collected 
during the study period. 
10. Willing and able to return to the study unit for specified study visits, and be able to 
self-monitor blood pressure while at home. 
11. Live and work in an area with reliable cellular services (e.g., Sprint®) for real time 
transmission of telemetry data to the core laboratory. 
 


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4.2 
Exclusion Criteria 
Subjects will be excluded from the study if they meet any of the following criteria: 
 
1. Have previously received PB1046 or have a known allergy to the study drug or any of 
its components; 
2. Participating in any other study and have received any other investigational 
medication or device within 30 days prior to screening or are taking part in a non-
medication study which, in the opinion of the Investigator, would interfere with study 
compliance or outcome assessments; 
3. Diagnosed with acute coronary syndrome (ACS) or an acute myocardial infarction 
(MI) within 3 months (90 days) of screening;  
4. Canadian Cardiovascular Society (CCS) Class III or IV angina necessitating frequent 
use of as needed short acting nitroglycerin (e.g., sublingual); 
5. Cardiac surgery or valvuloplasty within 3 months (90 days) prior to screening; 
6. Cerebrovascular accident or transient ischemic attack within 3 months (90 days) prior 
to screening; 
7. Sustained systolic blood pressure (SBP) < 100 mmHg and/or diastolic blood pressure 
(DBP) < 50 mmHg (confirmed by a duplicate seated reading) on at least 3 
consecutive readings (self-monitored or office) prior to randomization or overt 
symptomatic hypotension; 
8. Sustained resting heart rate >100 beats per minute (BPM) at screening (V1) or  prior 
to randomization (confirmed on baseline telemetry monitoring); 
9. History or evidence (documented on baseline telemetry monitoring) of clinically 
significant arrhythmias (uncontrolled by drug therapy or use of an implantable 
defibrillator), long QT syndrome or evidence of QT prolongation demonstrating 
QTcF > 460 ms (by ECG) prior to randomization;  
10. Clinically significant renal dysfunction as measured by the estimated glomerular 
filtration rate (eGFR) of < 40 mL/min/1.73m2 as calculated by the CKD-EPI 
creatinine-cystatin C equation: eGFR = 135 x min (Scr/k, 1)-a × max(Scr/k, 1)-0.601 × 
min(Scys/0.8, 1)-0.375 × max(Scys/0.8, 1)-0.711 × 0.995age [× 0.969 if female ] [× 1.08 if 
black ] at screening, or a significant change in renal function between screening and 
baseline; 
11. Clinically significant liver dysfunction as measured by: alanine aminotransferase >3.0 
× the upper limit of normal (ULN), aspartate aminotransferase >3.0 × the ULN, or 
serum bilirubin ≥ 1.6 mg/dL at screening, or a significant change in liver function 
between screening and baseline; 


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12. Pregnant or lactating female subjects; 
13. Known history of or active alcohol abuse or use of illicit drugs within 1 year prior to 
randomization;  
14. Positive screening for human immunodeficiency virus antibodies, hepatitis B surface 
antigen, or hepatitis C virus antibodies; 
15. Any major surgical procedure within 1 month (30 days) prior to screening or planned 
surgical procedure during the study period;  
16. Other medical or psychiatric condition which, in the opinion of the Investigator, 
would place the subject at increased risk or would preclude obtaining voluntary 
consent/assent or would confound the secondary objectives of study. 
5 
DESCRIPTION OF STUDY PROCEDURES  
A description of study procedures listed in the Schedule of Activities is provided within the 
content of this protocol. Refer to the Schedule of Activities for additional information on the 
frequency of each procedure.  
5.1 
Informed Consent 
All subjects must provide written informed consent prior to participating in any screening 
evaluations or any other study activities. The Investigator or his/her approved designee (as 
documented on the Delegation of Authority Log) must explain the nature of the study protocol 
and associated risks to the potential study participant. The potential participant must be allowed 
sufficient time to review the information and to ask questions. The date that the informed 
consent form is signed, a brief description of the consent process (e.g., questions asked by the 
subject) and the name of the individual who obtained the consent will be recorded in the 
subject’s source documentation. A copy of the signed informed consent should be provided to 
each subject. The date and confirmation that informed consent was obtained and consent form 
version will be recorded in the eCRF.  
During a subject’s participation in the study should an updated informed consent become 
available, it is the site’s responsibility to re-consent those subjects as directed by the 
Institutional Review Board following the same procedures as in the previous paragraph.  The 
date and confirmation that a revised informed consent was obtained will be recorded in the 
subject’s source documentation as well as the eCRF. 
5.2 
Demographics  
Subject demographic information will be recorded at screening. Demographic information will 
include date of birth, gender (at the time of birth), race, and ethnicity. Findings will be 
documented in the source documentation and the eCRF.  


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5.3 
Histories 
5.3.1 General Medical/Surgical and Social History 
Relevant medical and surgical history will be recorded at screening and will include medical 
diagnoses, major surgical procedures within the last 3 years. Social history (tobacco, drug, 
and alcohol use) as well as dietary habits (e.g., unrestricted, vegetarian, gluten-free, vegan, 
other) and allergies (food, medications and environmental) will also be recorded at screening. 
Findings will be documented in the source documentation and the eCRF. 
5.3.2 Targeted Medical History  
Subjects who qualify for this study, must have been diagnosed with heart failure. Date of initial 
diagnosis, New York Heart Association Classification, type: ischemic or non-ischemic, and 
date of and ejection fraction (EF) from the most recent echocardiogram and treatments for 
heart failure as well as other relevant cardiac history will be recorded in the eCRF and 
documented in the source documentation.  
5.3.3 Medications 
Chronic medications used to treated a relevant medical diagnosis that has taken within the 
last 3 months (90 days) prior to screening or acute (e.g., antibiotics) as needed medications 
(e.g., TUMS®, acetominophen) taken at the time of screening will be recorded in the source 
document and on the eCRF.  Also refer to Section 6.3 Concomitant Medications for 
additional information. 
5.4 
Physical Examination 
A general physical examination will include at minimum an examination of general 
appearance, skin, eyes, ears, nose, throat, neck/thyroid, lungs, heart, upper/lower extremities, 
lymph nodes, abdomen, musculoskeletal system and neurological system. Additional systems 
will be evaluated as needed. Physical exam findings must be recorded in the source 
documentation and include the date and name of the individual conducting the examination. 
Physical examinations must be performed by an individual licensed to conduct standard 
physical examinations. An abbreviated physical examination will include an examination of 
general appearance, lungs, heart, lower extremities and abdomen.  
 
Significant findings that are present prior to dosing with study drug will be recorded in the 
eCRF as pre-treatment adverse events. Clinically significant findings present after dosing will 
be recorded as an adverse event in the eCRF. 
5.5 
Telephone Contact 
The Investigator or designee will contact the subject by phone the evening of each dosing 
day (recommended to occur between 7 and 10 PM) to assess their status. All subject contacts 
will be documented in the source records.  


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5.6 
Directed Physical Exam 
A directed physical exam will be done as necessary during the study based upon signs and/ or 
symptoms that may have presented or reported adverse events that may have presented during 
a subject’s participation in the study.  If no signs or symptoms or an adverse event are present 
then no directed physical exam is necessary. 
5.7 
Height/Weight and Calculation of BMI and BSA 
Height and weight will be measured and will be used for calculation of body mass index (BMI) 
and Body Surface Area (BSA). The calculation for study drug administration will be based 
upon the weight taken on Day 0 and will remain the same throughout the subject’s participation 
in the study, unless there is a greater than 10% change in the subject’s weight between Day 0 
and subsequent dosing days.  If this were to occur sites are instructed to notify the Sponsor for 
instructions. 
Weight should be measured with shoes off and light clothing only.   A digital scale should be 
used and, for consistency, the same scale should be used for all weight measurements for a 
given subject. 
5.8 
Vital Signs - General 
Blood pressure and heart rate will be measured using an Omron automated blood pressure (BP) 
monitor (Model BP785N) provided by the Sponsor. This monitor is able to measure triplicate 
measurements one minute apart (as applicable). Vital signs should be measured on the SAME 
arm (location should be documented) throughout the study (including subject self-monitored 
blood pressure; refer to Section 6.6) for accurate comparison of readings over time.  
Position is critical for accurate BP measurements. Therefore, when the BP is measured, the 
arm (cuff) should be at the level of the heart. In the supine position, the arm should be kept at 
the side at the level of the body. When standing, the cuff should be at the level of the heart 
with the arm supported. Do not allow the arm to hang down. When sitting, feet should be flat 
on the floor with back supported and arm supported at the level of the heart (e.g., resting on a 
table). Additionally respiratory rate and temperature (oral or oral equivalent) will be captured 
once at each designated time point per the Schedule of Activities. 
It is important that vital signs be taken either before a meal, or at least 30 minutes after a meal 
or consuming caffeine. If the subject is a smoker, the subjects must not be permitted to smoke 
within 30 minutes prior to scheduled study activities. 
5.8.1 Orthostatic Blood Pressure  
Systolic and diastolic blood pressure and heart rate will be measured in the supine position 
after resting for at least ten (10) minutes (+ 2 minutes) (times to be recorded in the source 
document), followed by the standing position (time at standing position will be documented in 
the source record). The first measurement beginning immediately upon standing and the 
second measurement will be taken at 3 minutes after standing (Irvin & White, 2004).  The 


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subject should indicate if they experienced dizziness or other symptomatology upon standing. 
Findings will be recorded in the source document and in the eCRF.  
 
5.8.2 Seated Blood Pressure  
Blood pressure (systolic/diastolic) and heart rate will be assessed approximately one minute 
apart in triplicate per the Schedule of Activities after the subject has rested in a seated position 
for at least five (5) minutes. Each of these blood pressure readings and heart rate readings will 
be recorded in the eCRF along with the time they were taken. Temperature (oral or oral 
equivalent) and respiratory rate will be recorded once at each scheduled time point. Findings 
will be recorded in the source documentation and in the eCRF. 
 
5.9 
Injection Site Assessment 
The injection site(s) will be examined periodically for the absence/presence of pain, 
tenderness, erythema/redness (including size), induration/swelling (including size) and will be 
recorded in the source document. Injection site findings (with reference to injection site 
number; refer to Section 8.5.2) will also be recorded as an adverse event in the eCRF. Each 
injection site will be examined for a minimum of 7 days following injection or until any 
treatment-emergent skin lesions have resolved or stabilized. Refer to Schedule of Activities 
for frequency of assessments. Refer to Appendix A for toxicity grading. 
5.10 12 Lead Electrocardiogram 
All investigative sites will be provided with an identical make/model calibrated portable ECG 
machine. Site personnel must assess the quality of the ECG while the subject is still at the 
investigative site in the event that additional ECGs need to be performed (i.e., if artifact is 
present). QT intervals will be reported uncorrected as well as corrected for heart rate according 
to the Frederica Formula. All ECG’s will be read (confirmed report) by a central ECG core 
laboratory (BioTelemetry Research).  
5.10.1  Subject Preparation Procedure 
In accordance with the standards for collection of vital signs, it is suggested that the 12 lead 
ECG be collected either before a meal or at least 30 minutes after a meal or consuming caffeine. 
If the subject is a smoker, the subjects must not be permitted to smoke within 30 minutes prior 
to scheduled test.  
To ensure good electrode contact, dry shave any site containing excess hair.  Lightly abrade 
each electrode site.   
• ECGs need to be recorded with subjects in a supine position and resting for at least 10 
minutes before recording. 
• With the subject at rest in the supine position, attach the electrodes to the lead wires 
and then to the subject (refer to Figure 4).   


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5.10.2 ECG Measurement and Printouts 
The investigative site will print one original of each triplicate ECG performed at each time 
point for the source document file. The Investigator will review and sign the unconfirmed ECG 
(site source file copy) for initial evaluation of safety. ECGs will be electronically transmitted 
to the core laboratory (BioTelemetry Research) and read (confirmed). The Investigator will be 
notified of any clinically significant abnormal ECG findings.  A confirmed ECG will be 
provided to the clinical site for their records. Refer to ECG manual for additional details 
regarding data transmission.  
5.10.2.1  
Electrode Placement  
 
 
Figure 4: 12 Lead ECG Electrode Placement Diagram 
Precordial electrodes 
V1: Placed on the fourth intercostal space at the right sternal border. 
V2: Placed on the fourth intercostal space at the left sternal border. 
V3: Placed midway between V2 and V4. 
V4: Placed at the midclavicular line in the fifth intercostal space. 
V5: Placed at the anterior axillary line on the same horizontal level as V4 or if the anterior 
axillary line is ambiguous, midway between V4 and V6. 
V6: Placed at the mid-axillary line on the same horizontal level as V4 and V5. 
 
Limb electrodes 
 
Limb electrodes can be placed anywhere on the limbs.  However, the following placement is 
recommended: 
RA and LA: 
Place on the wrist. 
RL and LL: 
Place approximately 7cm (or 3 inches) above the ankle. 


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5.10.3 Verification of Qualifying QTcF at Randomization 
The Investigator will be required to verify the baseline (pre-dose) ECG findings with 
interpretation (should be documented on the third ECG in the pre-dose series) and will enter 
(or designee) the triplicated ECG measurements into the eCRF for calculation of mean 
triplicate QTcF and verification of study qualification prior to randomization.  
5.11 Remote 24/7 Mobile Telemetry Monitoring  
5.11.1 Device 
The Mobile Cardiac Outpatient Telemetry (MCOT™) monitoring device (Cardionet, Malvern, 
PA) will be used in this study. The device received FDA marketing clearance in February 2002. 
Each device is tested, programmed, and validated at Cardionet prior to shipment to the 
investigative site. This will ensure that the equipment is functioning properly and transmits 
successfully to the receiving center.   
 
A study subject will wear a sensor on a lanyard with 3 electrodes (Figure 5) as they continue 
their normal daily routine for approximately 5 weeks (starting 7 days (may be started as early 
as Day -10 if necessary) prior to randomization and first dose of study drug for 7 days following 
the last dose of study drug). Two leads of ECG data are monitored continuously. The algorithm 
uses rate, rhythm, QRS morphology and P wave recognition for arrhythmia detection. The 
subject will carry a PDA size monitor that has cellular capabilities. After acquiring ECG data, 
the sensor transmits the full disclosure data to the hand-held monitor unit with a range up to 
approximately 150 feet.  The hand-held monitor device contains a proprietary algorithm which 
analyzes the ECG data for arrhythmias. If an arrhythmia is detected, the monitor transmits an 
ECG strip of the arrhythmia over the cellular network to an Independent Diagnostic Testing 
Facility which is staffed 24/7/365. Note:  Wireless ECG transferred data is completely 
recoverable while the patient is being monitored. If the subject is out of cellular range, no data 
will be lost. No action is required by the subject or study personnel to transmit the ECG data. 
Customer Support-available 24 hours /7 days a week via phone at 866-326-1936 or via email: 
ClinicalStudies@cardionet.com. 
 
 
 
Figure 5. MCOT Monitoring Device  
 
 


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5.11.2 Notifications and Reporting 
5.11.2.1 Notifications 
When an arrhythmia is detected, the ECG is automatically transmitted to Cardionet where the 
ECG is immediately interpreted. Results will be called or sent via e-mail and/or fax to the 
Investigator. Additionally the report will be sent to the Sponsor’s Adverse Event Reporting fax 
line for automatic distribution to the Medical Monitor.   All alert reports will be stored with 
the subject records.  
 
The Investigator and subject will be notified immediately by Cardionet for the following 
rhythm issues:  
Emergent Criteria 
Rate 
Duration 
Pause 
All Events 
>8 Seconds 
Severe Tachycardia (All rhythms) 
>220 BPM 
Any 
Severe Bradycardia (All rhythms) 
<25 BPM 
Any 
Ventricular Tachycardia (symptomatic) 
>100 BPM 
>25 Beats 
Sustained VTach 
>150 BPM 
>30 Seconds 
Rapid VTach 
>190 BPM 
>6 Beats 
 
The Investigator will be notified immediately by Cardionet for the following rhythm issues: 
Urgent Criteria 
Rate 
Duration 
Pause/Asystole 
All Events 
>3 Seconds 
Syncope 
All Events 
All Events 
Severe Tachycardia (All rhythms) - Asymptomatic 
>190 BPM 
>30 Seconds 
Severe Tachycardia (All rhythms) - Symptomatic 
>170 BPM 
>30 Seconds 
Severe Bradycardia 
<35 BPM 
> 30 Seconds 
Atrial Fibrillation/Flutter 
New Onset 
>10 Seconds 
Notify 9A-5P,  
7 Days a Week 
NSVT 
>100 BPM 
>3 Beats w/ symptoms 
2nd Degree AVB – Mobitz Type II 
All Events 
All Events 
3rd Degree AV Block – Complete HB/AV 
Dissociation 
All Events 
All Events 
Defibrillator/Pacemaker – 
Failure to Capture/Sense 
All Events 
All Events 
 
If the subject reports an adverse event during the monitoring period, the “event” should be 
marked on the hand held transmitter.  
5.11.2.2 Reporting 
Daily reports will be available to the Investigator through Cardionet access portal at 
https://access.cardionet.com/Login.aspx?ReturnUrl=%2fMarketing%2fDefault.aspx. Prior to 


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dosing, the Investigator (or designee) will need to confirm that the subject has not experienced 
an episode(s) of sustained resting tachycardia (100 bpm +) during baseline period (Day -7 to 
Day 0 prior to dosing) that would exclude the subject from continued study participation.  
At the completion of the monitoring period, a final report will be generated by Cardionet and 
will be sent to the Investigator. This report should be maintained with the subject record. 
5.12 2-D Echocardiography with Doppler 
Two-dimensional echocardiography (2D-echo) will be performed utilizing the site’s 
echocardiography machine and will be performed by a qualified echocardiographer.  It is 
preferable that the same technician perform all 2D-echo evaluations for a given subject 
whenever possible.  An Informational questionnaire which pertains to the system as well as 
participating echocardiographers will be collected by BioTelemetry Research who will be 
responsible for training and centralized 2D-echo readings.  Each echocardiographer will be 
required to submit a test echocardiogram for certification purposes.  Certification 
echocardiogram is to be performed on a volunteer who is not participating in the study. Upon 
acceptable certification echo, BioTelemetry Research will send a Certification Echo certificate 
to the site. Certification must be received prior to performing a study echo. 
 
All echocardiograms will be reviewed by two independent blinded reviewers, one of whom is 
a Board Certified Cardiologist.  The echocardiography technician will not be required to 
perform or record any measurements on the echo screen.  
It is anticipated that it will take approximately 20 minutes to complete a resting echo evaluation 
for each subject at each time-point.   A detailed Echocardiography Procedure Manual will 
provide supplemental information to that contained in the protocol.  
The following parameters may be assessed: 
• Blood pressure (BP) and heart rate (HR) (arterial peak, mean and diastolic blood 
pressure)  
• Left ventricular internal diameter in diastole (cm) 
• Left ventricular internal diameter in systole (cm) 
• Left ventricular wall thickness in diastole (cm; both septum and posterior wall) 
• Left ventricular outflow tract diameter in mid-systole (cm) 
• Left ventricular volumes (end-diastole and end-systole, in mL; apical views) 
• Left ventricular outflow tract flow-time velocity integral (by pulsed Doppler; in cm) 
• Ascending aorta peak flow velocity (by Continuous Wave Doppler; in m/s) 
• Transmitral flow velocity pattern (both by pulsed and Continuous Wave Doppler) 


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• Doppler tissue imaging of tricuspid, septal and mitral annulus (velocity; in cm/s) 
• Left atrial volume (in mL/M2) 
• Derivation of: Left ventricular (LV) Ejection Fraction, Strain Rate (SR)/Strain Rate 
Image (SRI), LV Stroke Volume and Index, LV Cardiac Output and Index, Ejection 
Time, Systemic Vascular Resistance, Mitral E and A velocities, LV and index, 
Myocardial tissue velocities S' and e'. 
5.12.1 System Requirements  
• System must undergo routine maintenance check as recommend by the manufacturer 
and documentation of such maintenance will be made available upon request. 
• Harmonic imaging capable  
• Tissue Doppler capable 
• Digital (DICOM) acquisition is preferred  
• For all echocardiograms, if using a digital system, the files should be able to be burned 
as DICOM or AVI / JPEG format. Biotelemetry Research can NOT accept WMV, 
MP4, RAW or MPEG formats. Files will be sent to Biotelemetry Research for analysis. 
The echo images must be labelled with the subject ID, initials, date and time of 
evaluation.  
• Have the ability to keep a copy of all echocardiograms for the subject source records. 
5.13 Laboratory Testing 
5.13.1 Testing Facilities 
Blood samples for screening and routine safety laboratory testing will be analyzed by a 
centralized laboratory (Medpace Reference Laboratory, Cincinnati, OH) that is certified under 
the Clinical Laboratory Improvement Act (CLIA).  Pharmacokinetic and immunogenicity 
testing will be performed by PhaseBio Pharmaceuticals, Inc., Malvern, PA utilizing methods 
that are validated as appropriate for the stage of development that will be done in accordance 
with Good Laboratory Practice (GLP) standards. Additional exploratory sample analysis for 
various biomarkers will be conducted under a protocol for research purposes only and analysis 
may be done at PhaseBio Pharmaceuticals, Inc., or a specialty and/or academic facility in direct 
support of this study.  
 
