Clinical trial NCT03928353
Conditions: Healthy
Sponsor: SFJ Pharmaceuticals, Inc.
Start date: 2019-04-16; Completion date: 2019-10-09
Enrollment: 23 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 2A, randomized, double-blind, placebo-controlled, single dose, sequential group study to evaluate the safety, tolerability, PK, and PD of PB2452 vs matching placebo with ticagrelor (with or without acetylsalicylic acid (ASA)) pretreatment when various dose levels and administration regimens are administered to healthy younger (ages 18 to 50), older (ages 50 to 64 years) and elderly (ages 65 to 80 years) male and female subjects.

Up to 5 dose levels and/or administration regimens will be evaluated in up to 5 cohorts. Each cohort will include approximately 8 to 12 subjects randomized in a 3:1 ratio (PB2452:placebo).

Detailed description:
The study will consist of a Screening period, a Check-in day and Pretreatment Period, an on-site Randomization/Treatment day, 3 days on-site for treatment and safety monitoring, a Follow-up Visit (Day 7), and a Final Follow-up visit (Day 28). Seven days prior to Randomization, subjects in Cohorts 1 and 2 will be administered acetylsalicylic acid (ASA) 81 mg orally once daily (QD) until the final dose on the morning of Day 1 before receiving study drug. A ticagrelor 180 mg oral dose will be administered on the morning of Day -2 followed by either 90 mg or 180 mg every 12 hours (BID) until the 5th dose has been administered on the morning of Day 1.

On Day 1, subjects who meet all the inclusion criteria and none of the exclusion criteria will be randomized in a ratio 3:1 (PB2452:placebo), to receive an IV dose of PB2452 or placebo 2 hours following the 5th ticagrelor dose. Subjects may be discharged from the clinical site between Days 3 and 7 inclusive and will return for a Follow-up visit on Day 7, if already discharged, and on Day 28 (±2 days).

Arms: arm 1: PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses arm 2: PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses arm 3: PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg BID for a total of 5 doses arm 4: PB2452 Infusion or Placebo - Sodium Chloride With Ticagrelor Oral Tablet: 180 mg BID for a total of 5 doses arm 5: PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg BID for a total of 5 doses
Interventions: intervention 1: PB2452 Infusion intervention 2: Placebo - Sodium Chloride intervention 3: Ticagrelor Oral Tablet - Pre-Treatment intervention 4: Ticagrelor Oral Tablet - Pre-Treatment and Post-Treatment intervention 5: Ticagrelor Oral Tablet - Pre-Treatment intervention 6: PB2452 Infusion intervention 7: Placebo - Sodium Chloride
Intervention descriptions: intervention 1: 30 minute - 24 hour infusion intervention 2: 30 minute - 24 hour infusion intervention 3: Ticagrelor 180 mg + 90 mg BID for 5 doses prior to PB2452 or Placebo intervention 4: Ticagrelor 180 mg + 90 mg BID for 5 doses prior to PB2452 or Placebo and Ticagrelor 180 mg 24 hours following PB2452 or Placebo intervention 5: Ticagrelor 180 mg BID for 5 doses prior to PB2452 or Placebo intervention 6: 30 minute - 16 hour infusion intervention 7: Placebo - Sodium Chloride

Protocol documents:
Prot_000.pdf: 
PhaseBio Pharmaceuticals, Inc 
PB2452 
Protocol No. PB2452-PT-CL-0002 Part A 
Clinical Study Protocol
25July2019 
Page 1
 
CLINICAL STUDY PROTOCOL: PB2452-PT-CL-0002 
Part A: A Phase 2A, Randomized, Double-blind, Placebo-controlled, Single 
Dose, Sequential Group Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of PB2452 with Ticagrelor 
Pretreatment in Older and Elderly Subjects 
 
Version Number: 2 Part A 
 Study Drug Name: PB2452 
Phase 2A IND #: 125267 
Sponsor:  
PhaseBio Pharmaceuticals Inc.  
1 Great Valley Parkway, Suite 30  
Malvern, PA 19355 
Chief Medical Officer:
John Lee, MD, PhD 
 
 
 
 
 
PhaseBio Pharmaceuticals Inc. 
 
 
 
 
 
Phone: 610-981-6505 
  
 
 
 
 
 
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 
 
 
 
 
 
 
     PB2452 
Protocol No. PB2452-PT-CL-0002 Part A 
Clinical Study Protocol 
25July2019 
Page 3 
 
AGREEMENT OF INVESTIGATOR 
STUDY TITLE: Part A: A Phase 2A, Randomized, Double-blind, Placebo-controlled, Single 
Dose, Sequential Group Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of PB2452 with Ticagrelor Pretreatment in Older and Elderly Subjects 
 
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), responsible for initial and continuing review 
and approval of the clinical study, complies with the requirements of 21 CFR §56; 
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: ____________________________________________ 


PhaseBio Pharmaceuticals, Inc 
 
 
 
 
 
 
     PB2452 
Protocol No. PB2452-PT-CL-0002 Part A 
Clinical Study Protocol 
25July2019 
Page 4 
PROTOCOL SYNOPSIS 
PROTOCOL NO.: PB2452-PT-CL-0002 
TITLE: Part A: A Phase 2A, Randomized, Double-blind, Placebo-controlled Single Dose, Sequential 
Group Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of 
PB2452 with Ticagrelor Pretreatment in Older and Elderly Subjects  
STUDY PHASE: 2A 
STUDY SITE: 1 clinical site in the United States: PPD Phase 1 Clinic, 7551 Metro Center Drive, 
Suite 200, Austin, Texas 78744 
INDICATION: Reversal of ticagrelor anti-platelet activity 
DURATION OF STUDY: The estimated duration of the study for each subject, excluding 
Screening, is approximately 35 days. 
OBJECTIVES: 
Primary: 
• 
To evaluate the safety and tolerability of intravenous (IV) doses of PB2452 vs matching placebo 
with oral ticagrelor plus acetylsalicylic acid (ASA) pretreatment in older and elderly subjects 
• 
To assess the efficacy/pharmacodynamics (PD) of intravenous (IV) doses of PB2452 vs matching 
placebo in reversing ticagrelor antiplatelet activity by measuring P2Y12 reaction units (PRU) with 
VerifyNow® P2Y12 assay in older and elderly subjects    
Secondary: 
• 
To determine the pharmacokinetics (PK) of PB2452 in the presence of ticagrelor 
• 
To determine the PK of ticagrelor and the ticagrelor active metabolite AR-C124910XX (TAM) in 
the presence of PB2452  
• 
To evaluate the effect of PB2452 on ticagrelor antiplatelet activity by measuring platelet 
aggregation with light transmittance aggregometry (LTA) and platelet reactivity index (PRI)  
with vasodilator-stimulated phosphoprotein (VASP) assay by enzyme-linked immunosorbent 
assay (ELISA) 
• 
To evaluate the immunogenicity potential of PB2452 
Exploratory: 
• 
To evaluate the effect of PB2452 on the PK profile of unbound ticagrelor and unbound TAM 
plasma concentrations 
• 
To investigate the effect of PB2452 vs matching placebo on circulating biomarkers of platelet 
activation, such as P-selectin, in subjects pretreated with ticagrelor + ASA 
• 
To examine the correlation between estimated creatinine clearance (CrCl) and the PK of 
ticagrelor and TAM. 
STUDY DESIGN AND METHODOLOGY: 
This is Part A of a two-part Phase 2A, randomized, double-blind, placebo-controlled, single dose, 
sequential group study to evaluate the safety, tolerability, PK, and PD of PB2452 vs matching 
placebo. Part A investigates various dose levels and regimens of PB2452 administered intravenously 
to older (ages 50 to 64 years) and elderly (ages 65 to 80 years) male and female subjects pretreated 
with ticagrelor + aspirin (ASA) as part of dual antiplatelet therapy. Part B investigates various dose 
levels and regimens of PB2452 administered to healthy male and female subjects (ages 18-50) 
pretreated with a high dose of ticagrelor alone (180 mg twice daily (BID)). Part B is described in a 
separate protocol document. 


PhaseBio Pharmaceuticals, Inc 
 
 
 
 
 