5.13.2 Blood Volumes 
It is anticipated that approximately 365 mL of blood will be collected over the study period 
(screening, which can occur up to 60 days prior to randomization and through 12 weeks after 
randomization). Assuming that the majority of subjects will weigh at least 60 kg, it is 


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estimated that no more than 2.5% total blood volume (mL) will be collected in a 24 hour 
period and no more than 5% of total blood volume (mL) will be collected over a 30 day 
period.  
5.13.3 Sample Identification and Sample Banking 
Blood samples will be labeled with the 5-digit subject ID and initials and sample collection 
date/time and sample type.  The Sponsor will not have any information that would identify the 
subject.    
Blood samples may be retained indefinitely by the Sponsor for future testing for the purpose 
of investigating the study drug’s safety and effectiveness in support of future clinical research 
and/or to answer regulatory authority questions related to safety and effectiveness at the time 
of registration. Blood samples will not be shared with other research institutions for purposes 
outside of the stated purposes noted above. 
5.13.4 Screening and Safety Laboratory Testing 
5.13.4.1 Serology for HIV, Hepatitis B, and Hepatitis C 
All subjects will be screened for HIV, HBsAg, and HCV. Evaluation for HIV seropositivity 
will consist of enzyme-linked immunosorbent assay (ELISA) and, if positive, will be 
confirmed by the Bio Rad Multispot HIV-1/2 antibody differential test. Appropriate counseling 
will be made available to the subject in the event of a positive finding. Notification of state and 
federal authorities, as required by law, will be the responsibility of the Investigator. Samples 
will be analyzed by Medpace Reference Laboratory.  
5.13.4.2 Drug and Alcohol Testing 
A drug screen (urine) to test for the presence of amphetamines, benzodiazepines, cocaine 
metabolites, phencyclidine (PCP), barbiturates, cannabinoids, and opiates as well as an alcohol 
test (i.e., breath test, urine or serum) will be performed at screening and prior to dosing utilizing 
CLIA waived methodology.  Testing supplies will be provided by the Sponsor to be tested 
locally at the site.  
5.13.4.3  Pregnancy Test  
A pregnancy test is required for female subjects of childbearing potential. Results must be 
negative (serum) in order for subjects to be randomized in the study.  Samples will be analyzed 
by Medpace Reference Laboratory.  
Note: Women of childbearing potential who were not following an acceptable method of birth 
control and who were sexually active at the time of screening must have two negative serum 
pregnancy tests approximately 15 days apart to confirm that the subject is not pregnant prior 
to dosing with study drug.  
Additionally, a urine pregnancy test (local CLIA waived) will be done prior to each dose of 
study drug.  Testing supplies will be provided by the Sponsor to be tested locally at the site.  


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5.13.4.4 Follicle-Stimulating Hormone Level 
Medpace Reference laboratory will conduct and analysis of follicle-stimulating hormone 
levels in women 45 to 60 years of age for confirmation of postmenopausal status if not 
previously available. This testing will only be done as requested by the study site. 
5.13.4.5 Lipid Profile 
A fasting lipid profile includes (total cholesterol [TC], high-density lipoprotein cholesterol 
[HDL-C], low-density lipoprotein-cholesterol [LDL-C], low-density lipoprotein/high-density 
lipoprotein (LDL/HDL) ratio, and triglycerides [TG]).  Samples will be analyzed by Medpace 
Reference Laboratory. 
5.13.4.6 N-terminal Pro-B Type Natriuretic Peptide (NT-ProBNP) 
N-terminal pro-B type natriuretic peptide (NT-proBNP), is an indicator of myocardial stretch 
and is recognized as a robust prognostic marker at all stages of HF and related clinical 
outcomes (de Antonio, Lupon, Galan, Vila, Urrutia, & Bayes-Genis, 2012).  Samples will be 
analyzed using an inmmuno-electrochemiluminescence assay on the Modular Analytics E 
170 (Roche Diagnostics) with a sensitivity of 5 pg/mL.  Results lower than 5 pg/mL are 
reported as <5 pg/mL. Samples will be analyzed by Medpace Reference Laboratory. 
5.13.4.7 High Sensitivity Cardiac Troponin T Assay (hs-cTnT) 
Cardiac troponin is a marker of myocyte injury which may be able to predict adverse clinical 
outcomes in acute and chronic HF (de Antonio, et al, 2012; Sherwood, & Newby, 2014).  A 
high-sensitivity assay for cardiac troponin T (hs-cTnT) is able to detect low troponin 
concentrations and improves precision at the lower limit of detection.  Furthermore, some 
reports suggest that hs-cTnT also provides relevant prognostic information in HF. Troponin 
levels will be measured by an electrochemiluminescence immunoassay using an hs-cTnT assay 
on the Modular Analytics E 170 (Roche Diagnostics) with a sensitivity of 0.003 ng/mL. Results 
lower than 0.003 ng/mL are reported as <0.003 ng/mL. Samples will be analyzed by Medpace 
Reference Laboratory. 
 
5.13.4.8 Routine Safety Laboratory Testing  
The following safety laboratory panel will be analyzed by Medpace Reference Laboratory. For 
fasting samples, the subject must have fasted (no food or drink except for water) for at least 8 
hours prior to collection of sample. 
Test Group 
Parameter 
Serum Chemistry 
 
 
 
 
 
Alanine Amino Transferase (ALT) 
Aspartate Transaminase (AST) 
Albumin 
Alkaline phosphatase 
Amylase 
Anion gap 
Bilirubin (total, direct and indirect) 
Blood urea nitrogen (BUN) 


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Test Group 
Parameter 
Calcium 
Carbon dioxide 
Chloride 
Creatinine, serum  
Cystatin C 
Creatinine kinase (CK)  
Creatinine kinase MB Isoenzyme (CK-MB) 
Gamma glutamyl transferase (GGT) 
Lactate dehydrogenase (LDH) 
Lipase 
Magnesium 
Phosphorous  
Potassium 
Sodium 
Total protein  
Urea-N 
Plasma Chemistry 
Fasting plasma glucose (FPG) 
Hematology 
Complete blood count [red blood cells (RBC), hematocrit (HCT), 
hemoglobin (Hgb), white blood cells (WBC), platelets] (reported 
as % and absolute values) 
Differential (Automated) 
Urinalysis/Microscopy 
 
Appearance 
Bilirubin 
Blood 
Color 
Glucose 
Ketones 
Microscopic examination [bacteria, casts, red blood cells (RBC), 
white blood cells (WBC), crystals] 
pH 
Protein 
Protein/creatinine ratio  
Urobilinogen 
 
5.13.4.9 Calculation of Estimated Glomerular Filtration Rate  
Estimated glomerular filtration rate (eGFR) will be calculated by Medpace Reference 
Laboratory by the following methods: 
• CKD-EPI creatinine-cystatin C equation: eGFR = 135 x min (Scr/k, 1)-a × max(Scr/k, 
1)-0.601 × min(Scys/0.8, 1)-0.375 x max(Scys/0.8, 1)-0.711 × 0.995age [× 0.969 if female ] 
[× 1.08 if black ] 
• IDMS-Traceable MDRD Study Equation: eGFR (mL/min/1.73 m2) = 175 × (Scr in 
mg/dL)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 African American) (conventional 
units) 
• Cockcroft-Gault (C-G) Equation: CLcr in mL/min is estimated from a spot serum 
creatinine (mg/dL) determination using the following formula:  


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CLcr (mL/min) = 
[140 −age ( years)]×weight (kg) 
{×0.85 for female patients} 
72 ×serum creatinine (mg / dL) 
 
5.13.5 Immunogenicity (Antibody) Testing 
For details regarding collection, collection schedule, specimen processing, and shipping, see 
Schedule of Activities and Appendix B. Samples will be screened for the presence of binding 
anti-drug antibodies.  Samples testing positive and specific for antibodies against PB1046 will 
be further characterized to determine the domain specificity including whether the antibodies 
cross react with native VIP.   Additional characterization of the antibody response may be 
performed as warranted.  Samples testing positive and specific for anti-drug antibodies will be 
titered and further evaluated for their neutralizing potential using a cell based assay. 
Immunogenicity samples may be tested to measure PB1046 serum concentrations if necessary.  
Additional out of protocol (OOP) samples may be collected if clinically necessary (e.g., if last 
sample is positive for antibodies additional samples may be requested). 
5.13.6 Pharmacokinetic Testing 
Samples will be analyzed at PhaseBio Pharmaceuticals Inc. For details regarding collection, 
collection schedule, specimen processing, and shipping, see Schedule of Activities and 
Appendix B. 
5.13.7 Exploratory Biomarkers 
The exploratory biomarkers listed below may be considered for evaluation. Additional 
biomarkers may be evaluated as directed by the data.  Exploratory biomarkers will be analyzed 
at PhaseBio Pharmaceuticals Inc. or a PhaseBio designated testing facility, using good 
scientific principles and commercially available kits (validated or non-validated). This analysis 
will be done for research and development purposes. Additionally MicroRNA samples will be 
analyzed at a secondary research facility using the PAXgene® Blood RNA System 
(PreAnalytiX®, a Qiagen/BD Company). Test will be done on a research and development 
basis only.  
Exploratory Biomarkers 
 
 
CCD2+ (T cell % and number) 
CD2+DR 
CD3+ (T cells) 
CD3+/CD4+ 
CD4+ DR 
CD3+/CD8+ 
CD8+DR 
CD19+ (B cells) 
MMP-9 
CD25+ 
FOXP3+ 
TGF-B 
IL-10 
IL-4 
IL-6 


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IL-1beta 
 
IFN-gamma 
 
TNF alpha 
microRNA 
miRs related to cardiac remodeling/heart failure: miR-1,-23a, -26b, 
-27a, -133, -195, -199b, -208b, -423 and -499 
miRs related to cardiac fibrosis miR-21, -29b, and -30c 
miRs related to muscle atrophy miR-23a, -96, and -182) 
miRs related to oxidative stress/apoptosis: miR-361 and miR-1187 


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6 
STUDY GUIDELINES 
6.1 
New York Heart Association (NYHA) Classification for Heart Failure Symptoms 
The following description should be considered when assessing Inclusion Criteria No. 6. 
Class 
Description 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in 
fatigue, palpitation, dyspnea. 
III 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest.  If 
any physical activity is undertaken, discomfort increases. 
Source: American Heart Association. Retrieved on 09FEB2016 from: 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-
Failure_UCM_306328_Article.jsp 
 
6.2 
Canadian Cardiovascular Society (CCS) Classification for Angina 
The following description should be considered when assessing Exclusion Criteria No. 4. 
Classification  
Description 
I 
Ordinary physical activity does not cause angina, such as walking and climbing stairs. 
Angina with strenuous or rapid or prolonged exertion at work or recreation. 
II 
Slight limitation of ordinary activity. Walking or climbing stairs rapidly, walking uphill, 
walking or stair climbing after meals, or in cold, in wind or under emotional stress, or 
only during the few hours after awakening. Walking more than two level blocks and 
climbing more than one flight of ordinary stairs at a normal pace and in normal 
conditions. 
III 
Marked limitation of ordinary physical activity. Walking one or two level blocks and 
climbing one flight of stairs in normal conditions and at normal pace. 
IV 
Inability to carry out any physical activity without discomfort; angina may be present at 
rest. 
Source: Campeau Lucien. Grading of Angina Pectoris. Circulation 1976; 54:522–3 


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6.3 
Concomitant Medications 
6.3.1 General 
Use of chronic medications or as-needed medications (e.g., TUMS®, acetominophen) will be 
permitted during the screening and active study period (unless otherwise restricted, refer to 
Section 6.3.3) and should be recorded in the source document and on the eCRF. Any changes 
in concomitant medication usage will be recorded in the source documents and on the eCRF. 
If the reason for change is related to an adverse event, the event should be recorded in the 
source documents and as an adverse event in the eCRF.  
6.3.2 Concomitant Heart Failure Medications 
Concomitant evidence-based heart failure medications are permitted by the protocol and 
should be maintained at stable doses (with the exception of diuretics) for at least 1 month (30 
days) prior to screening and throughout the study period. Evidence-based medical therapy may 
include but is not limited to use of an angiotensin-converting enzyme inhibitor (ACEI), 
angiotensin-receptor blocker (ARB), beta blocker (BB),  aldosterone receptor antagonists (or 
mineralocorticoid receptor antagonists) and/or  hydralazine and isosorbide dinitrate.  
 
Although heart failure medications should be maintained at stable doses, dose will be permitted 
if deemed medically necessary (e.g., increase risk of hypotension) by the Investigator. Any 
changes in concomitant medication usage and reason for dose adjustment will be recorded in 
the source documents and on the eCRF.  
6.3.3 Medication Restrictions 
• PDE5 inhibitors are known to potentiate the effects of antihypertensives. Therefore it 
is recommended that subjects taking PDE5 inhibitors on an as needed basis (e.g., for 
erectile dysfunction), refrain from taking these medications while receiving study drug, 
and for a period of 14 days (approximately 5 half-lives of PB1046) following the last 
dose. 
• It is not known if fast acting nitrates taken in combination with PB1046 will cause an 
unsafe drop in blood pressure. Therefore, until more information is known, if it 
recommended that if a subject requires frequent use of as needed (PRN) nitrates (e.g., 
sublingual) to control angina (refer to Exclusion Criteria 4), they should not be included 
in the study.  
6.4 
Prevention of Pregnancy during the Study 
6.4.1 Instructions for Female Subjects 
Women who are pregnant or breastfeeding will not be allowed to participate in this study. If a 
female subject of childbearing potential is sexually active and has not been using an accepted 
method of birth control, two negative serum pregnancy tests performed approximately 15 days 
apart are required to check for possible early pregnancy prior to initial dosing with study drug.  


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Prior to administration of subsequent doses of study drug, a urine pregnancy test will be 
completed prior to dosing. 
Due to unknown risks and potential harm to the unborn fetus, female subjects must use a 
reliable method of birth control while participating in this study and for 30 days after the last 
dose of study drug. Reliable methods of birth control include the following: abstinence (not 
having sex), oral contraceptives, intrauterine device, Depo-Provera, Norplant®, surgically 
sterile (tubal ligation, bilateral oophorectomy or hysterectomy), vasectomy of the partner (with 
confirmed negative sperm counts) in a monogamous relationship, or careful use of condoms 
and a spermicidal foam or gel and/or a cervical cap or sponge. 
6.4.2 Instructions for Male Subjects 
Due to unknown risks and potential harm to the unborn fetus, male subjects of reproductive 
potential (capable of impregnating their partner) who are sexually active with a women of 
childbearing potential must use a reliable method of birth control while participating in this 
study and for 30 days after the last dose of study drug. Reliable methods of birth control include 
the following: abstinence (not having sex), vasectomy (with confirmed negative sperm counts), 
careful use of condoms and a spermicidal foam or gel and/or a cervical cap or sponge. For the 
female partner, oral contraceptives, intrauterine device, Depo-Provera, Norplant or be 
surgically sterile (tubal ligation, bilateral oophorectomy or hysterectomy).  
6.5 
Diet and Exercise 
Study subjects should maintain their usual caloric intake and exercise regimen during study 
participation.   
6.6 
Self-Monitored Blood Pressure (SBMP) 
Study subjects will be provided with a diary (refer to Appendix D) and will be asked to monitor 
their blood pressure (set to automatically measure in triplicate, 1 minute apart and will report 
the mean value) twice daily (morning and evening) starting approximately 1 week prior to 
randomization through 1 week following the last dose of study drug. An automated blood 
pressure cuff (Omron Blood Pressure Monitor with ComFit™ Cuff (Model BP785N) as shown 
in Figure 6 will be provided to subjects as needed for this assessment. Study personnel will 
provide training (and document in the source documents) to subjects on the use of the blood 
pressure monitoring unit. The subject should bring the monitor and diary with them to each 
study visit.  
 
Figure 6 
Omron ComFit™ Blood Pressure Cuff Model BP785N 
  


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7 
STUDY VISITS 
The procedures and assessments to be performed at each visit are indicated in the Schedule of 
Activities.  An estimated time for the conduct of each visit is provided as a guide only to the 
study site personnel and study subject for planning purposes. Note: it will not be considered a 
departure from the protocol if the visit length is shorter or longer than anticipated.  
7.1 
Screening (Visit 1) 
The screening visit can occur up to 60 days prior to randomization.  It is estimated that this 
visit will take approximately 4 hours to complete.  
• Informed Consent Process 
o The subject must provide written informed consent PRIOR to any study 
procedures being done. 
o Once signed, proceed with the following study procedures in the 
recommended sequence: 
• Subject Interview 
o Review and record prior medications (those taken within the last 3 months (90 
days)) and current concomitant medications;  
o Review and record prior histories; medical, targeted cardiac history; surgical 
and social  history (smoking, dietary restrictions/habits and alcohol 
consumption)  
o Record demographic information; and 
o Evaluate inclusion/exclusion criteria against responses obtained during the 
subject interview. 
• Assessments 
o Measure and record height and weight and calculate BMI and BSA;  
o 12 lead ECG (in triplicate 1 minute apart). ECG will be electronically 
transmitted to BioTelemetry, the ECG core laboratory;  
o Obtain and record vital sign measurements: 
 Temperature (oral or oral equivalent) and respiratory rate 
 Orthostatic  - BP and heart rate  
 Seated  - BP and heart rate in triplicate (1 minute apart); and  


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o Perform a complete physical examination and record results. 
• Sample Collection 
o Collect urine sample for local testing: 
 Alcohol and drug testing using CLIA waived testing supplies provided 
by Medpace Reference Laboratory. 
 Retain remaining urine sample for urinalysis that will be shipped to, and 
analyzed by, Medpace Reference Laboratory.  
o Obtain Medpace Reference Laboratory requisition booklet matched to Subject 
ID and collect the following samples: 
 Pregnancy testing (serum) for female subjects of childbearing potential. 
 If female is reported to be postmenopausal and is between the ages of 
45 and 60, they may be required to have an FSH level to confirm 
postmenopausal status unless they have other documented criteria to 
verify that they are not of childbearing potential. 
 Collect blood samples for the following testing: serology panel for HIV, 
HepB, HepC; safety laboratory assessments (hematology, chemistry). If 
the subject is fasting, a fasting lipid profile and fasting plasma glucose 
will be analyzed. If the subject is not fasting, this should be noted on the 
laboratory requisition form and these tests will not be done at this visit 
(not required for confirmation of study eligibility) but will be done at 
baseline (Visit 2, 7 days prior to scheduled randomization). All samples 
will be shipped to and analyzed by Medpace Reference Laboratory. 
• Schedule 2-D Echocardiogram 
o If the subject has had a 2-D echocardiogram within the last 60 days that   
confirms the subject has an ejection fraction (EF) ≤40%, this will be sufficient 
for confirmation of study eligibility for initial screening.  However, the subject 
must be scheduled for their baseline evaluation 7-14 days before scheduled 
randomization for final confirmation of qualifying EF by BioTelemetry (core 
laboratory) 
o If no recent 2-D echocardiogram is available, schedule screening test.   
• Instructions to Subject 
o Inform the subject that they will be notified (within about 2 weeks) whether or 
not they qualify for the study participation.  