 
     PB2452 
Protocol No. PB2452-PT-CL-0002 Part A 
Clinical Study Protocol 
25July2019 
Page 5 
In Part A described herein, up to 5 dose levels and/or administration regimens will be evaluated in up 
to 5 cohorts. Each cohort will include 8 to 12 subjects randomized in a 3:1 ratio (PB2452:placebo). 
All references to study drug within the content of the protocol apply to PB2452 or matching placebo.   
This initial cohort (Cohort 1) will include approximately 8 subjects ages 50 to 80 years pretreated 
with ASA + ticagrelor who will be randomized to 18 grams (g) of PB2452 or matching placebo 
administered as an initial 6 g bolus infused over 10 minutes, followed by 12 g infused over the next 
15 hours and 50 minutes to complete a 16 hour regimen. This initial regimen was shown to be safe 
and well tolerated in healthy young adults (18 to 50 years) in a prior Phase 1 study and provided 
immediate and sustained reversal of the antiplatelet effects of ticagrelor.  
Following completion of Cohort 1, subsequent cohort(s) may test the same, higher or lower dose 
levels, and/or different infusion regimens of PB2452 or matching placebo in the same population as 
in Cohort 1, or in different populations such as elderly subjects (65 to 80 years old) as determined by 
the Sponsor after examination of available PD and safety data from the prior cohort(s). A written 
Dosing Memo provided by the Sponsor to the clinical site will describe details of the dosing regimen, 
cohort population, cohort size, sampling schedules and other cohort-specific study activities prior to 
initiation of each cohort. The maximum total dose of PB2452 administered to any subject will not 
exceed 30g. Duration of study drug infusions will not exceed 48 hours. The maximum administration 
rate of PB2452 will not exceed 18g over 30 minutes.   
A Safety Review Committee (SRC) will review all available safety data from ongoing or completed 
cohorts and will document their review and assessment in written SRC minutes prior to initiation of a 
subsequent cohort. Dose escalation may occur only if the SRC affirms the dose and regimen from the 
previously completed cohorts were safe and well tolerated and no dose-limiting toxicities (DLTs) 
were observed.  
The study will consist of a Screening period (Days –45 to –4), a Check-in day (Day -3) and  
Pretreatment Period, an on-site Randomization/Treatment day (Day 1), 3 days on-site for treatment 
and safety monitoring, a Follow-up Visit (Day 7), and a Final Follow-up visit (Day 28 [±2 days]). 
Seven days prior to Randomization (Day -7), subjects will be administered ASA 81 mg orally once 
daily (QD) until the final dose on the morning of Day 1 before receiving study drug. A ticagrelor 
180 mg oral loading dose will be administered on the morning of Day -2 followed by 90 mg every 
12 hours until the 5th dose has been administered on the morning of Day 1. After completion of 
Cohort 1, the Sponsor may choose to have a 6th dose of ticagrelor administered 24 hours after the 
initiation of study drug in a subsequent cohort.  
Subjects will check in to the clinical site (PPD) on Day -3. In the morning on Day -2, subjects will 
begin pretreatment with ticagrelor as described in the preceding paragraph. On Day 1, subjects who 
meet all the inclusion criteria and none of the exclusion criteria will be randomized in a ratio 3:1 
(PB2452:placebo), to receive an IV dose of PB2452 or placebo 2 hours following the 5th ticagrelor 
dose. Subjects may be discharged from the clinical site between Days 3 and 7 inclusive and will 
return for a Follow-up visit on Day 7, if already discharged, and on Day 28 (±2 days).  
Serum and plasma sampling times for PB2452, ticagrelor, and TAM PK and PD assessments will be 
described in a detailed Dosing Memo for each cohort. Hour 0 will be the time for initiation of study 
drug infusion (2 hours following administration of the 5th ticagrelor dose). PK and PD time points for 
subsequent cohorts may be adjusted as needed based on available PK, PD, and safety data from prior 
cohorts. In any cohort subsequent to Cohort 1, there will be no more than 6 additional sampling time 
points.  The written Dosing Memo provided by the Sponsor prior to initiation of each cohort will 
include the following instructions: 
• 
Number of subjects to be randomized  
• 
Total PB2452 dose and administration regimen  


PhaseBio Pharmaceuticals, Inc 
 
 
 
 
 
 
     PB2452 
Protocol No. PB2452-PT-CL-0002 Part A 
Clinical Study Protocol 
25July2019 
Page 6 
• 
Whether or not a 6th ticagrelor dose will be administered 24 hours after the 5th ticagrelor dose 
• 
The PK and PD sampling schedule  
• 
Safety electrocardiogram (ECG) schedule  
• 
Biomarkers 
Safety and tolerability will be carefully monitored throughout the study. Immunogenicity samples 
will be collected from all subjects at Baseline and at Days 7 and 28 (±2 days) following 
administration of study drug.  
Dose Escalation 
An SRC will be formed to conduct a blinded review of all safety and tolerability data (e.g., clinical 
laboratory test results, adverse events [AEs], ECGs, Holter monitoring report, vital signs) after each 
cohort- prior to initiation of a subsequent cohort. Escalation to a higher total dose of PB2452 will 
occur only if the SRC affirms the safety, tolerability, and absence of dose limiting toxicity (DLTs) in 
the preceding cohort(s).  
The SRC will be minimally composed of the on-site PPD investigator/medical monitor, PhaseBio 
medical monitor, and PhaseBio clinical operations lead. Changes to the administration regimen (rate 
and duration) without escalation of the total dose or without increasing the infusion rate will not 
require formal SRC approval. Similarly, reductions in the total dose or the infusion rate will not 
require SRC approval.  
Stopping Criteria 
Dose escalation or ongoing infusions will be suspended, pending investigation by the SRC, if any of 
the following occur after confirmation the subject has received PB2452: 
• 
Any preclinical or clinical events that, in the opinion of the SRC, contraindicate further dosing of 
additional subjects with PB2452 
• 
Any serious adverse event (SAE) occurring prior to discharge from the clinical site  
• 
Data from previous cohorts indicate safety concerns for dosing at a higher level, such as 
unanticipated adverse responses (e.g., clinically significant [CS] changes in clinical 
laboratory test data, 12 lead ECGs, continuous 12-lead electrocardiogram (Holter monitor) 
results, vital signs, physical examinations) 
• 
Two or more subjects in a cohort experience any DLT, or 1 subject experiences a  
≥Grade 2 AE (DLT) that, in the opinion of the SRC, warrants suspension of dose escalation 
• 
Two or more subjects have >3 x upper limit of normal (ULN) of either alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST), or >2 x ULN of bilirubin or alkaline phosphatase 
(ALP) when no other reason can be found to explain the increases 
• 
One or more subjects experiences a ≥Grade 2 infusion-related reaction (IRR) despite having been 
premedicated for IRRs 
Continuation of dosing following suspension will be determined by the SRC and documented in an ad 
hoc SRC Safety Report. Dosing may also be suspended if, in the opinion of the SRC or Sponsor, any 
new or unexpected significant safety or tolerability issues related to ticagrelor or PB2452 are 
identified that warrant further evaluation before additional subjects are dosed. This may include 
emerging nonclinical data, clinically relevant AEs, or relevant data from other sources indicating 
safety concerns, even if the event(s) per se does not meet the protocol-specified definition of a DLT. 
INCLUSION CRITERIA: 
1. The subject provides written informed consent and agrees to comply with all 
protocol requirements. 


PhaseBio Pharmaceuticals, Inc 
 
 
 
 
 
 
     PB2452 
Protocol No. PB2452-PT-CL-0002 Part A 
Clinical Study Protocol 
25July2019 
Page 7 
2. The subject is male or female between 50 and 80 years of age, inclusive.    
3. The subject has a body mass index (BMI) between 18 and 35 kg/m2 and a weight of ≥50 kg but 
≤120 kg, inclusive, at Screening. 
4. The subject is considered by the investigator to be in good general health, as determined by 
medical history, clinical laboratory test results, vital sign measurements, 12-lead ECG results, and 
physical examination findings at Screening. Subjects with chronic, stable, and well-controlled 
medical conditions are eligible provided they meet all other inclusion/exclusion criteria. Some 
examples of stable and well-controlled medical conditions include but are not limited to: 
• 
Hypertension (HTN) controlled with ≤2 antihypertensive drugs 
• 
Diabetes controlled with diet/exercise or treated with up to 2 oral diabetes medications  
• 
Subjects with diabetes must have a glycosylated hemoglobin HbA1c ≤8 mg/dL at Screening. 
• 
Mild hepatic enzyme elevation (AST or ALT <1.5 x ULN or total bilirubin <1.2 x ULN) 
• 
Controlled hyperlipidemia (defined with a Screening low density lipoprotein LDL  
<160 mg/dL) 
5. Specific inclusionary laboratory values at Screening and Check-in require:  
• 
White blood cell (WBC) count, platelet count, hemoglobin (Hgb) level within normal range, 
as defined by the clinical laboratory 
• 
Thyroid stimulating hormone (TSH) level within normal range, as defined by the clinical 
laboratory at Screening 
• 
Prothrombin time (PT) and partial thromboplastin time (PTT) level within normal range, as 
defined by the clinical laboratory  
6. Subjects taking medications for well-controlled medical conditions must have been on a stable 
dose (meaning no changes in dose) for at least 30 days prior to Screening visit. 
7. Subjects entering the study who are not already taking daily ASA must be willing to start an 
81 mg daily dose of ASA on Day -7 and continue daily dosing until the final dose is administered 
on the morning of Day 1. Subjects entering the study who are already taking ASA daily will be 
administered 81 mg ASA daily between Day -7 and Day 1 and must suspend further ASA dosing 
until discharge from the clinical facility. 
8. Female subjects of childbearing potential must not be pregnant, lactating, or planning to become 
pregnant for 3 months after the last dose of study drug, and have a negative serum pregnancy test 
at Screening and Check-in. Female subjects of childbearing potential must use 2 effective 
methods of birth control from 30 days before study drug administration through to the end of 
the study.  
• 
Effective birth control methods include oral, implantable, patch, or injectable contraceptive 
hormone treatment, hormone-containing intrauterine device that has been in place ≥2 months 
prior to Screening, sponge, diaphragm, or cervical cap with spermicidal gel or cream for 
female subjects or condom or vasectomy for male subjects.  
• 
Women are considered to not be of childbearing potential if they have fulfilled one of these 
criteria: documentation of irreversible surgical sterilization (i.e., hysterectomy or bilateral 
oophorectomy [not tubal ligation]) or are postmenopausal (defined as amenorrhea for 
12 consecutive months following cessation of all exogenous hormonal treatments, and 
documented plasma follicle-stimulating hormone (FSH) level >40 IU/mL) or amenorrhea for 
24 consecutive months.  


PhaseBio Pharmaceuticals, Inc 
 
 
 
 
 