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7.2 
Run In Period (Visit 2, Day -10 to Day -7) 
Subjects who qualify for the study will meet all entry criteria at Visit 1 will be scheduled to 
return for Visit 2.   
 
7.2.1 Scheduling the Visit and Baseline Echocardiogram 
• Visit 2 can occur as early as 10 days before dosing but should be done at least 7 days 
prior to randomization/first dose.  This visit should take approximately 1.5 hours. 
• The 2D echocardiogram may be done up to 14 days prior to randomization.   
• Inform the subject that they will need to fast for a minimum of 8 hours (no food or 
drink except water) prior to the study visit. 
7.2.2 Visit 2  
• Subject Interview 
o Confirm that the subject has had/is schedule for their baseline 2-D 
echocardiogram completed.  When echocardiogram complete, send 
electronically sent to BioTelemetry, the Echo core laboratory; 
o Review concomitant medications and record; 
o Review changes in the subject’s health (pre-treatment adverse events) since the 
last visit; and  
o Evaluate inclusion/exclusion criteria (to ensure the subject still qualifies for 
participation). 
• Sample Collection 
o Collect urine sample for local testing: 
 Pregnancy testing for female subjects of childbearing potential using 
the CLIA waiver testing supplies provided by Medpace Reference 
Laboratory;  
 Alcohol and drug testing using CLIA waived testing supplies provided 
by Medpace Reference Laboratory; and  
 Retain remaining urine sample for urinalysis that will be shipped to, and 
analyzed by, Medpace Reference Laboratory. 
o Obtain Medpace Reference Laboratory requisition booklet matched to Subject 
ID and collect the following samples: 


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 Blood samples for safety laboratory assessments; hematology, 
chemistry, fasting lipid profile and fasting plasma glucose.  
 All samples will be shipped to and analyzed by Medpace Reference 
Laboratory. 
• Mobile Telemetry 
o Set up mobile telemetry and instruct subject on its use, marking “events”,  and 
how to change electrodes; and  
o Ensure that the data is capturing prior to subject leaving the study site. 
• Self-monitored Blood Pressure (SMBP) Training 
o Instruct subject on the use of the Omron ComFit™ Blood Pressure Cuff 
Model BP785N; and  
o Review blood pressure measuring requirements (morning and evening using 
the SAME arm) and completion of diary. 
• Instructions to Subject 
o Schedule Visit 3 and discharge from study site.  
o Remind subject to bring Omron blood pressure cuff and diary to next visit. 
7.3 
Visit 3 (Day 0) 
Subjects should be scheduled to return to the study in the morning, at around 07:30. This 
time is suggested as subsequent visits will need to occur ± 2 hours from dosing at this visit 
and to allow dosing to occur by 10:00. This visit should take approximately 7.5 hours (about 
1.5 hours for pre-dose assessments and dosing, and 6 hours after dosing for blood sample 
collection).  
• Pre-dose Subject Interview 
o Review concomitant medications and record; 
o Review changes in the subject’s health (pre-treatment adverse events) since the 
last visit; and  
o Evaluate self-monitored blood pressure diary; and  
o Evaluate inclusion/exclusion criteria (to ensure the subject still qualifies for 
participation. 
 


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• Pre-dose Assessments 
o Measure and record weight (needed for calculation of study drug dose);  
o Reset mobility telemetry for 30 day monitoring interval and ensure it is 
functioning and recording properly;  
 
o 12 lead ECG (in triplicate 1 minute apart). ECG will be electronically 
transmitted to BioTelemetry, the ECG core laboratory. Refer to protocol 
Section 5.10.3 regarding verification of qualifying ECG (QTcF) by 
Investigator;  
o Obtain and record vital sign measurements (using subject’s Omron blood 
pressure cuff. If not available use another Omron cuff and note in source 
documents): 
 Temperature (oral or oral equivalent) and respiratory rate 
 Orthostatic  - BP and heart rate  
 Seated  - BP and heart rate in triplicate (1 minute apart); and  
o Perform an abbreviated physical exam (at minimum to include general 
appearance, lungs, heart, lower extremities, and abdomen) and record results. 
• Pre-dose Sample Collection 
o Collect urine sample for local testing: 
 Pregnancy testing for female subjects of childbearing potential using 
the CLIA waiver testing supplies provided by Medpace Reference 
Laboratory.  
 Alcohol and drug testing using CLIA waived testing supplies provided 
by Medpace Reference Laboratory. 
 
o Obtain Medpace Reference Laboratory requisition booklet matched to Subject 
ID and collect the following samples: 
 Blood samples for pharmacokinetics, immunogenicity, exploratory 
biomarkers, NT-Pro-BNP and hs-cTnT.  
 Samples will be shipped to Medpace Reference Laboratory and 
PhaseBio Pharmaceuticals Inc. as directed per the laboratory procedure 
manual. 
 


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• Randomization 
o The Study Coordinator or designee will complete the Randomization Module 
and update status to Randomized in the eCRF system. The information to be 
entered, Study Part, subject weight, Cohort and dose level (Cohort 1 will be 
dosed at 0.2 mg/kg. and subsequent dosing for cohorts will be assigned after 
each SRC meeting).   
o Once completed, the Unblinded Study Drug Dispenser (USDD) will view the 
Randomization Module and treatment allocation (active or placebo) for the 
subject via the eCRF page (a central randomization system). Only the USDD 
has read access to the treatment allocation via the eCRF.   A subject will be 
assigned, in the order randomized into the study, the next corresponding 
treatment assignment per the randomization schedule generated by the study 
statistician.  
o The study drug will be prepared in accordance with the procedures outlined in 
Protocol Section 8.5. and as further described in the study specific pharmacy 
procedure manual.  
• Dosing 
o A subject will be dosed by a member of the study team in accordance with 
protocol Section 8.5.2.  
o Document the date and time of dosing and location of dosing (quadrant on the 
abdomen). It is suggested that dosing site be rotated in a clockwise fashion (e.g., 
first dose RUQ, second dose will be in the LUQ, etc.). 
• Post Dose Assessments 
o Obtain and record vital sign measurements at 1 and 6 hours (± 15 minutes) post 
dose using subject’s Omron blood pressure cuff: 
 Temperature (oral or oral equivalent) and respiratory rate 
 Seated  - BP and heart rate in triplicate (1 minute apart) 
o Assess injection site at 1 and 6 hours (± 15 minutes) post dose. 
• Post-dose Sample Collection 
o Obtain Medpace Reference Laboratory requisition booklet matched to Subject 
ID and collect the following samples: 
 Pharmacokinetic sample at 1, 3 and 6 hours (± 1 hour) post dose.  
 All samples will be shipped to Medpace Reference Laboratory. 


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• Subject Instructions 
o Subject will be instructed to return to the study unit on Day 1 (24 hours), Day 
2 (48 hours), Day 3 (72 hours) ± 1 hour after the dosing (injection) time and 
Day 5 (120 hours) ± 2 hours after the dosing time.  The subject does not need 
to be fasting for these visits.  
o Subject should bring with them their diary and blood pressure cuff at each 
visit.  
• Telephone Contact 
o Subject will be contacted by the Investigator or designee in the evening 
(between approximately 7:00 and 10:00 PM) to check on the status of the 
study subject. Contacts will be recorded in the source documents. 
7.4 
Visit 4 through 7 (Days 1, 2, 3 and 5) 
Each visit should take approximately 1 hour.  
• Subject Interview – at each visit 
o Review concomitant medications and record; 
o Review changes in the subject’s health (adverse events) since the last visit; and  
o Evaluate self-monitored blood pressure diary. 
• Assessments – at each visit unless otherwise noted 
o Ensure telemetry it is functioning and recording properly; 
o Assess injection site (± 2 hours) post the time of day of the last dose; 
o 12 lead ECG (in triplicate 1 minute apart) at 24 (Day 1), 48 (Day 2) and 72 (Day 
3) hours (± 1 hour) post the time of day of the last dose. Note: should be done 
within 30 minutes of collection of PK sample at each time point;  
o Obtain (± 2 hours) post the time of day of the last dose and record vital sign 
measurements using subject’s Omron blood pressure cuff. (If not available, use 
another Omron cuff and note in source document): 
 Temperature (oral or oral equivalent) and respiratory rate 
 Orthostatic  - BP and heart rate  
 Seated  - BP and heart rate in triplicate (1 minute apart) 


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o Directed physical examination – done only as needed to evaluate adverse 
events. Record results. 
• Sample Collection – at each visit unless otherwise noted 
o Obtain Medpace Reference Laboratory requisition booklet matched to Subject 
ID and collect the following samples: 
 Pharmacokinetics, NT-Pro BNP, hs-cTnT and exploratory biomarkers, 
at 24 (Day 1), 48 (Day 2) and 72 (Day 3) hours (± 1 hour) post the 
time of day of the last dose and prior to but within 30 minutes of 
collection of the 12 lead ECG.  
 Pharmacokinetics at Day 5 (± 2 hours) after the last dose. 
 Samples will be shipped to Medpace Reference Laboratory and 
PhaseBio Pharmaceuticals Inc. as directed. 
• Subject Instructions 
o Subject will be instructed to return to the study unit on Day 7, 14 and 21 for 
dosing; and   
o Subject should bring with them their diary and blood pressure cuff at each 
visit.  
7.5 
Visit 8 (Day 7), Visit 9 (Day 14) and Visit 10 (Day 21) 
It is estimated that each visit should take approximately 1.5 hours to complete.  
• Pre-dose Subject Interview – at each visit 
o Review concomitant medications and record; 
o Review changes in the subject’s health (adverse events) since the last visit; and  
o Evaluate self-monitored blood pressure diary.  
• Pre-dose Assessments – at each visit 
o Measure and record weight (Note: if weight increase or decreases greater than 
10% from Day 0, contact the Sponsor prior to dosing);  
o Ensure telemetry is functioning and recording properly; 
 
o Assess injection site (± 2 hours) post the time of day of the last dose;   
 
o 12 lead ECG (in triplicate 1 minute apart). ECG will be electronically 
transmitted to BioTelemetry, the ECG core laboratory;  


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o Obtain and record vital sign measurements using subject’s Omron blood 
pressure cuff. (If not available, use another Omron cuff and note in source 
document): 
 Temperature (oral or oral equivalent) and respiratory rate 
 Orthostatic  - BP and heart rate  
 Seated  - BP and heart rate in triplicate (1 minute apart) 
o Directed physical examination – done only as needed to evaluate adverse 
events. Record results. 
• Pre-dose Sample Collection – at each visit  
o Collect urine sample for local testing: 
 Pregnancy testing for female subjects of childbearing potential using 
the CLIA waiver testing supplies provided by Medpace Reference 
Laboratory.  
 Alcohol and drug testing using CLIA waived testing supplies provided 
by Medpace Reference Laboratory. 
 Retain remaining urine sample for urinalysis that will be shipped to, and 
analyzed by, Medpace Reference Laboratory. 
o Obtain Medpace Reference Laboratory requisition booklet matched to Subject 
ID and collect the following samples: 
 Blood samples for safety laboratory assessments; hematology, and 
chemistry; 
 Blood samples for pharmacokinetics, immunogenicity, exploratory 
biomarkers, NT-Pro-BNP and hs-cTnT.  
 Samples will be shipped to Medpace Reference Laboratory and to 
PhaseBio Pharmaceuticals Inc. as directed. 
• Dosing at each visit 
o A subject will be dosed by a member of the study team ± 2 hours from time of 
the previous weekly dose in accordance with protocol Section 8.5.2.  
o Document the date and time of dosing and location of dosing (quadrant on the 
abdomen).  It is suggested that dosing site be rotated in a clockwise fashion 
(e.g., first dose RUQ, second dose will be in the LUQ, etc.).  
• Post-dose Sample Collection  - Day 21 only 


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o Obtain Medpace Reference Laboratory requisition booklet matched to Subject 
ID and collect the following samples: 
 Blood sample for pharmacokinetics at 1, 3 and 6 hours (± 10 minutes) 
post dose.  
 Samples will be shipped to Medpace Reference Laboratory and 
PhaseBio Pharmaceuticals Inc. as directed. 
• Subject Instructions 
o Subject will be instructed to return to the study for Visits 11 through 14 (Days 
22, 23, 24 and 26).  
o Subject should bring with them their diary and blood pressure cuff at each 
visit.  
• Telephone Contact 
o Subject will be contacted by the Investigator or designee in the evening 
(between approximately 7:00 and 10:00 PM) of each dosing day check on the 
status of the study subject. Contacts will be recorded in the source documents. 
7.6 
Visit 11 through 14 (Days 22, 23, 24 and 26) 
It is estimated that each visit should take approximately 1.5 hours to complete. 
• Schedule 2-D Echocardiogram – Day 24 ± 1 day 
o Ensure examination complete. 
o Echo will be electronically sent to BioTelemetry, the Echo core laboratory. 
• Subject Interview – at each visit 
o Review concomitant medications and record; 
o Review changes in the subject’s health (adverse events) since the last visit; and  
o Evaluate self-monitored blood pressure diary. 
• Assessments – at each visit unless otherwise noted 
o Ensure telemetry it is functioning and recording properly; 
o Assess injection site (± 2 hours) post the time of day of the last weekly dose; 
o 12 lead ECG (in triplicate 1 minute apart) at 24 (Day 22), 48 (Day 23) and 72 
(Day 24) hours (± 1 hour) after the time of the last weekly dose and at 120 hours 


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(Day 26) ± 2 hours after the last dose. ECG will be electronically transmitted to 
BioTelemetry, the ECG core laboratory. ECG should be done within 30 minutes 
of collection of the PK sample;  
o Obtain (± 2 hours from the time of the last weekly dose) and record vital sign 
measurements (using subject’s Omron blood pressure cuff. If not available use 
another Omron cuff and note in source document): 
 Temperature (oral or oral equivalent) and respiratory rate 
 Orthostatic  - BP and heart rate  
 Seated  - BP and heart rate in triplicate (1 minute apart) 
o Directed physical examination – done only as needed to evaluate adverse 
events. Record results. 
• Sample Collection – at each visit unless otherwise noted 
o Obtain Medpace Reference Laboratory test booklet matched to Subject ID and 
collect the following samples: 
 Pharmacokinetics at 24 (Day 22), 48 (Day 23) and 72 (Day 24) hours 
(± 1 hour) post dose and prior to but within 30 minutes of collection of 
the 12 lead ECG.  
 Pharmacokinetics at Day 26 (± 2 hours) for time of dosing. 
 On Day 24 ± 1 day only, Biomarkers, NT-pro BNP and hs-cTnT 
should be done on the same day as the 2-D echocardiogram due. 
 Samples will be shipped to Medpace Reference Laboratory and 
PhaseBio Pharmaceuticals Inc. as directed. 
• Subject Instructions 
o Subject should be reminded to fast (no food or drink except water) for a 
minimum of 8 hours prior to Day 28 visit. 
o Subject should bring with them their diary and blood pressure cuff at each 
visit.  
7.7 
Visit 15 through 18 (Days 28, 29, 30 and 31) 
It is estimated that each visit should take approximately 1.5 hours to complete. 
• Subject Interview – at each visit 
o Review changes in the subject’s health (adverse events) since the last visit;  


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o Review concomitant medications; and  
o Evaluate self-monitored blood pressure diary. 
• Assessments – at each visit unless otherwise noted 
o Remove telemetry on Day 28; 
o Assess injection site (± 2 hours) post the time of day of the last weekly dose; 
o 12 lead ECG (in triplicate 1 minute apart) on Day 28 (± 1 hour) after the time 
of the last weekly dose. ECG will be electronically transmitted to BioTelemetry, 
the ECG core laboratory. Should be done within 30 minutes of collection of the 
PK sample;  
o Obtain (± 2 hours from the time of the last weekly dose) and record vital sign 
measurements (using subject’s Omron blood pressure cuff. If not available use 
another Omron cuff and note in source document): 
 Temperature (oral or oral equivalent) and respiratory rate 
 Orthostatic  - BP and heart rate  
 Seated  - BP and heart rate in triplicate (1 minute apart) 
o Directed physical examination – done only as needed to evaluate adverse 
events. Record results. 
• Sample Collection – at each visit unless otherwise noted 
o Obtain Medpace Reference Laboratory requisition booklet matched to Subject 
ID and collect the following samples: 
 Pharmacokinetics, ± 2 hours from the time of day of the last dose. 
Sample collection on day 28 only should be within 30 minutes of 
collection of the 12 lead ECG.  
 Collect urine sample for urinalysis that will be shipped to, and 
analyzed by, Medpace Reference Laboratory on Day 28 only. 
 Blood samples for immunogenicity, safety laboratory assessments; 
hematology, chemistry, fasting lipid profile and fasting plasma, 
exploratory biomarkers, NT-Pro-BNP and hs-cTnT on Day 28 only. 
 All samples will be shipped to Medpace Reference Laboratory and 
PhaseBio Pharmaceuticals Inc. as directed. 
• Subject Instructions 


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o Remind subject to bring with them their diary and blood pressure cuff at each 
visit. 
o Instruct subject to discontinue monitoring blood pressure at home on Day 31. 
o Inform the subject that they will need to fast for a minimum of 8 hours (no 
food or drink except water) prior to the study visit. 
7.8 
Visit 19 (Day 49 +/- 3 days) or Early Termination [ET] 
It is estimated that this visit should take approximately 2 hours.  
• Subject Interview  
o Review concomitant medications and record; 
o Review changes in the subject’s health (adverse events) since the last visit.  
• Assessments  
o Measure and record weight; 
o Assess injection site and record findings; 
o 12 lead ECG (in triplicate 1 minute apart). ECG will be electronically 
transmitted to BioTelemetry, the ECG core laboratory;  
o Obtain and record vital sign measurements using subject’s Omron blood 
pressure cuff. (If not available use another Omron cuff and note in source 
document.): 
 Temperature (oral or oral equivalent) and respiratory rate 
 Orthostatic  - BP and heart rate  
 Seated  - BP and heart rate in triplicate (1 minute apart) 
o Physical examination - complete 
• Sample Collection  
o Obtain Medpace Reference Laboratory test requisition booklet matched to 
Subject ID and collect the following samples: 
 Blood samples for immunogenicity, safety laboratory assessments; 
hematology, chemistry, fasting lipid profile and fasting plasma, 
exploratory biomarkers, NT-Pro-BNP and hs-cTnT. 


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 Samples will be shipped to Medpace Reference Laboratory and 
PhaseBio Pharmaceuticals Inc. as directed. 
7.9 
Visit 20 (Day 77 +/- 3 days) 
7.9.1 Final Immunogenicity Visit 
It is estimated that this visit will take approximately 15 minutes.  
• Sample Collection  
o Obtain Medpace Reference Laboratory test booklet matched to Subject ID and 
collect immunogenicity lab sample. 
o Remind subject that they will be required to return for additional 
immunogenicity sampling if the sample collected at this visit is positive for 
antibody development. 
7.10 Unscheduled Visit(s)  
In the event that additional immunogenicity testing is required, the subject may be asked to 
return for additional visits.   This may also be the case to follow up on open adverse events or 
to follow clinical significant abnormal laboratory results. 
7.11 Unscheduled Procedures 
It may be necessary to collect additional 12 lead ECGs as directed by the pharmacokinetic 
data and as recommend by the SRC. Other unscheduled procedures may be performed as 
clinically indicated for evaluation of subject safety.  
7.12 Subject Withdrawal and Early Termination (ET) 
7.12.1 General 
Subjects may withdraw from treatment or from the study at any time at their own request or 
they may be withdrawn at any time at the discretion of the Investigator or Sponsor for safety, 
behavioral, or administrative reasons. For safety reasons, a subject will also be discontinued 
from the study treatment if they test positive for alcohol or illicit drugs (tested prior to each 
dose) during the study. However these subjects will continue to be followed per the protocol.  
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject. In any circumstance, every effort should be made to document subject outcome, if 
possible. The Investigator should inquire about the reason for withdrawal and request that the 
subject return for the ET (complete procedures at final safety visit) and follow up with the 
subject regarding any unresolved adverse events. 