 
     PB2452 
Protocol No. PB2452-PT-CL-0002 Part A 
Clinical Study Protocol 
25July2019 
Page 8 
• 
Male subjects with partners of childbearing potential must agree to use appropriate and 
effective measures of contraception (e.g., condom plus diaphragm with spermicide, condom 
plus spermicide) during the study and for 30 days after the last dose of study drug, and refrain 
from donating sperm for ≥90 days following the last dose of study drug.  
EXCLUSION CRITERIA: 
1. Concern the subject may be unable to comply with study procedures and/or follow-up, or, in the 
opinion of the investigator, the subject is not suitable for entry into the study 
2. History of any acute or chronic medical disorder expected to decrease the life expectancy of 
the subject   
3. History or presence of gastrointestinal (GI), hepatic (with the exception of Gilbert’s syndrome), 
or any other condition known to interfere with absorption, distribution, metabolism, or excretion 
of drugs  
4. Significant renal insufficiency, as indicated by estimated glomerular filtration rate 
(eGFR) <30 mL/min/1.73m2 according to the Modification of Diet in Renal Disease  
(MDRD) equation   
5. Any CS acute illness, medical/surgical procedure, or trauma within 4 weeks of administration of 
study drug or any planned surgical procedure that will occur during the study (from Screening 
through the Day 28 [±2 days] Follow-up visit) 
6. Any CS abnormal findings in physical examination, vital signs, laboratory assessments, and ECG 
parameters identified during Screening or Check-in. Note: abnormal results may be repeated for 
confirmation immediately after the first out of range measurement. Abnormal vital signs may be 
repeated twice if needed, immediately after the first abnormal result and/or after the subject has 
rested for at least 10 minutes. 
Specific vital sign exclusionary criteria occurring after 10 minutes of supine rest are any of the 
following: 
• 
Systolic blood pressure (SBP) <100 or >160 mm Hg 
• 
Diastolic blood pressure (DBP) <40 or >95 mm Hg 
• 
Resting heart rate (HR) <50 or >100 beats per minute (bpm) 
Specific exclusionary criteria for ECG parameters at Screening or Check-in include any of the 
following: 
• 
Prolonged Fridericia-corrected QT interval (QTcF) >450 milliseconds (msec), shortened 
QTcF <340 msec, or pause >3 seconds, or family history of long QT syndrome 
7. Any specific contraindication to Brilinta® as described in the Brilinta® prescribing 
information and: 
• 
History of intracranial hemorrhage, active bleeding, or hypersensitivity or allergic reaction to 
ticagrelor or any component of the product 
• 
Any history of severe head trauma, intracranial neoplasm, arteriovenous malformation, 
aneurysm, or proliferative retinopathy 
• 
Any history of intraocular, retroperitoneal, or spinal bleeding 
• 
Have taken, within 30 days of Screening, any oral or parenteral anticoagulant, including low 
molecular-weight heparin 
• 
Stool sample testing positive for occult blood within 3 months of Screening or at any time 
during the Screening Period 
8. Receiving chronic treatment with nonsteroidal anti-inflammatory drugs (NSAIDS; [including 
ASA >100 mg daily]), anticoagulants, or other antiplatelet agents that cannot be discontinued 


PhaseBio Pharmaceuticals, Inc 
 
 
 
 
 
 
     PB2452 
Protocol No. PB2452-PT-CL-0002 Part A 
Clinical Study Protocol 
25July2019 
Page 9 
14 days prior to randomization (including clopidogrel, prasugrel, ticlopidine,  dipyridamole, 
or cilostazol) 
9. Positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or 
human immunodeficiency virus (HIV) types 1 or 2 antibodies at Screening 
10. Concomitant oral or IV therapy with strong cytochrome P450 3A4 (CYP3A) inhibitors, CYP3A 
substrates with narrow therapeutic indices, or strong CYP3A inducers, which cannot be stopped 
within at least 5 half-lives, but not fewer than 10 days, before randomization (a list of examples 
may be found in Appendix 7.2) 
11. Consumption of grapefruit or grapefruit juice, Seville orange or Seville orange-containing 
products (e.g., marmalade), or xanthine-containing products within 48 hours before dosing with 
study drug 
12. Prescription or over-the-counter (OTC) medications within 14 days before the first dose of study 
drug unless specifically allowed by protocol. (Permitted medications include multivitamins, 
paracetamol [up to 2g per day], and/or treatments for chronic stable diseases, provided the drug 
and dose have been stable for ≥30 days prior to administration of study drug)   
13. Has received another investigational drug (defined as a small molecule or biologic compound 
which has not been approved for marketing) within 30 days of the administration of study drug in 
this study or within 5 half-lives of the prior study drug, whichever is longer       
14. Positive test result for alcohol or drugs of abuse at Screening or Check-in 
15. Participated in strenuous activity or contact sports within 24 hours before the infusion of study 
drug or while confined in the clinical site 
16. History of severe or ongoing allergy/hypersensitivity to any drug or biologic therapeutic agent 
17. Involvement with any PhaseBio or study site employee or their close relatives (e.g., spouse, 
parents, siblings, or children whether biological or legally adopted) 
18. Previously received PB2452 or had been randomized to receive study drug in an earlier cohort for 
this study 
 
EVALUATION CRITERIA: 
Safety Endpoints: 
Safety and tolerability will be assessed by monitoring and recording of AEs, clinical laboratory test 
results (hematology, coagulation, serum chemistry, and urinalysis), vital sign measurements (systolic 
blood pressure (SBP) and diastolic blood pressure (DBP), oral body temperature, respiratory rate 
[RR], and HR), 12-lead ECG, immunogenicity, biomarkers and physical examination findings. 
Pharmacodynamic Endpoints: 
VerifyNow®P2Y12: 
• 
Minimum %inhibition of PRU within 4 hours after the initiation of study drug. %inhibition of 
PRU is calculated as 100 * [(PRUbsl – PRUtrt)/PRUbsl]. PRUbsl refers to the PRU value measured 
before treatment with ticagrelor and PRUtrt refers to the PRU value measured posttreatment 
with the study drug. 
• 
PRU area under the curve (AUC) for the first 4 hours.  
• 
Proportion of patients with normalized platelet reactivity units within 4 hours after the initiation 
of study drug. Normalized platelet reactivity is defined as PRU ≥ 180. 
• 
Proportion of patients with ≥60%, ≥80%, and 100% of PRU response rate within 4 hours after 
the initiation of study drug. A PRU response rate is defined as the 100 * (PRUtrt/PRUbsl). 