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7.12.2 Discontinuation from Treatment 
If a subject experiences an adverse event and the Investigator determines that the subject 
should be discontinued from study treatment, subjects should continue to be followed in the 
study as per the protocol.  
7.12.3 Discontinuation from the Study 
If the subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations 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. 
 
 


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8 
STUDY TREATMENT 
8.1 
Method for Assigning Treatment/Randomization 
A central randomization code for each cohort in the study is generated by the study statistician 
in a ratio of 3 active to 1 placebo and is uploaded into the secured eCRF randomization module. 
The assigned treatment (active or placebo), can only be viewed within the eCRF system by the 
USDD. A subject will be assigned, in the order randomized into the study to the next 
corresponding treatment assignment per the randomization schedule. 
8.1.1 Study Coordinator (or designee)  
At Visit 3 (Day 0), the Study Coordinator or designee will complete the Randomization 
Module and update status to Randomized in the eCRF system. The information to be entered, 
Study Part, subject weight, Cohort and dose level (Cohort 1 will be dosed at 0.2 mg/kg. and 
subsequent dosing for cohorts will be assigned after each SRC meeting).   
8.1.2 Unblinded Study Drug Dispenser (USDD) 
Once completed, the Unblinded Study Drug Dispenser (USDD) will view the Randomization 
Module and Dosing and Treatment Allocation (active or placebo) for the subject via the eCRF 
page. The Dosing module will provide an auto-calculated dosing volume based on the assigned 
dose, subject weight (entered by the Study Coordinator or designee) and the study drug 
concentration (PB1046 at 40 mg/mL). Additional detailed instructions on access and the 
randomization procedure are provided in the pharmacy procedure manual.  
8.2 
Drug Supplies 
8.3 
Formulation, Packaging and Labelling of Vasomera (PB1046) Injection 
 
Vasomera™ (PB1046) Injection 
 0.5 mL (40 mg/mL) 
Lot No.: 1-FIN-1047       Mfg. Date: 04Mar11 
Recommended Storage at ≤ -70°C  
(Short Term Excursions Permitted. Refer to COA) 
Caution: New Drug – Limited by Federal (or United States)  
Law to Investigational Use 
Manufactured for PhaseBio Pharmaceuticals, Inc by  
Althea Technologies, Inc. 
11040 Roselle St., San Diego, CA 92121 


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8.3.1 Formulation and Packaging of Placebo 
Sterile 0.9% sodium chloride (NaCl) USP for Injection will provided by the Sponsor to the 
study site and will be stored in accordance with the manufacturer’s labeled recommendations.  
A manufacturer’s COA will be provided and will be kept in the study file.  
8.4 
Study Drug Storage   
Vials will be stored long term at ≤ -70°C and, if necessary, may be stored frozen (-10 to -
30°C) or refrigerated (2 to 8°C) at the clinical research site based on stability data and 
Certificate of Analysis (COA). The study drug must be stored in a secure locked area under 
the responsibility of the Principal Investigator or designee.  All unused study drug will be 
returned to PhaseBio Pharmaceuticals Inc. 
8.5 
Preparation and Dispensing     
Since the active study drug is supplied as open labeled bulk vials and placebo may not be 
identical in appearance, randomization, preparation of syringes, and blinding will be performed 
by an Investigator-designated USDD (see Appendix C) who is not otherwise involved in the 
assessment of study subjects. As an additional precaution to maintain the study blind, study 
drug will be administered by a qualified care giver who will not perform any study assessments. 
 
8.5.1 Dose Preparation 
1. The study drug (PB1046) is provided at a concentration of 40 mg/mL with each vial 
containing 0.5 mL (20 mg per vial). Calculate the total dose (mg) for administration 
Investigational Drug Product for Use Only with Protocol <insert> 
 
This box contains ____ single use vials of  
Vasomera (PB1046) Injection 0.5 mL (40 mg/mL) 
 
Refer to above referenced protocol for detailed dosing instructions  
Caution: New Drug – Limited by Federal (or United States) Law to 
Investigational Use 
 
Lot No. 1-FIN-1047      Mfg. Date: 04Mar11 
Recommended Storage at ≤ -70°C (Short Term Excursions Permitted. Refer to COA) 
Manufactured for PhaseBio Pharmaceuticals Inc. by 
Althea Technologies, Inc. 
11040 Roselle St., San Diego, CA 92121 


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based on weight and assigned Cohort/dose level (calculated in the eCRF) and retrieve 
the appropriate number of vials from storage.  
2. Remove the vial(s) from the freezer/refrigerator. Note: If stored frozen, allow to thaw 
at room temperature for approximately 15-30 minutes. Invert, tap and swirl the vials 
to ensure that the material is free flowing and homogeneous. 
3. The mixed solution should be clear and essentially free from particulate matter. 
4. The USSD will immediately draw up the study drug (Vasomera or equal volume of 
placebo) in either a 0.5 or 1.0 mL polypropylene syringe(s) with a 28 gauge 1/2 inch 
needle. Note: If the total volume to be delivered is >1mL, the volume should be split 
evenly between syringes.  
5. The barrel of the syringe(s) will be wrapped with a clear yellow covering and will 
also be labeled with the study number, subject ID, subject initials and date and time 
of dose preparation. Labeling should be placed so as not to obscure verification of the 
injection volume.  
6. Study drug will be administered at room temperature. Note: From the time the vials 
are removed from storage to the time of administration should not be less than 30 
minutes but should not be more than 4 hours. The time the vial(s) are removed from 
storage and the time the drug is prepared should be recorded on the inventory log.   
8.5.2 Administration 
Dosing should occur in the morning between approximately 8:00 and 10:00.  The subject does 
not need to be fasting prior to injection. The study drug (PB1046 [Vasomera] or equal volume 
of placebo) will be injected into the subcutaneous layer of the abdomen. Do not inject in an 
area where tissue is compromised (i.e., scarring, tattoos, broken or irritated skin).  If more than 
one injection is required to deliver the complete dose, injections should be given in close 
proximity (approximately 2 inches) in one quadrant (refer to Figure 7). It is suggested that the 
dosing site be rotated in a clockwise fashion (e.g., first dose RUQ, second dose will be in the 
LUQ, etc.).  The location of injection(s) must be recorded in the source document records in 
order to perform accurate injection site assessments.  
 
Figure 7 
Documenting Location of Injection Sites 
 


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8.6 
Restricted Use of Cold or Heat Applications to Site of Injection 
PB1046 is comprised of VIP fused to an elastin-like polypeptide (ELP) biopolymer to extend 
the half-life and slow the rate of absorption. Direct application of a heat or cold source to the 
site of injection may alter the rate of absorption. Therefore, use of cold or heat applied at the 
site of injection is prohibited.  
8.7 
Compliance 
Study drug will be administered to the subject in the study unit.  
 
8.8 
Study Drug Accountability 
Study drug will be received, dispensed and returned to the Sponsor (unused study drug at the 
end of the study) by the USDD designated by the Principal Investigator and will be 
accounted for by the study drug dispenser on a study drug inventory/accountability log and 
will include: 
• Subject ID and initials and randomization ID 
• Date/time vials removed from storage 
• Amount dispensed for injection 
• Date/time dose prepared 
• Amount remaining in inventory 
 
Inventory records will not be reviewed by the study monitor during routine monitoring visits 
in order to maintain blinding.  
8.9 
Blinding 
The treatment assignment will not be known to investigators, research staff, or study subjects.  
The following study procedures will be in place to ensure double-blind administration of study 
treatments.   
Active study drug and placebo are supplied as open labelled vials and the content of these vials 
may not be identical in appearance.  Randomization, preparation of syringes and blinding will 
be done by an Investigator designated unblinded study drug dispenser (USDD) who is 
otherwise not involved in the assessment of study subjects.   As an added precaution, in order 
to maintain the blind, study drug will be administered by a qualified caregiver who will not 
perform study assessments.   This may also be the USDD. 
Once the USDD has prepared the study drug to be administered using syringes, the barrel of 
the syringe will be wrapped in a clear yellow covering in order to maintain the blind to any 
staff member who may view the syringe. 
For safety studies requiring decision on dose escalation, the blind will be broken after each 
dose cohort to evaluate safety, PK and PD, by the study statistician. Decisions regarding dose 
escalation by the Safety Review Committee (SRC) will be done on a blinded basis.    


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The study blind will be broken on completion of the clinical study and after the study database 
has been locked. After database lock, a request may be submitted to the Sponsor to receive 
study treatment assignment for a subject.  
8.10  Breaking the Study Blind 
During the study, the blind may be broken only in emergencies when knowledge of the 
subject’s treatment group is necessary for further medical management. When possible, the 
Investigator should discuss the emergency with the Medical Monitor prior to unblinding.  
In case of an emergency that requires unblinding of study drug assignment, the USDD will 
unblind the subject’s treatment assignment to the Investigator (Principal or his/her designee) 
and the Medical Monitor using the Sponsor provided Protocol Inquiry Form (PIF), to document 
the reason for unblinding.  A copy of the PIF will be maintained with the dispensing and 
inventory records until the completion of the study. 
8.11 Replacement of Subjects 
Subjects who withdraw from the study and who do not have adequate collection of safety and 
pharmacokinetic samples for evaluation of decisions regarding dose escalation may be 
replaced at the discretion of the Sponsor. 
9 
PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, investigator, or Sponsor fails to adhere to 
significant protocol requirements affecting the inclusion, exclusion, subject safety and primary 
endpoint criteria.  Protocol violations for this study include, but are not limited to, the 
following: 
• 
Failure to meet inclusion/exclusion criteria 
• 
Dosing error 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation. The Sponsor will determine if a protocol violation will result in withdrawal of a 
subject or if data analysis will be censored. 
When a protocol violation occurs, it will be discussed with the Investigator and a Protocol 
Inquiry Form (PIF) detailing the violation will be generated. This form will be signed by a 
Sponsor representative and the Investigator. A copy of the form will be filed in the site’s 
regulatory binder and in the Sponsor’s files. 
 
 


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10 ADVERSE EVENTS 
10.1 Adverse Events 
All observed or volunteered adverse events regardless of treatment group or suspected causal 
relationship to the study drug will be reported as described in the following sections.  
For all adverse events, the Investigator (Principal Investigator or Sub-Investigator) must pursue 
and obtain information adequate both to determine the outcome of the adverse event and to 
assess whether it meets the criteria for classification as a serious adverse event requiring 
immediate notification to PhaseBio Pharmaceuticals, Inc.  For all adverse events, sufficient 
information should be obtained by the Investigator to determine the causality of the adverse 
event. The Investigator (Principal or physician Sub-Investigator) is required to assess causality. 
For adverse events with a causal relationship to the study drug, follow-up by the Investigator 
(Principal or physician Sub-Investigator) is required until the event or its sequelae resolve or 
stabilize at a level acceptable to the Investigator (Principal or physician Sub-Investigator) and 
PhaseBio’s Medical Monitor concurs with that assessment. 
10.2 Reporting Period 
Serious adverse events require immediate notification to PhaseBio Pharmaceuticals, Inc. 
beginning from the time that the subject provides informed consent, which is obtained prior to 
the subject’s participation in the study, i.e., prior to undergoing any study-related procedure 
and/or receiving study drug (investigational product), through and including 28 calendar days 
after the last dose of study drug. Any serious adverse event occurring any time within the 
reporting period must be promptly reported if a causal relationship to investigational product 
is suspected.  
• Adverse events (serious and non-serious) should be recorded on the eCRF from the 
time the subject has signed informed consent through last subject safety visit, unless 
otherwise specified. 
• Any changes in the subject’s baseline status between enrollment (signing informed 
consent) up to the time of study drug administration will be recorded as a pre-treatment 
adverse event and severity will be assessed.  
10.3  Definition of an Adverse Event 
An adverse event is any untoward medical occurrence associated with the use of a drug in 
humans whether or not considered drug related.   This may include worsening of a pre-existing 
medical condition (e.g., diabetes, congestive heart failure, rheumatoid arthritis, psoriasis) that 
occurs at any time after signing of the informed consent (IC). Examples of adverse events 
include, but are not limited to:   
• Clinically significant abnormal test findings; 
• Clinically significant signs and symptoms; 


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• Clinically relevant changes in physical examination findings; 
• Hypersensitivity; 
• Progression/worsening of an underlying disease. 
10.4 Assessment of Severity 
• Mild – An event that is usually transient in nature and generally not interfering with 
normal activities. 
• Moderate – An event that is sufficiently discomforting to interfere with normal 
activities. 
• Severe – An event that is incapacitating with inability to work or do usual activity or 
inability to work or perform normal daily activity. 
10.5 Assessment of Toxicity 
If applicable, adverse events (also refer to Appendix A, Adverse Events of Special Interest for 
criteria and grading) should be graded according to the following grade scale:    
Grade 1 – Mild 
Grade 2 – Moderate 
Grade 3 – Severe 
Grade 4 – Life threatening or disabling 
10.6 Causality Assessment 
The relationship of an adverse event to the administration of the study drug is to be assessed 
according to the following definitions: 
No – (unrelated, not related, no relation) – The time course between the administration of study 
drug and the occurrence or worsening of the adverse event rules out a causal relationship and 
another cause (concomitant drugs, therapies, complications, etc.) is suspected. 
Yes – The time course between the administration of study drug and the occurrence or 
worsening of the adverse event is consistent with a causal relationship and no other cause 
(concomitant drugs, therapies, complications, etc.) can be identified. 
The following factors should also be considered: 
• The temporal sequence from study medication administration: The event should occur 
after the study medication is given. The length of time from study medication exposure 
to event should be evaluated in the clinical context of the event. 


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• Underlying, concomitant, intercurrent diseases: Each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other 
disease the subject may have. 
• Concomitant medication: The other medications the subject is taking or the treatment 
the subject receives should be examined to determine whether any of them might be 
recognized to cause the event in question. 
• Known response pattern for this class of study medication: Clinical and/or preclinical 
data may indicate whether a particular response is likely to be a class effect. 
• Exposure to physical and/or mental stresses: The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event. 
• The pharmacology and pharmacokinetics of the study medication: The known 
pharmacologic properties (absorption, distribution, metabolism, and excretion) of the 
study medication should be considered. 
10.6.1 Suspected Adverse Reaction 
An adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. For the purposes of Investigational New Drug safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the drug and the adverse 
event. 
10.7 Unexpected Adverse Events 
An adverse event or suspected adverse reactions is considered “unexpected” if it is not listed 
in the investigator brochure (IB) or it is not listed at the specificity or severity that has been 
observed; or, if an IB is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as 
amended. Unexpected, as used in this definition, also refers to adverse events or suspected 
adverse reactions that are mentioned in the IB as occurring with a class of drug or as anticipated 
from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 
10.8 Serious Adverse Event Definition 
An adverse event or suspected adverse event reaction is considered serious if, in the view of 
either the Investigator or Sponsor, it results in any of the following outcomes: 
• Death; 
• A life-threatening adverse event; 
• NOTE: An adverse event or suspected adverse event is considered “life-threatening” 
if, in view of either the Investigator or Sponsor, its occurrence places the subject at 


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immediate risk of death. It does not include an event that, had it occurred in a more 
severe form, might have caused death. 
• Requires hospitalization or prolongation of existing hospitalizations; 
NOTE: Any hospital admission will be considered an inpatient hospitalization, 
regardless of duration. An emergency room visit without hospital admission will not 
be recorded as an SAE under this criterion, nor will hospitalization for a procedure 
scheduled before signing of informed consent. However, unexpected complications 
and/or prolongation of hospitalization that occur during elective surgery should be 
recorded as adverse events and assessed for seriousness. 
Admission to the hospital for a pre-planned procedure or social or situational reasons 
(i.e., no place to stay, lives too far away to come for hospital visits) will not be 
considered inpatient hospitalizations.  
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; 
• A congenital anomaly/birth defect; or 
• Other important medical event (event that may jeopardize the patient or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
definition above). 
NOTE: Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalizations, or the development of drug dependency. 
10.9 Reporting 
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse 
event. If a serious adverse event occurs, expedited reporting will follow local and international 
regulations, as appropriate. 
All adverse events will be reported on the adverse event page(s) of the CRF. It should be noted 
that the form for collection of serious adverse event information is not the same as the adverse 
event CRF. Where the same data are collected, the forms must be completed in a consistent 
manner. For example, the same adverse event term should be used on both forms.  Adverse 
events should be reported using concise medical terminology on the CRFs as well as on the 
form for collection of serious adverse event information. 


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10.9.1 Serious Adverse Event Reporting Requirements 
If a serious adverse event occurs, PhaseBio Pharmaceuticals, Inc. is to be notified (see below) 
within 24 hours of awareness of the event by the Investigator. In particular, if the serious 
adverse event is fatal or life-threatening, notification to PhaseBio Pharmaceuticals, Inc. must 
be made immediately, irrespective of the extent of available adverse event information. This 
timeframe also applies to additional new information (follow-up) on previously forwarded 
serious adverse event reports as well as to the initial and follow-up reporting of Exposure in 
utero cases.   
Medical Monitor 
Sponsor Safety Coordinator 
Poul Strange, MD, PhD 
Lauren Richardson 
Office Tel 
609-897-0505 
Ext. 113 
Office Tel 
610-981-6507 
SAE/Study 
Fax: 
1-484-971-5974 
SAE/Study 
Fax 
1-484-971-5974 
Cellular 
609-897-0505 
Ext. 113 
SAE 
(24h/7d) 
610-981-6507/      
610-608-8619 
 
In the rare event that the Investigator does not become aware of the occurrence of a serious 
adverse event immediately (e.g., if an outpatient trial subject initially seeks treatment 
elsewhere), the Investigator is to report the event within 24 hours after learning of it and 
document the time of his/her first awareness of the adverse event. 
 
For all serious adverse events, the Investigator is obligated to pursue and provide information 
to PhaseBio Pharmaceuticals, Inc. in accordance with the timeframes for reporting specified 
above.  In addition, an Investigator may be requested by PhaseBio Pharmaceuticals, Inc. to 
obtain specific additional follow-up information in an expedited fashion. This information may 
be more detailed than that captured on the adverse event case report form. In general, this will 
include a description of the adverse event in sufficient detail to allow for a complete medical 
assessment of the case and independent determination of possible causality.  Information on 
other possible causes of the event, such as concomitant medications and illnesses must be 
provided.  In the case of a subject death, a summary of available autopsy findings must be 
submitted as soon as possible to PhaseBio Pharmaceuticals, Inc. or its designated 
representative. The Investigator must continue to follow the subject until the SAE has subsided 
or until the condition becomes chronic in nature, stabilizes (in the case of persistent 
impairment) or the subject dies. Within 24 hours of receipt of follow-up information, the 
Investigator must update the SAE form and submit to PhaseBio. 
10.9.2 Non-Serious Adverse Event Reporting Requirements and Ongoing Safety 
Review 
Non-serious adverse events are to be reported in the CRF which will be reviewed by PhaseBio 
Pharmaceuticals, Inc. Medical Monitor on an ongoing basis. 


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10.10  Pregnancy Reporting 
If the subject or partner of a subject participating in the study becomes pregnant during the 
study or within 28 days of discontinuing study medication, the Investigator should report the 
pregnancy to the Sponsor, or its representative, within 24 hours of being notified. The Exposure 
In Utero form must be completed by the site. 
The subject or partner should be followed by the Investigator until completion of the 
pregnancy. If the pregnancy ends for any reason before the anticipated date, the Investigator 
should notify the Sponsor. At the completion of the pregnancy, the Investigator will document 
the outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, 
neonatal death, or congenital anomaly), the Investigator should follow the procedures for 
reporting an SAE. Otherwise, a follow up Exposure in Utero form should be completed. 