PhaseBio Pharmaceuticals, Inc 
 
 
 
 
 
 
     PB2452 
Protocol No. PB2452-PT-CL-0002 Part A 
Clinical Study Protocol 
25July2019 
Page 10 
• 
Time to 60%, 80%, 100% of PRU response rate within 4 hours after the initiation of study drug  
• 
Duration of 80% and 100% of PRU response rate by PRU. 
LTA: 
• 
Minimum %inhibition of LTA within 4 hours after the initiation of study drug. 
• 
LTA AUC for the first 4 hours.  
• 
Proportion of patients with ≥60%, ≥80%, and 100% of LTA response rate within 4 hours after 
the initiation of study drug. LTA response rate is defined as the 100 * (LTAtrt/LTAbsl). 
• 
Time to 60%, 80%, 100% LTA response rate within 4 hours after the initiation of study drug. 
• 
Duration of 80% and 100% of LTA response rate. 
VASP by ELISA: 
• 
Minimum %inhibition of PRI within 4 hours after the initiation of study drug. 
• 
PRI AUC for the first 4 hours.  
• 
Proportion of patients with ≥60%, ≥80%, and 100% of PRI response rate within 4 hours after 
the initiation of study drug. A PRI response is defined as the 100 * (PRItrt/PRIbsl). 
• 
 Time to 60%, 80%, 100% PRI response rate within 4 hours after the initiation of study drug 
• 
Duration of 80% and 100% of PRI response rate 
For Cohorts receiving a 6th dose of ticagrelor 24 hours following study drug, PD parameters will be 
calculated for Days 1 and Day 2 separately. Additional PD parameters may be generated, if needed. 
Pharmacokinetic Endpoints:   
Plasma PK 
Plasma concentrations of total PB2452, unbound PB2452, total Ticagrelor, total TAM, unbound 
Ticagrelor, and unbound TAM, will be assessed at predetermined timepoints.  
PK parameters for PB2452 include:  
• 
Observed maximum plasma concentration (Cmax) 
• 
Area under the plasma concentration versus time curve (AUC) from time zero to the time of the 
last quantifiable concentration (AUC0-t) 
• 
Time to reach the observed maximum plasma concentration (Tmax) 
• 
AUC from time zero to 24 hours post-dose (AUC0-24) 
• 
AUC from time zero to 48 hours post-dose (AUC0-48)  
• 
Area under the plasma concentration versus time curve (AUC) from time zero to the time of the 
end of the dosing period(AUC0-tau) 
• 
AUC from time zero extrapolated to infinity (AUC0-∞; if data permit) 
• 
Terminal elimination half-life (t½; if data permit) 
• 
Clearance (CL; if data permit) 
• 
Volume of distribution (Vd)  
PK parameters for Ticagrelor/TAM include: 
• 
Cmax  
• 
AUC0-t 
• 
Tmax 
• 
AUC0-24 


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• 
AUC0-48  
• 
AUC0-tau 
• 
AUC0-∞; if data permit 
• 
t½; if data permit 
 
For Cohorts receiving a 6th dose of ticagrelor 24 hours following study drug initiation, AUC0-48 will 
not be calculated for neither plasma PB2452 nor ticagrelor/TAM. The remaining PK parameters may 
be calculated for Days 1 and 2 separately. Additional PK parameters may be generated, if needed.   
Details will be provided in a separate document, the statistical analysis plan (SAP). 
Urine PK 
Pooled urine samples to assess urine PB2452, ticagrelor, and TAM concentrations will be collected 
over these intervals: before dosing (within 60 minutes prior to the first ticagrelor dose on Day -2) and 
0 to 6, 6 to 12, and 12 to 24 hours. In patients receiving a 6th dose of ticagrelor, pooled urine samples 
to assess urine ticagrelor and TAM concentrations will be collected over these intervals beginning 
with the 6th ticagrelor dose: 0 to 6, 6 to 12, 12 to 24 hours.  
Pharmacokinetic parameters for PB2452, ticagrelor, and TAM concentrations in urine for all subjects 
in the PK population to be calculated are: 
• 
Total amount of drug excreted in urine at 24 hours after dosing (Ae24) and at 48 hours after 
dosing (Ae48)  
• 
Total amount of drug excreted in urine from time t1 to t2 (Aet1-t2) hours when the values of t1 to 
t2 are 0 to 6, 6 to 12, 12 to 24 and 24 to 48 hours  
• 
Fraction excreted in urine from 1 to 24 hours after dosing (Fe24) and from 1 to 48 hours after 
dosing (Fe48) 
• 
Renal clearance (CLr) for 24 hours after dosing 
For Cohorts receiving a 6th dose of ticagrelor 24 hours following study drug initiation, Fe48 and  
Ae24-48 will not be calculated. Other urine PK parameters may be calculated for Day 1 and 2 
separately.   
Additional PK parameters may be generated, if needed. Details will be provided in a separate 
document, the SAP. 
STUDY DRUG, DOSAGE, AND ROUTE OF ADMINISTRATION: 
PB2452: 
PB2452 IV infusion, prepared according to the Pharmacy Manual, will be administered on Day 1 for 
up to 48 hours. The total dose for each subject will not exceed 30 g. The infusion rate will not exceed 
18 g over 30 minutes and the concentration will not exceed 24g in 250mL. Subjects will not receive 
more than 250 mL of study drug infusion within any 1-hour period.  
For each cohort, the dose, infusion rate, and duration will be communicated from the Sponsor to PPD 
in a Dosing Memo issued prior to initiation of each treatment cohort.  
Matching Placebo: 
0.9% sodium chloride single IV infusion, to be delivered at a rate and volume matching the 
active infusion.  