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11 DATA ANALYSIS AND STATISTICAL METHODS 
11.1 Sample Size Determination  
The sample size is not driven by inferential statistics. The sample size of four (4) (3 active and 
1 placebo) for cohort 1 and eight (8) (6 active and 2 placebo) for subsequent cohorts for the 4 
week multiple dose escalation study is set for qualitative investigation of toxicity as well as 
pharmacokinetics and to explore the potential of a pharmacodynamic response.   
11.2 Analysis Populations 
Three subject populations will be defined. The Safety and Intent-to-Treat (ITT) population will 
be the same and defined as all subjects who receive at least one dose of the study drug.  The 
Per-Protocol (PP) population will be a subset of the ITT population excluding subjects who 
have any major violation of protocol. The pharmacokinetic analysis population will consist of 
all subjects that receive active study drug and have sufficient data for pharmacokinetic 
analysis. 
11.3 Statistical Analysis 
11.3.1 Safety 
Safety will be evaluated by analyses of the incidence and severity of AEs and their relationship 
to study drug. Changes from baseline vital signs, 12 lead ECG, ECG telemetry (e.g., average 
heart rate, rhythm abnormalities), and safety laboratory parameters will be presented 
descriptively by dose and pooled placebo. 
 
Additional analysis specific to 12 lead ECG, will include an analyses of central tendency 
(effect of PB1046 on the QT/QTc interval and analysis of changes occurring around the Cmax) 
and categorical analyses of QT/QTc interval (e.g., absolute QT/QTc intervals > 500 msec or 
changes from baseline; increases from baseline > 30 and > 60).  
 
11.3.2 Pharmacokinetic and Pharmacokinetic Analyses 
Actual blood sampling times will be used in all pharmacokinetic analyses.  Per protocol times 
will be used to calculate mean serum concentrations for tabular and graphical displays.  All 
non-compartmental pharmacokinetic calculations and generation of individual subject serum 
concentration vs. time graphs will be done using SAS for Windows Version 9.4 under 
Windows 8.1.  Graphs of mean serum concentrations vs. time and other in-text figures will be 
prepared using SigmaPlot for Windows Version 12.5. Compartmental modeling will be done 
using Phoenix WinNonlin 6.4 or higher. Exploratory pharmacokinetic/pharmacodynamics 
analyses will be done using appropriate software.  
11.3.2.1 Pharmacokinetic Parameters — Non-Compartmental Analysis 
Pharmacokinetic parameters for PB1046 will be calculated using non-compartmental analysis.  
Only serum concentrations equal to or greater than the validated lower limit of the assay (LOQ) 


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will be used in the pharmacokinetic analysis.  Serum concentrations <LOQ will be taken as 0 
for the calculation of the descriptive statistics for serum concentrations at each sampling time.  
For the pharmacokinetic analysis, serum concentrations < LOQ that occur from pre-dose to the 
first concentration ≥ LOQ will be taken as 0 and those that occur thereafter will be taken as 
missing. 
• First Dose 
Cmax and Tmax will be taken directly from the data.  The area under the curve over the 7-day 
dosing interval [AUC(0-τ)] will be calculated using the linear trapezoidal method. 
• Fourth Dose 
Cmax and Tmax will be taken directly from the data.  The elimination rate constant, λz, will be 
calculated as the negative of the slope of the terminal log-linear segment of the serum 
concentration-time curve.  The slope will be determined from a plot of the natural log of the 
terminal serum concentrations against time; at least 3 terminal serum concentration time 
points, beginning with the final concentration ≥ LOQ, will be selected for the determination of 
λz and the regression will have a coefficient of determination (r²) ≥ 0.9000.  The range of data 
to be used for each subject and treatment will be determined by visual inspection of a semi-
logarithmic plot of concentration vs. time.  Elimination half-life (t½) will be calculated 
according to the following equation: 
                         
 
 
t½ = 
0.693
𝜆𝜆𝜆𝜆  
Area under the curve over the 7-day dosing interval [AUC(0-τ)] will be calculated using the 
linear trapezoidal. 
Total serum clearance (CL) and volume of distribution (Vz), uncorrected for bioavailability 
(F), will be calculated according to 
 
 
 
CL/F = 
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷
𝐴𝐴𝐴𝐴𝐴𝐴 (0−𝜏𝜏)       and        Vz/F = 
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷
𝜆𝜆𝜆𝜆 𝑥𝑥 𝐴𝐴𝐴𝐴𝐴𝐴 (0−𝜏𝜏) 
respectively.  For those subjects for whom λz cannot be estimated, λz, t½, CL/F, and Vz/F will 
be assigned a value of missing. 
The attainment of steady-state will be assessed from the pre-dose serum concentrations 
measured at Weeks 1 through 4 and the concentration 10 days after the last dose. 
11.3.2.2 Pharmacokinetic Parameters — Compartmental Modeling 
If the graphical presentations of the individual subject serum concentrations vs. time suggest 
that a compartmental model may be consistent with the data, then an appropriate model will 
be fit to each subject's complete set of data.  The specific model will be determined after 
examination of the graphs and/or a statistical comparison of the fit of various models.   


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11.3.2.3 Pharmacokinetic/Pharmacodynamic Analysis 
Relationships between pharmacodynamic and pharmacokinetic metrics may be explored 
graphically.  If suggested by the graphs, appropriate models may be fit to the data. 
11.3.3 Immunogenicity (Antibody) Analysis 
Immunogenicity (antibody) samples will be screened for the presence of binding anti-drug 
antibodies (ADA).  Samples testing positive and specific for antibodies against PB1046 will 
be further characterized to determine the domain specificity including whether the antibodies 
cross react with native VIP.   Additional characterization of the antibody response may be 
performed as warranted.  Samples testing positive and specific for anti-drug antibodies will be 
titered and further evaluated for their neutralizing potential using a cell based assay. 
11.3.4 Exploratory  
11.3.4.1 2-D Echocardiography 
Change from baseline in select derived parameters such as  Left ventricular (LV) Ejection 
Fraction, LV Stroke Volume and Index, LV Cardiac Output and Index, Ejection Time, 
Systemic Vascular Resistance, Mitral E and A velocities, LV and index, Myocardial tissue 
velocities S' and e', and myocardial strain (strain rate (SR)/strain rate image (SRI)), may be 
presented descriptively by dose and pooled placebo . If possible, inferential analyses (e.g., 
simple ANOVA) may be conducted to explorer the difference between treatment groups as 
measured by 2-D echocardiography with Doppler.  Measurements may include:  
• Blood pressure (BP) and heart rate (HR) (arterial peak, mean and diastolic blood 
pressure)  
• Left ventricular internal diameter in diastole (cm) 
• Left ventricular internal diameter in systole (cm) 
• Left ventricular wall thickness in diastole (cm; both septum and posterior wall) 
• Left ventricular outflow tract diameter in mid-systole (cm) 
• Left ventricular volumes (end-diastole and end-systole, in mL; apical views) 
• Left ventricular outflow tract flow-time velocity integral (by pulsed Doppler; in cm) 
• Ascending aorta peak flow velocity (by Continuous Wave Doppler; in m/s) 
• Transmitral flow velocity pattern (both by pulsed and Continuous Wave Doppler) 
• Doppler tissue imaging of tricuspid, septal and mitral annulus (velocity; in cm/s) 
• Left atrial volume (in mL/M2) 


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11.3.4.2 Biomarkers 
Change from baseline in select biomarkers may be presented descriptively by dose and pooled 
placebo.  
11.4 Interim (cohort) Safety Analysis for Dose Escalation 
Analysis will be done after 75% of the subjects have received at least three doses (Day 14) of 
study drug and followed for a minimum of 7 days after the third dose. Summary tables 
(descriptive only) of safety, pharmacokinetic, immunogenicity, and other exploratory 
endpoints, as indicated, will be presented using the subjects of that dose group and summary 
data will be provided to the investigators and Study Review Committee in a blinded fashion.


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12 DATA COLLECTION, RETENTION AND MONITORING 
12.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents designed 
to record all observations and other pertinent data for each subject treated with the study drug.  
Study personnel at each site will enter data from source documents corresponding to a subject’s 
visit into the protocol-specific electronic Case Report Form (eCRF) when the information 
corresponding to that visit is available.  Subjects will not be identified by name in the study 
database or on any study documents to be collected by the Sponsor (or designee), but will be 
identified by a site number, subject number and initials. If a correction is required for an eCRF, 
the time and date stamps track the person entering or updating eCRF data and creates an 
electronic audit trail. The Investigator is responsible for all information collected on subjects 
enrolled in this study.  All data collected during the course of this study must be reviewed and 
verified for completeness and accuracy by the Investigator.  Copies of final completed eCRFs 
will be provided on a compact disk (CD) or other similar media for archiving at the study site 
following database lock and at or prior to study closure. 
12.2 Data Management Procedures 
The data will be entered into a validated database.  The Data Management group will be 
responsible for data processing, in accordance with procedural documentation.  Database lock 
will occur once quality assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for the handling and analysis of data for clinical trials. 
12.2.1 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. Queries are entered, 
tracked, and resolved through the electronic data capture (EDC) system directly.  The study 
database will be updated in accordance with the resolved queries.  All changes to the study 
database will be documented. 
12.2.2 Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel 
must log into the system using their secure user name and password in order to enter, review, 
or correct study data. These procedures must comply with Title 21 of the Code of Federal 
Regulations (21 CFR Part 11) and other appropriate international regulations. All passwords 
will be strictly confidential. 
Data should be entered onto the eCRF approximately no later than 72 hours after the visit has 
taken place. 
 


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12.2.3 Medical Information Coding 
For medical information, the following thesauri will be used: 
• Latest version of the Medical Dictionary for Regulatory Activities for medical history 
and adverse events; and 
• World Health Organization Drug Dictionary for prior and concomitant medications. 
12.2.4 Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the uploaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, 
will be referred to the investigative site for resolution through data queries. 
The CRFs must be reviewed and electronically signed by the Investigator who signed the 
protocol. 
12.3 Archival of Data 
The database is safeguarded against unauthorized access by established security procedures; 
appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with any 
updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final reports), data 
for analysis is locked and cleaned per established procedures. 
12.4 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., FDA) 
inspectors upon request.  A file for each subject must be maintained that includes the signed 
Informed Consent, HIPAA Authorization and Assent Form and copies of all source 
documentation related to that subject.  The Investigator must ensure the reliability and 
availability of source documents from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study File 
Notebook, etc.) must be kept secured for a period of two years following marketing of the 
investigational product or for two years after centers have been notified that the IND has been 
discontinued.  There may be other circumstances for which the Sponsor is required to maintain 
study records and, therefore, the Sponsor should be contacted prior to removing study records 
for any reason. 


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12.5 Monitoring 
Monitoring visits will be conducted by representatives of the Sponsor (or designee) according 
to the U.S. CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).  By signing 
this protocol, the Investigator grants permission to the Sponsor (or designee), and appropriate 
regulatory authorities to conduct on-site monitoring and/or auditing of all appropriate study 
documentation. 
12.6 Subject Confidentiality 
In order to maintain subject confidentiality, only a site number, subject number and subject 
initials will identify all study subjects on CRFs, blood samples, and other documentation 
submitted to the Sponsor.  Additional subject confidentiality issues (if applicable) are covered 
in the Clinical Study Agreement. 
12.7 Retained Blood Samples 
Blood samples collected during the study for pharmacokinetic or immunogenicity analysis 
may be retained for future testing as necessary. Subject confidentiality will be maintained 
and only the site and subject number and initials will identify the sample. No other linked or 
identifying information is maintained by the Sponsor.   


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13 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Subjects (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312 Subpart D). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be kept 
in a locked file cabinet.  The Investigator must also comply with all applicable privacy 
regulations (e.g., Health Insurance Portability and Accountability Act of 1996, EU Data 
Protection Directive 95/46/EC). 
13.1 Protocol Amendments 
Any amendment to the protocol will be written by PhaseBio Pharmaceuticals Inc.  Protocol 
amendments cannot be implemented without prior written IRB/IEC approval except as 
necessary to eliminate immediate safety hazards to patients.  A protocol amendment intended 
to eliminate an apparent immediate hazard to patients may be implemented immediately, 
provided the IRBs are notified within five working days. 
13.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse experiences regardless of 
causality will be reported to the IRB/IEC in accordance with the standard operating procedures 
and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC informed as to the 
progress of the study.  The Investigator will obtain assurance of IRB/IEC compliance with 
regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning patient 
recruitment, payment or compensation procedures, or other pertinent information) will be 
submitted to the IRB/IEC.  The IRB/IECs written unconditional approval of the study protocol 
and the informed consent form will be in the possession of the Investigator before the study is 
initiated.  The IRB/IECs unconditional approval statement will be transmitted by the 
Investigator to the Sponsor prior to the shipment of study supplies to the site.  This approval 
must refer to the study by exact protocol title and number and should identify the documents 
reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB/IEC approval except when necessary to eliminate immediate hazards to the 
patients or when the change(s) involves only logistical or administrative aspects of the study.  
Such modifications will be submitted to the IRB/IEC and written verification that the 
modification was submitted and subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new information 


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that may affect adversely the safety of the patients of the conduct of the study; an annual update 
and/or request for re-approval; and when the study has been completed. 
13.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, 
US Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 
50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act 
(HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization and 
provide the documents to the Sponsor or designee for approval prior to submission to the 
IRB/IEC.  The consent form generated by the Investigator must be acceptable to the Sponsor 
and be approved by the IRB/IEC.  The written consent document will embody the elements of 
informed consent as described in the International Conference on Harmonization and will also 
comply with local regulations. The Investigator will send an IRB/IEC-approved copy of the 
Informed Consent Form to the Sponsor (or designee) for the study file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial and conducting any Screening visits.  Information should be 
given in both oral and written form and subjects (or their legal representatives) must be given 
ample opportunity to inquire about details of the study.  If appropriate and required by the local 
IRB/IEC, assent from the subject will also be obtained.  If a subject is unable to sign the 
informed consent form (ICF) and the HIPAA authorization, a legal representative may sign for 
the subject.   A copy of the signed consent form (and assent) will be given to the subject or 
legal representative of the subject and the original will be maintained with the subject’s 
records. 
13.4 Publications  
The preparation and submittal for publication of manuscripts containing the study results shall 
be in accordance with a process determined by mutual written agreement among the study 
Sponsor and participating Investigators.  The publication or presentation of any study results 
shall comply with all applicable privacy laws, including, but not limited to, the Health 
Insurance Portability and Accountability Act of 1996.  
14 SPONSOR DISCONTINUATION CRITERIA 
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB, drug safety problems, or at the discretion of PhaseBio 
Pharmaceuticals, Inc. In addition, PhaseBio Pharmaceuticals, Inc. retains the right to 
discontinue development of the referenced investigational drug at any time. 
 
If the study is prematurely terminated or discontinued, PhaseBio Pharmaceuticals, Inc. will 
promptly notify the Investigator. After notification, the Investigator must contact all 
participating subjects within 5 business days. As directed by PhaseBio Pharmaceuticals, Inc., 
all study materials must be collected and all CRFs completed to the greatest extent possible. 


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15 REFERENCES 
de Antonio, M., Lupon, J., Galan, A., Vila, J., Urrutia, A., & Bayes-Genis, A. (2012). 
Combined use of high-sensitivity cardiac troponin T and N-terminal pro-B type 
natriuretic peptide improves measurements of performance over established 
mortality risk factors in chronic heart failure. The American Heart Journal, 163(5), 
821-828. doi:http://dx.doi.org/10.1016/j.ahj.2012.03.004 
Dvoráková, M. C. (2005). Cardioprotective Role of the VIP Signaling System. Drug News 
& Perspectives, 18(6), 387-391. PMID:16247516 
Irvin, J.J., & White, M. (2004). The importance of accurately assessing orthostatic 
hypotension. Geriatric Nursing, 25(2), 99-101. doi:10.1016/j.gerinurse.2003.10.022 
Sezma, A., & Hamidi, S.A. (2014). Gene deletion of VIP leads to increased mortality 
associated with progressive right ventricular hypertrophy. Journal of 
Cardiovascular Disease, 2(2). 2330-460X (Online). Retrieved from: 
http://www.researchpub.org/journal/jcvd/jcvd.html 
Sherwood, M.W., & Newby, K.D. (2014). High-sensitivity troponin assays: evidence, 
indications, and reasonable use. Journal of the American Heart Association, 3, 1-
10. Doi: 10.1161/JAHA.113.000403 
Tsutsumi, M., Claus, T. H., Liang, Y., Li, Y., Yang, L., Zhu, J., …Pan, C. (2002). A potent 
and highly selective VPAC2 agonist enhances glucose-induced insulin release and 
glucose disposal: A potential therapy for type 2 diabetes. Diabetes, 51(5), 1453-
1460. doi: 10.2337/diabetes.51.5.1453 
 
 
 


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APPENDIX A:  
ADVERSE EVENTS OF SPECIAL INTEREST 
 
Adverse Events of Interest 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially Life Threatening 
(Grade 4) 
Injection site adverse events 
Pain  
Does not interfere with activity  
Repeated use of non-narcotic 
pain reliever for >24 hours or 
interferes with activity  
Any use of narcotic pain reliever 
or prevents daily activity  
Emergency room  
visit or hospitalization  
Tenderness  
Mild discomfort to touch  
Discomfort with movement  
Significant discomfort at rest  
Emergency room visit or 
hospitalization  
Erythema/redness *  
2.5 – 5 cm  
5.1 – 10 cm  
>10 cm  
Necrosis or exfoliative 
dermatitis  
Induration/swelling **  
2.5 – 5 cm and does not 
interfere with activity  
5.1 – 10 cm or interferes with  
activity  
>10 cm or prevents daily 
activity  
Necrosis  
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a continuous variable.  
** Induration/swelling should be evaluated and graded using the functional scale as well as the actual measurement. 


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APPENDIX B:  
IMMUNOGENICITY (ANTIBODY) AND PHARMACOKINETIC 
SAMPLE HANDLING, LABELING, AND SHIPMENT 
INSTRUCTIONS  
Sample Identification and Specimen Collection 
 
Specimen kits, requisition forms, and labels will be provided to appropriately identify 
specimens. At minimum, each label will contain the protocol number, subject number, and 
specimen collection date and time point. Refer to Laboratory Procedure Manual for additional 
instructions.  
 
Labels should be placed on the tube such that all information is legible. Assure that labels 
adhere to the tubes and will not detach during storage. 
 
Sample information must be accurately recorded on the PK and Immunogenicity Specimen 
Collection eCRF page and on the source documentation maintained by the site.   
 
 
Collection and Processing of PK Samples  
  
• Collect venous blood in 1 × 3.5 mL marble top serum separator tube (pre dose baseline) 
and 1 × 3.5 mL marble top serum separator tube for all subsequent sample collection 
time points. Each collection tube yields approximately 1.5 to 2 mL serum if filled 
completely. 
• Gently invert each collection tube approximately 3 times. 
• Allow the clot to form for approximately 30 minutes prior to centrifugation. 
• Separate the serum centrifugation at 2500-3000 rpm (approximately1800 G or until 
there is complete separation of the serum and blood cells via the separator gel) for 
15 minutes at room temperature. 
• For each sampling time point, transfer an equal amount of serum (1.5-2.0 mL) into each 
of 2 pre-labeled 1.5 mL polypropylene tubes (label as set A and set B) and immediately 
store in a freezer at -70°C or lower until shipment is initiated. 
 
Collection and Processing of Immunogenicity Samples  
  
• Collect venous blood in 2 × 3.5 mL marble top serum separator tube (pre dose baseline) 
and 1 x 3.5 mL for all subsequent sample collection time points. Each collection tube 
yields approximately 1.5 to 2 mL serum if filled completely. 
• Gently invert each collection tube approximately 3 times. 


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• Allow the clot to form for approximately 30 minutes prior to centrifugation. 
• Separate the serum centrifugation at 2500-3000 rpm (approximately1800 G or until 
there is complete separation of the serum and blood cells via the separator gel) for 
15 minutes at room temperature. 
• For each sampling time point, transfer an equal amount of serum into each of 4 pre-
labeled 1.5 mL polypropylene tubes (label two vials as set A and two vials as set B) 
and immediately store in a freezer at -70°C or lower until shipment is initiated. 
 
Shipment 
 
The US Department of Transportation and the International Air Transport Association regulate 
shipments of blood and blood components because it is a biohazardous material. Federal rules 
require that anyone wishing to ship biohazardous material must have shipping training. 
 
All samples will be shipped frozen to Medpace Reference Laboratory unless otherwise directed 
by the Sponsor or as further described in the laboratory manual.  Additionally refer to the 
Laboratory Manual for specific specimen handling instructions.  
 
 


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 APPENDIX C: 
RESPONSIBILITIES OF THE UNBLINDED STUDY DRUG 
DISPENSER (USDD) 
General Responsibilities 
The Investigator (Principal Investigator) will assign via the Delegation of Authority Log 
individual(s) who are qualified by training and experience to prepare study drug as the study 
designated Unblinded Study Drug Dispenser (USDD). 
The USDD will sign a statement that assures PhaseBio Pharmaceuticals Inc. and regulatory 
authorities that he/she understands his/her obligations and responsibilities as specified in the 
protocol (i.e., correct dispensing of study drug and the manner in which it is to be 
administered).  The original and/or copy of the signed statement will be forwarded to PhaseBio 
Pharmaceuticals Inc. and a copy will be retained in the Essential Document Regulatory File. 
The USDD is responsible for all study drug inventory records will be responsible for 
maintaining the confidentiality and security of the treatment assignment/inventory records. 
From time-to-time throughout the study, an unblinded Quality Assurance Representative from 
the Sponsor will evaluate (secured blinded document portal within the eCRF) the study drug 
inventory forms and request clarifications as needed.  
Treatment Assignment and Preparation 
The USDD will view the Randomization Module and Dosing and Treatment Allocation (active 
or placebo) for the subject via the eCRF page. The Dosing module will provide an auto-
calculated dosing volume based on the assigned dose, subject weight (entered by the Study 
Coordinator or designee) and the study drug concentration (PB1046 at 40 mg/mL). Additional 
detailed instructions on access and the randomization procedure are provided in the pharmacy 
procedure manual.  The USDD will prepare the study drug in accordance with Section 8.5.1. 
Dispensing 
The USDD will prepare study drug that is appropriately blinded and labeled with the Subject 
ID, Randomization Number, subject initials and date/time dose prepared. The USDD will 
deliver the prepared blinded study drug to the Investigator or designee. 
The USDD will complete all dispensing information on the dispensing and inventory records 
provided by PhaseBio Pharmaceuticals Inc. 
The USDD may be permitted to administer the study drug to the study subject but will not 
participate in the safety/efficacy evaluations for any study subject.  
 
 
 


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APPENDIX D 
SELF-MONITORED BLOOD PRESSURE DIARY 
 
 

SAP_001.pdf: 


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Table of Contents 
1 
OVERVIEW ............................................................................................................................................. 6 
1.1 
INTRODUCTION ........................................................................................................................................ 6 
1.2 
OBJECTIVES .................................................................................................................................................. 6 
1.2.1 
Primary Objective ........................................................................................................................... 6 
1.2.2 
Secondary Objectives ...................................................................................................................... 6 
1.2.3 
Exploratory Objectives .................................................................................................................... 6 
2 
INVESTIGATIONAL PLAN ........................................................................................................................ 7 
2.1 
STUDY DESIGN AND RANDOMIZATION .................................................................................................... 7 
2.1.1 
Study Design ................................................................................................................................... 7 
2.1.2 
Inclusion Criteria ............................................................................................................................. 7 
2.1.3 
Exclusion Criteria ............................................................................................................................ 8 
2.1.4 
Sample Size Justification ............................................................................................................... 10 
2.1.5 
Randomization .............................................................................................................................. 10 
2.1.6 
Scheduled Procedures and Flow Chart .......................................................................................... 10 
3 
ENDPOINTS .......................................................................................................................................... 19 
3.1 
SAFETY ENDPOINTS...................................................................................................................................... 19 
3.2 
PHARMACOKINETIC ENDPOINTS ..................................................................................................................... 19 
3.3 
IMMUNOGENICITY ENDPOINTS ....................................................................................................................... 20 
3.4 
EFFICACY ENDPOINTS ................................................................................................................................... 20 
4 
ANALYSIS POPULATIONS...................................................................................................................... 21 
SAFETY AND INTENT-TO-TREAT (ITT) POPULATION ...................................................................................................... 21 
PER-PROTOCOL (PP) POPULATION: .......................................................................................................................... 21 
PHARMACOKINETIC (PK) POPULATION:..................................................................................................................... 21 
5 
GENERAL ASPECTS OF STATISTICAL ANALYSIS ...................................................................................... 21 
5.1 
GENERAL METHODS .................................................................................................................................... 21 
5.2 
KEY DEFINITIONS ......................................................................................................................................... 22 
5.2.1 
Baseline Values ............................................................................................................................. 22 
5.2.2 
Study Day ...................................................................................................................................... 22 
5.2.3 
End of Study .................................................................................................................................. 22 
5.3 
DATA HANDLING ......................................................................................................................................... 22 
5.3.1 
Missing Data ................................................................................................................................. 22 
5.3.2 
Per Protocol Time Points Vs Actual Time Points ........................................................................... 23 
5.3.3 
Repeated and Unscheduled Visit .................................................................................................. 23 
6 
PLANNED ANALYSIS ............................................................................................................................. 23 
6.1 
SUBJECT DISPOSITION .................................................................................................................................. 23 
6.2 
PROTOCOL VIOLATIONS ................................................................................................................................ 23 
6.3 
DEMOGRAPHICS .......................................................................................................................................... 23 
6.4 
MEDICAL HISTORY ....................................................................................................................................... 24 
6.5 
DOSING INFORMATION AND COMPLIANCE ....................................................................................................... 24 
6.6 
PRIOR AND CONCOMITANT MEDICATIONS ....................................................................................................... 24 
6.7 
EFFICACY ANALYSIS ...................................................................................................................................... 24 
6.7.1 
2-D Echocardiogram ..................................................................................................................... 24 
6.7.2 
N-terminal Pro-B Type Natriuretic Peptide (NT-ProBNP) .............................................................. 25 
6.7.3 
High Sensitivity Cardiac Troponin T Assay (hs-cTnT)..................................................................... 25 
6.7.4 
Exploratory biomarkers ................................................................................................................ 25 


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6.8 
SAFETY ANALYSIS ........................................................................................................................................ 26 
6.8.1 
Adverse Events (AE) ...................................................................................................................... 26 
6.8.2 
Injection Site Reactions (ISRs) ....................................................................................................... 27 
6.8.3 
ECG ............................................................................................................................................... 27 
6.8.4 
Telemetry ...................................................................................................................................... 29 
6.8.5 
Vital Signs ..................................................................................................................................... 29 
6.8.6 
Physical Examination .................................................................................................................... 29 
6.8.7 
Laboratory Evaluations ................................................................................................................. 29 
6.8.8 
Self-monitored Blood Pressure (SMBP) ......................................................................................... 30 
6.9 
PHARMACOKINETICS (PK) ............................................................................................................................. 30 
6.9.1 
Measurements and Collection Schedule ....................................................................................... 30 
6.9.2 
Pharmacokinetic Data Handling ................................................................................................... 31 
6.9.3 
PK Analysis .................................................................................................................................... 32 
6.9.4 
Pharmacokinetic Parameters — Compartmental Modeling ......................................................... 32 
6.10 
IMMUNOGENICITY (ANTIBODY) ................................................................................................................. 32 
6.11 
DEVIATIONS FROM THE PROTOCOL SPECIFIED ANALYSIS ................................................................................. 33 
7 
REFERENCE LIST ................................................................................................................................... 33 
8 
LIST OF PLANED LISTING, TABLE AND FIGURES .................................................................................... 34 
9 
SOFTWARE DOCUMENTATION ............................................................................................................. 35 
10 
APPENDIX ............................................................................................................................................ 36 
 
 
 


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ABBREVIATIONS 
 
Abbreviations 
Definitions 
ADA 
Anti-drug Antibodies 
AE 
Adverse Event 
BMI 
Body mass index 
BSA 
Body surface area 
BP 
Blood Pressure 
Cmax 
Maximum Serum Concentration 
CFB 
Change from baseline 
DLT 
Dose Limiting Toxicity 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
ECHO 
Echocardiography 
eCRF 
electronic Case Report Form 
eGFR 
Estimated glomerular filtration rate 
ITT 
Intent-to-Treat 
OSBP 
Office-seated Blood Pressure 
PB1046 
Vasomera 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
PT 
Preferred Term 
QTcB 
QT interval corrected for heart rate 
QTcF 
QT corrected by Fredericia's formula 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SC 
SD 
SMBP 
Subcutaneous 
Standard Deviation 
Self-monitored blood pressure 
SOC 
System Organ Class 
SRC 
Study Review Committee 


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ABBREVIATIONS 
 
Abbreviations 
Definitions 
ADA 
Anti-drug Antibodies 
TEAE 
Treatment emergent adverse event 


PB1046-PT-CL-0003 Part 1 SAP 
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1 OVERVIEW 
1.1 INTRODUCTION  
This documentation describes the data analyses for PhaseBio PB1046-PT-CL-0003-
P1 clinical trial.  
1.2 OBJECTIVES   
1.2.1 Primary Objective 
To evaluate the safety and tolerability of escalating doses of PB1046 administered 
once weekly for 4 weeks in adult subjects with stable NYHA Class II/III heart failure 
with a reduced ejection fraction (HFrEF). 
1.2.2 Secondary Objectives 
 Characterize the pharmacokinetic profile of a subcutaneous dose of PB1046 
administered once weekly for 4 weeks; 
 Evaluate the immunogenicity profile of a subcutaneous dose of PB1046 
administered once weekly for 4 weeks. 
1.2.3 Exploratory Objectives 
 Characterize the effect of escalating doses of PB1046 on cardiac function as 
measured by 2-D echocardiography with Doppler; 
 Characterize the effect of PB1046 on cardiac, anti-inflammatory and anti-fibrotic 
biomarkers. 


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2 INVESTIGATIONAL PLAN 
2.1 STUDY DESIGN AND RANDOMIZATION 
2.1.1 Study Design 
 
 
This study is a randomized, double-blind, placebo-controlled study that will assess 
the safety, tolerability, pharmacokinetics and explore the pharmacodynamics of 
PB1046 following 4 weeks of once weekly subcutaneous injections.  
This study will be conducted in two parts:  
 Part 1 will be a sequential multiple-dose escalation study that will enroll 
(randomize and dose) approximately 28 (3A:1P in Cohort 1 and 6A:2P in 
subsequent cohorts) subjects total of 4 cohorts.  
 Part 2 of the study will be further described and conducted under a separate 
Part 2 protocol (PB1046-PT-CL-0003-P2).  
2.1.2 Inclusion Criteria 
 
Subjects will be eligible for inclusion in the study if they meet all of the following 
criteria: 
 
1. Willing and able to sign a written informed consent and follow all study-related 
procedures; 
2. Male or female subject ≥ 18 years of age; 
3. Male subjects and female subjects of reproductive or childbearing potential 
must practice effective contraception during the study and be willing and able 
to continue contraception for 30 days after their last dose of study drug. 
Female subjects of non-childbearing potential are defined as being surgically 
sterile by bilateral tubal ligation, bilateral oophorectomy, or hysterectomy.  A 
female subject 45 to 60 years of age, inclusive who is post-menopausal for at 
least 1 year and has a follicle-stimulating hormone level confirmation 
indicating post-menopausal status will be considered of non-childbearing 
potential.  Female subjects > 60 years of age are considered post-
menopausal and of non-childbearing potential;  


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4. Body mass index ≥ 18 kg/m2 and ≤ 45 kg/m2; 
5. Receipt of stable (no change in dose (except diuretics) or addition or removal 
of a therapy) pharmacological therapy(ies) for heart failure for a minimum of 1 
month (30 days) prior to screening and between screening and randomization 
and are in stable clinical condition; 
6. NYHA Class II or III heart failure with reduced ejection fraction diagnosis 
confirmed by medical history at least (≥) 6 months (180 days) prior to 
screening and/or ischemic or non-ischemic cardiomyopathy with reduced 
ejection fraction confirmed by medical history at least (≥) 6 months (180 days) 
prior to screening and historical echocardiography of ejection fraction ≤ 40% 
prior to screening;  
7. Stable HF defined as no hospitalizations for cardiac related issues within the 
previous 3 months (90 days) prior to the screening visit or between screening 
and randomization; 
8. Screening hemoglobin ≥ 9.0 g/dL secondary to the volume of blood to be 
collected during the study period. 
9. Willing and able to return to the study unit for specified study visits, and be 
able to self-monitor blood pressure while at home. 
10. Live and work in an area with reliable cellular services (e.g., Sprint®) for real 
time transmission of telemetry data to the core laboratory. 
2.1.3 Exclusion Criteria 
 
Subjects will be excluded from the study if they meet any of the following criteria: 
 
1. Have previously received PB1046 or have a known allergy to the study drug 
or any of its components; 
2. Participating in any other study and have received any other investigational 
medication or device within 30 days prior to screening or are taking part in a 
non-medication study which, in the opinion of the Investigator, would interfere 
with study compliance or outcome assessments; 
3. Diagnosed with acute coronary syndrome (ACS) or an acute myocardial 
infarction (MI) within 3 months (90 days) of screening;  


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4. Canadian Cardiovascular Society (CCS) Class III or IV angina necessitating 
frequent use of as needed short acting nitroglycerin (e.g., sublingual); 
5. Cardiac surgery or valvuloplasty within 3 months (90 days) prior to screening; 
6. Cerebrovascular accident or transient ischemic attack within 3 months (90 
days) prior to screening; 
7. Sustained systolic blood pressure (SBP) < 110 mmHg and/or diastolic blood 
pressure (DBP) < 50 mmHg (confirmed by a duplicate seated reading) on at 
least 3 consecutive readings (self-monitored or office) prior to randomization 
or overt symptomatic hypotension; 
8. Sustained resting heart rate >100 beats per minute (BPM) at screening (V1) 
or prior to randomization (confirmed on baseline telemetry monitoring); 
9. History or evidence (documented on baseline telemetry monitoring) of 
clinically significant arrhythmias (uncontrolled by drug therapy or use of an 
implantable defibrillator), long QT syndrome or evidence of QT prolongation 
demonstrating non-paced QTcF > 460 ms (by ECG) prior to randomization 
(Subjects with QTcF > 460 ms due to electronic pacing by an implanted 
pacemaker/ICD device or a stable bundle branch block (BBB), may be 
enrolled);  
10. Clinically significant renal dysfunction as measured by the estimated 
glomerular filtration rate (eGFR) of < 40 mL/min/1.73m2 as calculated by the 
CKD-EPI creatinine-cystatin C equation: eGFR = 135 x min (Scr/k, 1)-a × 
max(Scr/k, 1)-0.601 × min(Scys/0.8, 1)-0.375 × max(Scys/0.8, 1)-0.711 × 
0.995age [× 0.969 if female ] [× 1.08 if black ] at screening, or a significant 
change in renal function between screening and baseline; 
11. Clinically 
significant 
liver 
dysfunction 
as 
measured 
by: 
alanine 
aminotransferase >3.0 × the upper limit of normal (ULN), aspartate 
aminotransferase >3.0 × the ULN, or serum bilirubin ≥ 1.6 mg/dL at 
screening, or a significant change in liver function between screening and 
baseline; 
12. Pregnant or lactating female subjects; 
13. Known history of or active alcohol abuse or use of illicit drugs within 1 year 
prior to randomization;  


PB1046-PT-CL-0003 Part 1 SAP 
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14. Positive screening for human immunodeficiency virus antibodies, hepatitis B 
surface antigen, or hepatitis C virus antibodies; 
15. Any major surgical procedure within 1 month (30 days) prior to screening or 
planned surgical procedure during the study period;  
16. Other medical or psychiatric condition which, in the opinion of the 
Investigator, would place the subject at increased risk or would preclude 
obtaining voluntary consent/assent or would confound the secondary 
objectives of study. 
2.1.4 Sample Size Justification 
The sample size is not driven by inferential statistics. The sample size of four (4) (3 
active and 1 placebo) for cohort 1 and eight (8) (6 active and 2 placebo) for 
subsequent cohorts for the 4 week multiple dose escalation study is set for 
qualitative investigation of toxicity as well as pharmacokinetics and to explore the 
potential of a pharmacodynamic response.  
2.1.5 Randomization  
Qualifying subjects will be randomly assigned via a central randomization system to 
receive either PB1046 or placebo. Only the unblinded study drug dispenser (USDD) 
at the study site will have access to the randomization assignment. However,  in 
preparation of the Study Review Committee (SRC) meeting, when at least 75% of 
subjects assigned to a cohort have received at least 3 doses, independent study 
statistician, unblinded safety reviewer at BioTelemetry  and pharmacokineticist 
(including PK analytical lab) will have access to the randomization codes for that 
cohort in order to prepare data summaries required for the study review meetings to 
assist in decisions regarding dose escalation.  Displays will be provided to the 
committee in a blinded and partially unblinded (group) manner. 
2.1.6 Scheduled Procedures and Flow Chart 


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SCHEDULE OF ACTIVITIES 
Week/Description 
 
Screen 
 
Week -1  
 
Week 1/ 
Dose 1 
Week 1/ 
Daily 
Visits 
Week 2/ 
Dose 2 
Week 3/ 
Dose 3 
Week 4/ 
Dose 4 
Week 4/ 
 Daily Visits 
Week 5/ 
 Daily Visits 
Week 8/  
Safety 
Week 12/ 
Immuno-
genicity 
 Visit Number 
 V1 
 V2 
V3 
 V4-V7 
V8 
 V9 
 V10 
 V11-V14 
 V15-18 
V19 or ET 
 V20 
Study Day 
-60 
-7  
(-10 to -
7) 
0 
1, 2, 3 
and 5 
7 
14 
21 
22, 23, 24 
and 26 
28, 29, 30, 
and  31 
49 ± 3 
days 
77 
 ± 3 days 
Test  
Protocol Reference 
ml/ 
test 
Number of Tests 
Adverse Events 
Refer to 
Section:Error! 
eference source 
not found.  
 
 
1 
1 
4 
1 
1 
1 
4 
4 
1 
 
Concomitant 
Medications  
Refer to 
Section:Error! 
eference source 
not found.  
 
1 
1 
1 
4 
1 
1 
1 
4 
4 
1 
 
Consent 
Refer to Section 
Error! Reference 
ource not found. 
 
1 
 
 
 
 
 
 
 
 
 
 
Demographics 
Refer to Section 
Error! Reference 
ource not found. 
 
1 
 
 
 
 
 
 
 
 
 
 
Directed Physical 
Examination  
Refer to Section 
Error! Reference 
ource not found. 
 
 
As needed only for Evaluation of Adverse Events 
Dosing (in office) 
Refer to Section 
Error! Reference 
ource not found. 
 
 
 
1 
 
1 
1 
1 
 
 
 
 
Blood 
Volume 


PB1046-PT-CL-0003 Part 1 SAP 
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Week/Description 
 
Screen 
 
Week -1  
 
Week 1/ 
Dose 1 
Week 1/ 
Daily 
Visits 
Week 2/ 
Dose 2 
Week 3/ 
Dose 3 
Week 4/ 
Dose 4 
Week 4/ 
 Daily Visits 
Week 5/ 
 Daily Visits 
Week 8/  
Safety 
Week 12/ 
Immuno-
genicity 
 Visit Number 
 V1 
 V2 
V3 
 V4-V7 
V8 
 V9 
 V10 
 V11-V14 
 V15-18 
V19 or ET 
 V20 
Study Day 
-60 
-7  
(-10 to -
7) 
0 
1, 2, 3 
and 5 
7 
14 
21 
22, 23, 24 
and 26 
28, 29, 30, 
and  31 
49 ± 3 
days 
77 
 ± 3 days 
Test  
Protocol Reference 
ml/ 
test 
Number of Tests 
Dose Preparation 
(USDD) 
Refer to Section 
Error! Reference 
ource not found.  
 