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Ticagrelor: 
Ticagrelor 90 mg oral tablet (immediate release) will be administered as a180 mg (2 × 90 mg tablets) 
loading dose plus 90 mg every 12 hours for 4 additional doses. In successive cohorts following cohort 
1, if indicated in a Dosing Memo from Sponsor to site, one or more cohorts may also receive an 
additional single oral dose of 90 mg ticagrelor 24 hours after the initiation of the study drug infusion 
(6th ticagrelor dose). 
Aspirin (acetylsalicylic acid; ASA): 
Aspirin (ASA) 81 mg oral tablet (enteric coated) will be administered daily between Day -7 and in the 
morning before receiving study medication on Day 1. Subjects may resume ASA after discharge from 
the study. Subjects entering the study who are already taking ASA daily must be willing to document 
a daily 81 mg dose between Day -7 and Day 1 and must suspend further ASA doses until discharge 
from the clinical facility. 
 
STATISTICAL METHODS: 
Sample Size: 
The sample size for this study is based on clinical and practical considerations and not on a formal 
statistical power calculation. The sample size will provide preliminary safety, efficacy and PK 
information in a dose/regimen finding fashion.  
Analysis Populations: 
• 
The Safety Population will include all subjects who receive any amount of study drug. 
• 
The PK Population will include subjects in the safety population who have ≥1 measurable PK 
concentration. 
• 
The PD Population will include subjects in the safety population who receive ≥1 dose of 
ticagrelor and have ≥1 measurable post dose PRU value. 
Safety Analyses:  
Adverse events will be coded by preferred term and system-organ-class (SOC) using the latest 
version of the Medical Dictionary for Regulatory Activities (MedDRA). All AE data will be 
presented in Data Listings. Treatment-emergent AEs (TEAEs) will be summarized by treatment and 
overall, as well as by severity and relationship to study drug. All SAEs and AEs leading to 
discontinuation of study drug will be presented in the Data Listings. 
Actual values and changes from Baseline in clinical laboratory test results, vital sign measurements, 
and 12-lead ECG results will be summarized by treatment at each time point using descriptive 
statistics (number of subjects, mean, standard deviation [SD], median, minimum, and maximum). 
Clinical laboratory test results, vital sign measurements, 12-lead ECGs, Holter monitor report data, 
immunogenicity results, and physical examination findings will be presented in Data Listings.  
Pharmacokinetic Analyses: 
Plasma concentrations will be listed and summarized descriptively (number of subjects, arithmetic 
mean, SD, coefficient of variation [CV], median, minimum, and maximum). Plasma concentration 
versus time profiles for each subject will be presented graphically. The mean plasma concentration 
versus scheduled time profiles will be presented graphically by dose. 
Pharmacokinetic parameters will be summarized by time point for each dose level using descriptive 
statistics (number of subjects, mean, SD, CV, median, minimum, and maximum). Geometric means 
will be reported for AUCs and Cmax.  


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Pharmacodynamic Analyses: 
Pharmacodynamic data will be summarized for each time point using descriptive statistics (number of 
subjects, mean, SD, CV, median, minimum, and maximum). Pharmacodynamic parameters will also 
be summarized for each cohort.  
 
 
 


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TABLE OF CONTENTS 
Section 
Page 
SIGNATURE PAGE ................................................................................................................2 
PROTOCOL SYNOPSIS ........................................................................................................4 
TABLE OF CONTENTS .......................................................................................................14 
TABLE OF TABLES .............................................................................................................18 
LIST OF ABBREVIATIONS AND DEFINITIONS ...........................................................19 
1. 
INTRODUCTION...................................................................................................23 
1.1 
PRODUCT AND BACKGROUND INFORMATION .............................................23 
1.1.1 
Non-clinical Pharmacology ......................................................................................24 
1.1.2 
Summary of Human Data .........................................................................................24 
1.1.3 
Benefit/Risk Assessment ...........................................................................................26 
1.2 
RATIONALE FOR STUDY .....................................................................................27 
1.3 
RATIONALE FOR DOSE SELECTION .................................................................27 
2. 
STUDY OBJECTIVES AND METHODOLOGY ...............................................29 
2.1 
OBJECTIVES ...........................................................................................................29 
2.2 
EVALUATION CRITERIA ......................................................................................29 
2.2.1 
Safety Endpoints .......................................................................................................29 
2.2.2 
Pharmacodynamic Endpoints ....................................................................................29 
2.2.3 
Pharmacokinetic Endpoints ......................................................................................31 
3. 
INVESTIGATION PLAN ......................................................................................33 
3.1 
STUDY DESIGN AND METHODOLOGY ............................................................33 
3.2 
SELECTION OF STUDY POPULATION ...............................................................35 
3.2.1 
Inclusion Criteria ......................................................................................................35 
3.2.2 
Exclusion Criteria .....................................................................................................37 
3.2.3 
Subject Restrictions During the Study ......................................................................39 
3.3 
WITHDRAWAL OF SUBJECTS FROM THE STUDY ..........................................39 
3.3.1 
Reasons for Withdrawal ............................................................................................39 
3.3.2 
Handling of Withdrawals ..........................................................................................40 
3.3.3 
Replacement of Subjects ...........................................................................................40 
3.4 
STUDY TREATMENTS ..........................................................................................40 
3.4.1 
Method of Assigning Subjects to Treatment Groups ................................................40 
3.4.2 
Treatments Administered ..........................................................................................41 