 
 
1 
 
1k 
1k 
1k 
 
 
 
 
Echocardiography 
- 2D with Doppler 
Refer to Section 
Error! Reference 
ource not found. 
 
1g 
1b,d 
 
1v 
 
 
 
1i 
 
 
 
Electrocardiogra
m 12- lead 
Refer to Section 
Error! Reference 
ource not found. 
 
1 
 
3t,u 
4o,n,u 
1b 
1b 
1b,u 
4o,n,u 
1h,u 
1 
 
Height/Weight/BM
I/BSA 
Refer to Section 
Error! Reference 
ource not found. 
 
1 
 
 
 
 
 
 
 
 
 
 
Histories – 
Medical, Targeted 
Medical, Surgical, 
Social and 
Medications 
Refer to Section 
Error! Reference 
ource not found. 
 
1 
 
 
 
 
 
 
 
 
 
 
Blood 
Volume 


PB1046-PT-CL-0003 Part 1 SAP 
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Week/Description 
 
Screen 
 
Week -1  
 
Week 1/ 
Dose 1 
Week 1/ 
Daily 
Visits 
Week 2/ 
Dose 2 
Week 3/ 
Dose 3 
Week 4/ 
Dose 4 
Week 4/ 
 Daily Visits 
Week 5/ 
 Daily Visits 
Week 8/  
Safety 
Week 12/ 
Immuno-
genicity 
 Visit Number 
 V1 
 V2 
V3 
 V4-V7 
V8 
 V9 
 V10 
 V11-V14 
 V15-18 
V19 or ET 
 V20 
Study Day 
-60 
-7  
(-10 to -
7) 
0 
1, 2, 3 
and 5 
7 
14 
21 
22, 23, 24 
and 26 
28, 29, 30, 
and  31 
49 ± 3 
days 
77 
 ± 3 days 
Test  
Protocol Reference 
ml/ 
test 
Number of Tests 
Inclusion/Exclusio
n 
Refer to Sections 
Error! Reference 
ource not found., 
Error! Reference 
ource not found., 
Error! Reference 
ource not found., 
Error! Reference 
ource not found., 
and Error! 
eference source 
not found. 
 
1 
1 
1b 
 
 
 
 
 
 
 
 
Injection Site 
Assessment 
Refer to section 
Error! Reference 
ource not found. 
 
 
 
1a 
4f 
1b 
1b 
1b 
4f 
4f 
1 
 
LAB – Alcohol 
and drug screen 
(urine)q 
Refer to Section 
Error! Reference 
ource not found. 
NA 
1 
1 
1b 
 
1b 
1b 
1b 
 
 
 
 
Blood 
Volume 


PB1046-PT-CL-0003 Part 1 SAP 
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Week/Description 
 
Screen 
 
Week -1  
 
Week 1/ 
Dose 1 
Week 1/ 
Daily 
Visits 
Week 2/ 
Dose 2 
Week 3/ 
Dose 3 
Week 4/ 
Dose 4 
Week 4/ 
 Daily Visits 
Week 5/ 
 Daily Visits 
Week 8/  
Safety 
Week 12/ 
Immuno-
genicity 
 Visit Number 
 V1 
 V2 
V3 
 V4-V7 
V8 
 V9 
 V10 
 V11-V14 
 V15-18 
V19 or ET 
 V20 
Study Day 
-60 
-7  
(-10 to -
7) 
0 
1, 2, 3 
and 5 
7 
14 
21 
22, 23, 24 
and 26 
28, 29, 30, 
and  31 
49 ± 3 
days 
77 
 ± 3 days 
Test  
Protocol Reference 
ml/ 
test 
Number of Tests 
LAB - NT-proBNP  
and hs-cTnT 
Refer to Sections 
Error! Reference 
ource not found. 
and Error! 
eference source 
not found. 
4.0 
1c 
 
1b 
3o 
1b 
1b 
1b 
1i 
1h 
1 
 
LAB - Exploratory 
Biomarkers: 
microRNA 
Refer to Section 
Error! Reference 
ource not found. 
2.5 
 
 
1b 
3o 
1b 
1b 
1b 
1i 
1h 
1 
 
LAB- Exploratory 
Biomarkers:Other 
Refer to Section 
Error! Reference 
ource not found. 
8 
 
 
1b 
3o 
1b 
1b 
1b 
1i 
1h 
1 
 
LAB - 
Immunogenicity  
Refer to Section 
Error! Reference 
ource not found.  
3.5 
 
 
1b,s 
 
1b 
1b 
1b 
 
1h 
1 
1 
LAB – Lipids/FPG  
Refer to Sections 
Error! Reference 
ource not found. 
and Error! 
eference source 
not found. 
9 
1p 
1p 
 
 
 
 
 
 
 
1 
 
Blood 
Volume 


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Week/Description 
 
Screen 
 
Week -1  
 
Week 1/ 
Dose 1 
Week 1/ 
Daily 
Visits 
Week 2/ 
Dose 2 
Week 3/ 
Dose 3 
Week 4/ 
Dose 4 
Week 4/ 
 Daily Visits 
Week 5/ 
 Daily Visits 
Week 8/  
Safety 
Week 12/ 
Immuno-
genicity 
 Visit Number 
 V1 
 V2 
V3 
 V4-V7 
V8 
 V9 
 V10 
 V11-V14 
 V15-18 
V19 or ET 
 V20 
Study Day 
-60 
-7  
(-10 to -
7) 
0 
1, 2, 3 
and 5 
7 
14 
21 
22, 23, 24 
and 26 
28, 29, 30, 
and  31 
49 ± 3 
days 
77 
 ± 3 days 
Test  
Protocol Reference 
ml/ 
test 
Number of Tests 
LAB - 
Pharmacokinetics  
Refer to Section 
Error! Reference 
ource not found. 
3.5 
 
 
4b,e 
4o,n 
1b 
1b 
4b,e 
4o, n 
4f 
 
 
LAB - Safety Labs 
(Hematology, 
chemistry UA, 
eGFR calculation) 
Refer to Sections 
Error! Reference 
ource not found. 
and Error! 
eference source 
not found. 
12 
1 
1 
 
 
1b 
1b 
1b 
 
1h 
1 
 
LAB - Serology  
(HIV, HepB and 
Hep C) 
Refer to Section 
Error! Reference 
ource not found. 
4 
1 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
Testing (females of 
CBP) 
Refer to Error! 
eference source 
not found.  
NA 
1 
1 
1q,b 
 
1b,q 
1b, q 
1b, q 
 
 
 
 
Blood 
Volume 


PB1046-PT-CL-0003 Part 1 SAP 
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Week/Description 
 
Screen 
 
Week -1  
 
Week 1/ 
Dose 1 
Week 1/ 
Daily 
Visits 
Week 2/ 
Dose 2 
Week 3/ 
Dose 3 
Week 4/ 
Dose 4 
Week 4/ 
 Daily Visits 
Week 5/ 
 Daily Visits 
Week 8/  
Safety 
Week 12/ 
Immuno-
genicity 
 Visit Number 
 V1 
 V2 
V3 
 V4-V7 
V8 
 V9 
 V10 
 V11-V14 
 V15-18 
V19 or ET 
 V20 
Study Day 
-60 
-7  
(-10 to -
7) 
0 
1, 2, 3 
and 5 
7 
14 
21 
22, 23, 24 
and 26 
28, 29, 30, 
and  31 
49 ± 3 
days 
77 
 ± 3 days 
Test  
Protocol Reference 
ml/ 
test 
Number of Tests 
Physical 
Examination 
Refer to Section  
Error! Reference 
ource not found. 
 
1 
 
1b,j 
 
 
 
 
 
 
1 
 
Registration 
Refer to Section 
Error! Reference 
ource not found. 
 
 
1 
 
 
 
 
 
 
 
 
 
Randomization 
Refer to Section 
Error! Reference 
ource not 
found.Error! 
Reference source 
not found. 
 
 
 
1 
 
 
 
 
 
 
 
SMBPm 
Refer to Section 
Error! Reference 
ource not found. 
 
 
 
 
 
Telemetry - 
mobilel 
Refer to Section 
Error! Reference 
ource not found. 
 
 
 
 
Telephone 
contactr 
Refer to section 
Error! Reference 
ource not found. 
 
 
 
1 
 
1 
1 
1 
 
 
 
 
Blood 
Volume 


PB1046-PT-CL-0003 Part 1 SAP 
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Week/Description 
 
Screen 
 
Week -1  
 
Week 1/ 
Dose 1 
Week 1/ 
Daily 
Visits 
Week 2/ 
Dose 2 
Week 3/ 
Dose 3 
Week 4/ 
Dose 4 
Week 4/ 
 Daily Visits 
Week 5/ 
 Daily Visits 
Week 8/  
Safety 
Week 12/ 
Immuno-
genicity 
 Visit Number 
 V1 
 V2 
V3 
 V4-V7 
V8 
 V9 
 V10 
 V11-V14 
 V15-18 
V19 or ET 
 V20 
Study Day 
-60 
-7  
(-10 to -
7) 
0 
1, 2, 3 
and 5 
7 
14 
21 
22, 23, 24 
and 26 
28, 29, 30, 
and  31 
49 ± 3 
days 
77 
 ± 3 days 
Test  
Protocol Reference 
ml/ 
test 
Number of Tests 
Vital Signs – 
Orthostatic 
Refer to Section 
Error! Reference 
ource not found. 
 
1 
 
1b 
4f 
1b 
1b 
1b 
4f 
4f 
1 
 
Vital Signs - 
Seated 
Refer to Section 
Error! Reference 
ource not found. 
 
1 
 
3b,a 
4f 
1b 
1b 
1b,a 
4f 
4f 
1 
 
Weight  
Refer to Section 
Error! Reference 
ource not found. 
 
 
1b 
1b 
1b 
1b 
 
 
1 
 
Total Blood Volume 
369 mL 
 
29 
21 
35.5 
57.5 
33.5 
33.5 
44 
28.5 
44 
39 
3.5 
 
a 
1 and 3 hours post dose (± 15 minutes) 
b 
Prior to dosing 
c 
 NT-proBNP only 
d 
Can occur up to 2 weeks (14 days) prior to scheduled randomization but should be done before placement of the mobile telemetry device. 
e 
1 and 3 hours (± 10 minutes) 
f 
Daily ± 2 hours from previous dose time.  
g 
If an historical (routine care) echo was within 60 days prior to screening and EF ≤ 40%, the screening echo will not need to be repeated. However, the baseline echo must be done 
between Day -14 and Day -7 to confirm final study eligibility by central reader.  
h 
Day 28 only (± 2 hours after last dose) 
i 
Day 24 only ± 1 day (collect biomarker and echo on the same days) 
j 
Abbreviated physical examination  
k 
± 2 hours from time of day of previously weekly dose 
l 
Continuous monitoring from approximately 7 days prior to dosing (baseline) through 7 days after the last dose of study drug. 
m 
Omron Blood Pressure Monitor with ComFit™ Cuff (Model BP785N) for use of self-monitoring of blood pressure at home starting approximately 7 days prior to randomization.  Subjects 
will be required to collect blood pressure and heart rate using the same arm every morning and every evening. 
n 
120 hours (± 26 hours) after last dose from previous dose time. 
o 
Completed at 24, 48, and 72 hours (± 1 hour) after last dose. When PK and ECG are required at a given time point, the ECG should be done within 30 minutes and BEFORE collection of 
PK sample. 
Blood 
Volume 


PB1046-PT-CL-0003 Part 1 SAP 
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Page 18 of 36 
p 
Only performed/analyzed at screening if subject was fasting for at least 8 hours otherwise they will only be reported at Visit 2 when subject was instructed to fast prior to visit. 
q 
r 
Local testing only. 
Should occur in evening (suggested time between 7 and 10 PM). 
s 
Collect 2 x 3.5mL tubes at baseline. 
t 
Prior to dosing, at approximately -60 minutes, -30 minutes, -15 minutes 
u 
Triplicate measurement, approximately 1 minute apart 
v 
48 (-6 to +24 hours) hours after dosing 


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Page 19 of 36 
3 ENDPOINTS 
3.1 SAFETY ENDPOINTS 
 
 Treatment emergent adverse events (TEAEs), serious adverse events (SAE), 
severity and relationship to study drug of TEAEs, adverse events (AEs) 
leading to discontinuation from the study, and deaths 
 Actual and change from Baseline in clinical laboratory results 
 Actual and change from Baseline in vital signs 
 Actual and change from Baseline in physical examinations 
 Actual and change from Baseline in ECG findings (heart rate (HR), QTcF, PR 
interval, and QRS) 
 Actual and change from Baseline in telemetry data 
 
3.2 PHARMACOKINETIC ENDPOINTS 
 
For patients with enough PK data, the following parameters will be estimated for 
PB1046 by non-compartmental analysis methods in Phoenix® WinNonLin® 6.4 or 
higher.   
 
Dose 1 
Cmax 
Maximum plasma concentration (ng/mL)  
 
Tmax 
Time of maximum concentration (h) 
 
AUC(0-τ) 
 
Area under the plasma concentration-time curve for 
the 7 day dosing period, calculated by linear 
trapezoidal summation. 
 
AUC(0-tmax) 
Area under the plasma concentration-time curve 
from time zero (predose) to Tmax, calculated by linear 
trapezoidal summation. 
 
AUC(tmax-) 
Area under the plasma concentration-time curve 
from Tmax to last measurable concentration of the 7-
day dosing period, calculated by linear trapezoidal 
summation. 
Dose 4 
Cmax 
Maximum plasma concentration (ng/mL), obtained 
directly from the observed concentration versus time 
data  
 
tmax 
Time of maximum concentration (h), obtained directly 
from the observed concentration versus time data  
 
Z 
The elimination rate constant, Z, will be calculated 
as the negative of the slope of the terminal log-linear 


PB1046-PT-CL-0003 Part 1 SAP 
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segment of the serum concentration-time curve.  The 
slope will be determined from a plot of the natural log 
of the terminal serum concentrations against time; at 
least 3 terminal serum concentration time points, 
beginning with the final concentration  LOQ, will be 
selected for the determination of  Z and the 
regression will have a coefficient of determination (r²) 
 0.9000.   
 
t½ 
 
t½ = 
0.693
𝜆𝑧 
 
AUC(0-τ) 
 
Area under the plasma concentration-time curve for 
the 7 day dosing period, calculated by linear 
trapezoidal summation. 
 
AUC(0-tmax) 
Area under the plasma concentration-time curve 
from time zero (predose) to Tmax, calculated by linear 
trapezoidal summation. 
 
AUC(tmax-) 
Area under the plasma concentration-time curve 
from Tmax to last measurable concentration of the 7-
day dosing period, calculated by linear trapezoidal 
summation. 
 
CL/F 
Total serum clearance (CL), corrected for 
bioavailability (F) 
CL/F = 
𝐷𝑜𝑠𝑒
𝐴𝑈𝐶 (0−𝜏)        
 
Vz/F 
Volume of distribution (Vz) corrected for 
bioavailability (F) 
Vz/F = 
𝐷𝑜𝑠𝑒
𝜆𝑧 𝑥 𝐴𝑈𝐶 (0−𝜏) 
 
Ctrough 
Pre-dose serum concentrations  
 
3.3 IMMUNOGENICITY ENDPOINTS 
 Incidence and characteristics of the anti-drug antibody (ADA) immune 
response  
 Relationship of ADA with clinical safety and efficacy 
 Relationship of ADA with pharmacokinetics (PK) and, when relevant, 
pharmacodynamic biomarkers 
3.4 EFFICACY ENDPOINTS 
 


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4 ANALYSIS POPULATIONS 
 
Safety and intent-to-treat (ITT) population: The Safety and Intent-to-Treat (ITT) 
population will be the same and defined as all subjects who receive at least one 
dose of the study drug. 
 
Per-protocol (PP) Population: The Per-Protocol (PP) population will be a subset of 
the ITT population excluding subjects who have any major violation of the protocol. 
 
Pharmacokinetic (PK) Population: The pharmacokinetic population will consist of 
all subjects that receive active study drug and have sufficient data for 
pharmacokinetic analysis. 
 
5 GENERAL ASPECTS OF STATISTICAL ANALYSIS 
5.1 General Methods 
 
The proposed statistical analysis methodologies are in accordance with the 
principles outlined by the International Conference on Harmonization (ICH) E9 
guidelines[1]. Subject listings of all data represented in the electronic case report form 
(eCRF) and other vendor sourced assessments (eg, Diary) will be provided. 
Measurements from subjects excluded from the predefined analysis populations or 
extra measurements (such as unscheduled or repeat assessments) will not be 
included in summary tables, unless specified otherwise, but will be included in the 
subject listings. In general, the subject listings will be sorted by cohort, subject 
number, and assessment date (and time), if applicable. For summary tables, data 
will be presented by treatment group with placebo pooled. 
 
Unless otherwise specified, continuous/quantitative variables will be summarized 
using descriptive statistics, which will include the number of subjects with data to be 
summarized (n), mean, standard deviation (SD), median, minimum, and maximum. 
The same number of decimal places as in the raw data will be presented when 
reporting the minimum and maximum, 1 more decimal place than in the raw data will 
be presented when reporting the mean and median, and 2 more decimal places than 
in the raw data will be presented when reporting the SD.  
 
 Actual and change from Baseline in 2-D echocardiographic parameters  
 Actual and change from Baseline in exploratory cardiac, anti-inflammatory, 
and anti-fibrotic biomarkers 


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All categorical/qualitative data will be presented using frequency counts and 
percents.  The total number of subjects in the treatment group overall (N) will be 
used as the denominator for percentage calculations, unless stated otherwise in the 
table shell. All percents will be presented as 1 decimal point, unless otherwise 
specified. Percents equal to 100 will be presented as 100% and percents will not be 
presented for zero frequencies.  
 
All statistical tests will be 2-sided and have an associated α-level=0.05 unless 
mentioned otherwise. Confidence limits will be 2-sided and calculated with a 95% 
confidence coefficient, unless stated otherwise. 
 
All statistical analyses will be done using SAS® (SAS Institute, Cary, NC) statistical 
software version 9.1.3 or higher. 
5.2 Key Definitions 
5.2.1 Baseline Values 
For the safety, immunogenicity, and efficacy parameters assessed at the scheduled 
study visits, the baseline value is defined as the last non-missing measurement or 
assessment prior to the first dose of study drug.  
5.2.2 Study Day 
Subjects will be randomized and the first dose of randomized medication will be 
administered on Day 0. The Study Day is calculated as Event Date – First Dose 
Date.  
5.2.3 End of Study 
The end of study is defined as the date of early termination or the date of last safety 
assessment. It will be obtained from the eCRF. The end of study value is defined as 
the last non-missing measurement or assessment on or before the end of study. 
5.3 Data Handling 
5.3.1 Missing Data 
When Baseline is missing, screening data may be used to impute Baseline value. 
Other missing data will not be imputed. 
 


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5.3.2 Per Protocol Time Points Vs Actual Time Points  
Actual blood sampling times will be used unless mean plasma concentrations is 
required, in which case, per protocol times will be used. Details on PK data handling 
will be included in the PK section in the Appendix.   
5.3.3 Repeated and Unscheduled Visit 
 
The principle of ‘last observation priority’ will be used to handle the situation of 
repeated visit. Note that repeated visit is different from unscheduled visit, which can 
be identified from eCRF. The data will be updated base on the following rule: 
 
 If a variable (except dates and all lab transferred data) is measured/collected 
at the repeated visit, the value of that variable will be replaced with the value 
from the repeated visit. 
 Dates and Lab transferred data will be determined case by case based on its 
medical meaning. 
 If a variable is not collected at the repeated visit, then the value from the 
original visit will be kept intact. 
 Data from unscheduled visit will only be used in the analysis if specific visit 
has corresponding missing values and it is in a suitable time window. This 
change has to be reviewed and signed off by the medical monitor. 
 
6 PLANNED ANALYSIS 
6.1 Subject Disposition 
 
Disposition will be summarized for each study period for all enrolled subjects. The 
number and percentage of subjects who complete or discontinue prematurely will be 
summarized by treatment group and overall. A listing of disposition will be provided 
for all subjects.  
6.2 Protocol Violations 
 
Protocol violations will be evaluated by the medical monitor and determined whether 
or not they are major protocol violations. Subjects with major protocol violations will 
be excluded from the PP population. 
6.3 Demographics   
 


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Demographics and baseline characteristics will be listed and summarized by 
treatment group and overall for the safety population. Demographic characteristics 
will include age, sex, race, ethnicity, height, weight, body mass index (BMI), body 
surface area (BSA). Age (years) will be calculated as INTEGER ((Date of Informed 
Consent – Date of Birth)/365.25). 
6.4 Medical History 
 
Medical History, general and targeted, will be listed. 
6.5  Dosing Information and Compliance 
 
Information regarding dose cohort, dose level, volume, total dose and compliance be 
will be summarized by treatment group and study visit. Compliance is calculated as: 
compliance (%) = (actual volume injected) / (expected volume injected) x 100. All 
data will be listed as well. 
6.6 Prior and Concomitant Medications 
 
All medications and other treatments taken by subjects within 90 days prior to the 
screening period will be recorded on the eCRF. Prior medications are defined as 
medications taken prior to the first dose of study medication, regardless of whether 
they were continued or not after the first dose of study medication.  
Concomitant medications are defined as medications that were taken on or after the 
first dose date, including those that started before the first dose date but continued 
into the Treatment Period. 
 
Both prior and concomitant medications will be summarized by ATC code, preferred 
name and drug name. All data will be listed as well.  
6.7 Efficacy Analysis 
 
All efficacy analyses will be exploratory. The following efficacy variables will be 
considered in the efficacy analyses.  
6.7.1 2-D Echocardiogram  
 
2D Echocardiography is measured at screening, Day -7, Day 2 and Day 24. Day -7 
value will be used as Baseline. The following echocardiographic parameters may be 
considered for evaluation. Change from baseline of these parameters will be 
calculated and all data will be listed by subject. 
 


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Blood pressure (BP) and heart rate (HR) (arterial peak, mean and diastolic blood pressure) 
Left ventricular internal diameter in diastole (cm) 
Left ventricular internal diameter in systole (cm) 
Left ventricular wall thickness in diastole (cm; both septum and posterior wall) 
Left ventricular outflow tract diameter in mid-systole (cm) 
Left ventricular volumes (end-diastole and end-systole, in mL; apical views) 
Left ventricular outflow tract flow-time velocity integral (by pulsed Doppler; in cm) 
Ascending aorta peak flow velocity (by Continuous Wave Doppler; in m/s) 
Transmitral flow velocity pattern (both by pulsed and Continuous Wave Doppler) 
Doppler tissue imaging of tricuspid, septal and mitral annulus (velocity; in cm/s) 
Left atrial volume (in mL/M2) 
6.7.2 N-terminal Pro-B Type Natriuretic Peptide (NT-ProBNP) 
 
NT-ProBNP measurement will be collected at Screening, day 0, day 1, 2, 3, 7, 14, 
21, 24, and 28.   Arithmetic and geometric mean of actual and change from Baseline 
NT-ProBNP will be summarized by treatment group and visits. Graphical 
presentation of mean change from Baseline NT-ProBNP vs study day will be 
included.  
6.7.3 High Sensitivity Cardiac Troponin T Assay (hs-cTnT) 
 
Hs-cTnT assessed at Screening, day 0, day 1, 2, 3, 7, 14, 21, 24, and 28. Arithmetic 
and geometric mean actual and change from Baseline NT-ProBNP will be 
summarized by treatment group and visits. Graphical presentation of mean change 
from Baseline hs-cTnT vs study day will be included.  
6.7.4 Exploratory biomarkers 
 
Exploratory biomarkers will be taken at day 0 prior to dosing, day 1, 2, 3, 7, 14, 21, 
24, and 28.  Samples taken at day 0, 14, and 28 are being evaluated.  Change from 
baseline of these parameters will be calculated.  Additional timepoints will be 
evaluated as warranted.  This data will be provided by Sponsor but will not be 
incorporated into the eCRF system. Actual and change from Baseline of each 
biomarker value will be summarized by treatment group and visits. All data will be 
listed by subject.  
 
Exploratory Biomarkers (list may not be all encompassing) 
 
 Flow 
Cytometry 
CD2, CD3, CD4, CD8, CD16, CD19, CD25, CD45, and CD26 
 3 plex kit 
MMP-1, MMP-3, MMP-9 (matrix metalloproteinases) 
  
TGF-β1 
 
CRP (C-Reactive Protein) 


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Galectin-3 
 10 plex kit 
IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IFN-γ, and TNF α 
  
TIMP-1 (tissue inhibitor of metalloproteinase 1) 
 
ST2 (growth stimulation expressed gene 2) 
 
IL-33 
 
6.8 Safety Analysis 
6.8.1 Adverse Events (AE) 
 
TEAEs are defined as any AEs that started on or after the first dose of study drug. 
All reported AEs (including non-TEAEs) will be listed, but only TEAEs will be 
summarized in tables.  
 
An overall summary of TEAEs will be provided, by treatment group and overall, the 
number and percentage of subjects who reported: 
 
 Subjects reporting at least one TEAE (n, %) 
 Total number of TEAEs 
 Subjects reporting at least one severe TEAEs (n, %) 
 Total number of severe TEAEs 
 Subjects reporting a TEAE related to study treatment (n, %) 
 Total number of related TEAEs 
 Subjects reporting a serious adverse event (SAE) (n, %) 
 Total number of SAEs 
 Subjects reporting dose limiting toxicity (DLT) (n, %) 
 Total number of DLT 
 Number of subjects who had a TEAE leading to study discontinuation 
 Subjects who died (n, %) 
 
 
A set of summary tables of TEAEs by SOC and PT will also be presented for the 
following categories. 
 
 TEAEs 
 SAEs 
 Severe TEAEs 
 Treatment-related TEAEs 
 TEAEs leading to study discontinuation 
 
In the summary tables subjects may be counted under multiple SOCs and PTs, but 
for each SOC and PT, subjects are only counted once. If a subject has the same AE 


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on multiple occasions, the highest severity (severe > moderate > mild) or drug 
relationship (definitely related > probably related > possibly related > unlikely related 
> not-related) recorded for the event will be presented as needed by the table 
summary of interest. If severity of AE is missing in the database, it will be 
programmed to be ‘severe’ for the counts in the summary table. If drug relationship 
is missing then the AE will be considered as ‘related’ for the summary table. 
 
Listings will be provided for all AEs, SAEs, AEs leading to study discontinuation, and 
deaths. 
 
6.8.2  Injection Site Reactions (ISRs) 
 
ISRs are captured under AE domain but will be evaluated separately by severity and 
toxicity grade. The toxicity is graded as the following: 
 Grade 1 – Mild 
 Grade 2 – Moderate 
 Grade 3 – Severe 
 Grade 4 – Life threatening or disabling 
 
ISRs will be summarized by PTs, toxicity grade. The following overall summary will 
be included in the beginning part of the table: 
 
 Subjects reporting at least one ISR (n, %) 
 Total number of ISRs 
 Subjects reporting at least one severe (toxicity ≥ 3) ISR (n, %) 
 Total number of severe ISRs 
 Subjects reporting dose limiting toxicity (DLT) (n, %) 
 Total number of DLT 
 Number of subjects who had a ISR leading to study discontinuation 
 Subjects who died (n, %) 
6.8.3 ECG  
 
 
ECG parameters will be imported directly from the electronic ECG database 
(BioTelemetry) based on the data transfer specifications.  
Change from baseline will be calculated for each visit day (refer to schedule below).  
Baseline is defined as the mean of 9 pre-dose ECG collected at approximately -60 
(T2, T3, T4). -30 (T5, T6, T7) and -15 (T8, T9, T10) minutes before dosing on Day 0.   
Visit Description 
Time Point 
Data Handling 
Screening 
1 


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Day 0 / Pre-Dose (-60 mins) 
2, 3, 4 
Baseline = mean of 9 measurements 
Day 0 / Pre-Dose (-30 mins) 
5, 6, 7 
Day 0 / Pre-Dose (-15 mins) 
8, 9, 10 
Day 1 
11, 12, 13 
Mean of three measurements 
Day 2 
14, 15, 16 
Mean of three measurements 
Day 3 
17, 18, 19 
Mean of three measurements 
Day 5 
20, 21, 22 
Mean of three measurements 
Day 7 
23 
Day 14 
24 
Day 21 
25, 26, 27 
Mean of three measurements 
Day 22 
28, 29, 30 
Mean of three measurements 
Day 23 
31, 32, 33 
Mean of three measurements 
Day 24 
34, 35, 36 
Mean of three measurements 
Day 26 
37, 38, 39 
Mean of three measurements 
Day 28 
40, 41, 42 
Mean of three measurements 
Day 49 (± 3 days) 
43 
Unscheduled 
99 
 
The following ECG parameters will be recorded: heart rate (bpm), PR interval 
(msec), QRS interval (msec), QT interval (msec), and corrected QT (QTc) intervals 
(msec). QT will be corrected for heart rate using Fridericia’s (QTcF) interval and 
Bazett's (QTcB).  
For each ECG parameter, the observed value and change from Baseline value will 
be summarized using descriptive statistics by study visit and treatment group for all 
subjects in the safety population. 
In addition, counts and percentages of subjects with outlying QT/QTc values 
(absolute value >500 msec, increase from Baseline value of >30 or >60 msec, or 
15% or more change from Baseline) based on ICH Guidance E14[2] will be presented 
by study visit and treatment group. 
Changes of QTc vs serum exposure from PK data might also be investigated. 
Graphical presentation of actual and change from Baseline in ECG parameters over 
time will be included. 


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All ECG data will be included in subject listings. 
 
6.8.4  Telemetry 
 
Telemetry data will be listed by subjects. 
6.8.5 Vital Signs 
 
Vital signs include blood pressure (seated and orthostatic), heart rate, respiratory 
rate, and body temperature. Orthostatic blood pressure will be assessed at 
screening, prior to each dosing and daily on Week 1, Week 4 and Week 5. The rest 
of the vital signs will be assessed at screening, prior to dosing of each week, 1hr and 
3 hrs post dosing of Week 1 and Week 4, daily on the rest of the days of Week 1 
and Week 4, and daily on Week 5.  
For each vital sign parameter, the observed value and change from Baseline value 
will be summarized using descriptive statistics by study visit and treatment group. 
Percent change from Baseline in seated blood pressure will also be summarized. 
Mean of the actual and change from Baseline seated and orthostatic blood pressure 
will be plotted against study days to visualize the changes over time. % change from 
Baseline in seated blood pressure vs study days will also be plotted. 
 
All vital signs data will be presented in the subject listings. 
6.8.6 Physical Examination 
 
Physical examination includes but not limited to examination of general appearance, 
skin, eyes, ears, nose, throat, neck/thyroid, lungs, heart, upper/lower extremities, 
lymph nodes, abdomen, musculoskeletal system and neurological system. Clinically 
significant findings will be recorded as an adverse event. 
Weight is measured on Screening, prior to each dosing from Week 1 to Week 4, and 
on Week 8. Change from Baseline weight value will be calculated. 
Physical examination and weight results will be presented in a data listing. 
6.8.7 Laboratory Evaluations 
 
Laboratory tests include safety labs (Hematology, Chemistry, Urinalysis, eGFR), 
Serology (HIV, HepB and Hep C), lipid, drug and alcohol test, pregnancy test (urine 
and serum).  


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Hematology, Chemistry, eGFR results and their changes from Baseline value will be 
summarized by treatment group and analysis visit using descriptive statistics. The 
Baseline value and change from Baseline value at each visit will be provided for all 
subjects in the safety population. 
 
The laboratory test result will be reported as “High”, “Low”, or “Normal” with respect 
to relevant reference ranges.  
All laboratory data will be listed. Laboratory test results falling out of the normal 
range will be marked as high or low in the listings.  
 
6.8.8 Self-monitored Blood Pressure (SMBP) 
 
SMBP will be entered in the eCRF from the paper source subject diary. Missing 
blood pressure values will not be imputed. SMBP is collected by patient once in the 
morning and once in the evening. Mean of the actual and change from Baseline 
SMBP for morning or evening will be plotted against study days to visualize the 
changes over time. 
6.9 Pharmacokinetics (PK) 
 
PK assessments will be performed on serum concentrations from subjects receiving 
PB1046. All non-compartmental pharmacokinetic calculations and generation of 
individual subject serum concentration vs. time graphs will be performed using 
Phoenix WinNonlin 6.4 or higher.  Graphs of mean serum concentrations vs. time 
and other in-text figures will be prepared using Phoenix WinNonlin 6.4 or higher. 
Compartmental modeling will be done using Phoenix WinNonlin 6.4 or higher, or 
Phoenix NLME 1.3 or higher, or NONMEM 7.3 or higher. Exploratory 
pharmacokinetic/pharmacodynamics analyses will be done using appropriate 
software. 
 
 
6.9.1 Measurements and Collection Schedule 
Blood samples to determine serum concentrations of PB1046 will be collected as 
follow: 
 
-Week 1: 0 (pre-dose), 1, 3, 24, 48, 72, and 120 hours post-dose,  
-Week 2 and 3: 0 (pre-dose) hour, 
-Week 4: 0 (pre-dose), 1, 3, 24, 48, 72, 120, 168, 192, 216, and 240 hours 
post-dose.  
 


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The acceptable windows for collection of blood samples for PK are the following: ± 
10 minutes (sampling at 1 and 3 hours post-dose), ± 1 hour (sampling at 24, 47, and 
72 hours post-dose), ± 26 hours (sampling at 120 hours post-dose). 
 
6.9.2 Pharmacokinetic Data Handling 
PK parameters from serum concentrations for PB1046 will be calculated using a 
non-compartmental approach based on the concentration vs time data. The 
parameters listed in the table below (but not limited to) will be obtained, as data 
permit.   
 
The PK parameters will be provided according to PB1046 dose levels. Subjects for 
whom there is insufficient data to calculate the PK parameters will have available 
data included in the concentration tables with descriptive statistics only. Only serum 
concentrations equal to or greater than the validated lower limit of the assay (LOQ) 
will be used in the pharmacokinetic analysis. Serum concentrations <LOQ will be 
taken as 0 for the calculation of the descriptive statistics for serum concentrations at 
each sampling time. For the calculation of the PK parameters, serum concentrations 
< LOQ that occur from pre-dose to the first concentration  LOQ will be taken as 0 
and those that occur thereafter will be taken as missing. 
 
Actual blood sampling times relative to dosing will be used in the computation of PK 
parameters. A minimum of 3 descending concentration-time points, excluding the 
Cmax, above the lower limit of quantification (LLOQ) will be used in the estimation of 
the elimination rate constant (z) and the regression will have a coefficient of 
determination (r²)  0.9000, for the determination of the elimination half-life (t1/2). For 
those subjects for whom z cannot be estimated, z, t1/2, CL/F, and Vz/F will be 
assigned a value of missing. 
 
Unless otherwise specified below, missing sampling or concentration values will not 
be imputed, but left missing in the calculation of derived PK parameters. If the actual 
sampling time is missing, but a valid concentration value has been measured, the 
scheduled protocol time will be used for the calculation of derived PK parameters. 
 
On a case by case basis, it may be necessary to exclude individual PK 
concentration values for the calculation of derived PK parameters because they are 
erroneous, abnormal or appear implausible to the pharmacokineticist in charge of 
the analysis. Any excluded data will be flagged in the individual data listings. The 
reason for exclusion will also be documented. If the exclusion has a meaningful 
impact on the overall interpretation of the results, then it will be discussed in the PK 
report. 
 


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6.9.3 PK Analysis 
Actual blood sampling times will be used in the generation of individual 
concentration-time profiles. Per protocol times will be used to calculate mean serum 
concentrations for tabular and graphical displays. 
 
Pharmacokinetic analysis will be carried out for the PK population.  Individual PK 
parameters will be listed. Descriptive statistics (number of non-missing observations 
(N), arithmetic mean, SD, minimum, median, maximum, coefficient of variation 
(CV%), geometric mean and geometric CV%) will be used to summarize the 
calculated PK parameters by dose levels and dosing weeks. 
 
Individual concentration profiles with actual blood sampling times will be listed. 
Descriptive summary statistics (N, arithmetic mean, SD, minimum, median, 
maximum, CV%, geometric mean and geometric CV%) will be used to summarize 
the concentration profiles by dose levels and dosing weeks. 
 
Individual time-concentration graphs will be provided for each subject in both linear 
and semi-log scales. Mean time-concentration graphs will be provided for each dose 
levels in both linear and semi-log scales to provide visual examination of PK profiles 
after multiple doses of PB1046 and to facilitate steady state and accumulation 
assessments. Descriptive statistics of the pre-dose serum concentrations (Ctrough) 
measured from Weeks 1 through 4 and the concentration 7 days after the last dose 
and the plot of individual/mean Ctrough-time profiles will be presented to facilitate 
the steady-state assessment. 
 
6.9.4 Pharmacokinetic Parameters — Compartmental Modeling 
If the graphical presentations of the individual subject serum concentrations vs. time 
suggest that a compartmental model may be consistent with the data, then an 
appropriate model will be fit to each subject's complete set of data.  The specific 
model will be determined after examination of the graphs and/or a statistical 
comparison of the fit of various models, as data permit. 
6.10  Immunogenicity (Antibody) 
 
Immunogenicity results will be presented in tabular, text, or graphical form as 
appropriate.  The extent of analysis for evaluating the clinical relevance of ADA-
positive samples depends upon the phase of development, sample size, and ADA 
incidence. Thus the type and extent of analysis will be driven by sound scientific 
judgement and justified in the CSR4.   
 
Counts and percentages of subjects will be classified by their ADA status and 
treatment group.   
 


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In a post-hoc analysis, immunogenicity data will be assessed to determine the 
clinical relevance.  The relationship to anticipated or relevant adverse events, such 
as the occurrence of injection site reactions, in antibody positive and antibody 
negative PB1046 treated subjects will be evaluated.  In addition to the potential 
impact on safety, subjects testing positive for anti-drug antibodies may be evaluated 
for any impact on PK and clinical efficacy.  
6.11 Deviations From the Protocol Specified Analysis  
 
There are no deviations from the protocol-specified analysis. 
 
7 REFERENCE LIST 
 
1. ICH Harmonised Tripartite Guideline “E9 Statistical principles for clinical trials” 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/
E9/Step4/E9_Guideline.pdf. Accessed May 15, 2015. 
 
2. ICH Guidance "E14 Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs” Error! Hyperlink reference 
not 
valid.http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformat
ion/guidances/ucm073153.pdf. Accessed May 04, 2015 
 
3. ICH Guidance “E3 Structure and Content of Clinical Study Reports”. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/
E3/E3_Guideline.pdf. Accessed May 04, 2015. 
 
4. Shankar G, Arkin S, Cocea L, Devanarayan V, Kirshner S, Kromminga 
A, Quarmby V, Richards S, Schneider CK, Subramanyam M, Swanson 
S, Verthelyi D, Yim S.  Assessment and Reporting of the Clinical Immunogenicity 
of Therapeutic Protein and Peptides – Harmonized Terminology and Tactical 
Recommendations.  AAPS J. 2014 Jul;16(4):658-73. 
 


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8 LIST OF PLANED LISTING, TABLE AND FIGURES 
 
Please see the Appendix 1. 
 
Numbering of TLFs will follow ICH E3 guidance[3], unless otherwise specified. 
Note that this is the planned Table of Content, based on the actual data, table 
numbers, table names and structures may change. 


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9 SOFTWARE DOCUMENTATION 
 
PC SAS – Windows version 9.1.3 or higher. 
PC R - Windows version 12.0 or higher. 
WinNonlin - Professional Version 5.2 or higher. 
Excel - Microsoft Excel 2007 or higher. 
 
 


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10 APPENDIX 
 
1. Statistical Analysis Plan V1 - Appendix 1 Table of contents V1.xlsx