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3.4.2.1 Dose Escalation ........................................................................................................ 41 
3.4.2.2 Infusion-related or Allergic Reactions ..................................................................... 42 
3.4.2.3 Dose-limiting Toxicities ........................................................................................... 43 
3.4.2.4 Stopping Criteria ...................................................................................................... 43 
3.4.3 
Identity of Investigational Product............................................................................44 
3.4.4 
Management of Clinical Supplies .............................................................................44 
3.4.4.1 Packaging and Storage ............................................................................................. 44 
3.4.4.2 Drug Accountability ................................................................................................. 44 
3.4.5 
Blinding.....................................................................................................................45 
3.4.6 
Treatment Compliance ..............................................................................................45 
3.4.7 
Breaking the Blind ....................................................................................................45 
3.4.8 
Prior and Concomitant Medication ...........................................................................46 
3.4.8.1 Prior Medication and Therapies ............................................................................... 46 
3.4.8.2 Concomitant Medication and Therapies .................................................................. 46 
3.5 
STUDY PROCEDURES ..........................................................................................46 
3.5.1 
Pharmacokinetic Sample Collection .........................................................................50 
3.5.1.1 Bioanalytical Methods ............................................................................................. 50 
3.5.1.2 Pharmacodynamic Sample Collection ..................................................................... 51 
3.5.2 
Adverse Events .........................................................................................................51 
3.5.2.1 Adverse Event Definitions ....................................................................................... 51 
3.5.2.2 Eliciting and Documenting Adverse Events ............................................................ 53 
3.5.2.3 Reporting Adverse Events........................................................................................ 53 
3.5.2.4 Assessment of Severity ............................................................................................ 54 
3.5.2.5 Assessment of Causality .......................................................................................... 54 
3.5.2.6 Follow-up of Adverse Events................................................................................... 55 
3.5.3 
Clinical Laboratory Testing ......................................................................................55 
3.5.4 
Vital Signs Measurements.........................................................................................57 
3.5.5 
Twelve-lead Electrocardiogram ................................................................................58 
3.5.6 
Holter Monitoring (Continuous Twelve-lead ECG) .................................................58 
3.5.7 
Physical Examinations ..............................................................................................59 
3.5.8 
Infusion Site Assessments .........................................................................................59 
3.5.9 
Immunogenicity Assessments ...................................................................................59 
3.6 
STATISTICAL CONSIDERATIONS .......................................................................59 
3.6.1 
Sample Size Calculations ..........................................................................................59 
3.6.2 
Analysis Populations .................................................................................................60 
3.6.3 
Statistical Analysis ....................................................................................................60 
3.6.3.1 Pharmacokinetic Analyses ....................................................................................... 60 


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3.6.3.2 Pharmacodynamic Analyses .................................................................................... 61 
3.6.3.3 Safety Analyses ........................................................................................................ 61 
3.6.4 
Handling of Missing Data .........................................................................................61 
3.6.5 
Interim Analyses .......................................................................................................61 
3.7 
DATA QUALITY ASSURANCE .............................................................................62 
4. 
INVESTIGATOR OBLIGATIONS .......................................................................63 
4.1 
CONFIDENTIALITY...............................................................................................63 
4.2 
INSTITUTIONAL REVIEW ....................................................................................63 
4.3 
SUBJECT CONSENT ..............................................................................................63 
4.4 
STUDY REPORTING REQUIREMENTS ..............................................................64 
4.5 
FINANCIAL DISCLOSURE AND OBLIGATIONS ...............................................64 
4.6 
INVESTIGATOR DOCUMENTATION ..................................................................64 
4.7 
STUDY CONDUCT .................................................................................................65 
4.8 
DATA COLLECTION ..............................................................................................65 
4.8.1 
Case Report Forms and Source Documents..............................................................65 
4.9 
ADHERENCE TO PROTOCOL ..............................................................................65 
4.10 
REPORTING ADVERSE EVENTS .........................................................................65 
4.11 
INVESTIGATOR’S FINAL REPORT .....................................................................66 
4.12 
RECORD RETENTION ...........................................................................................66 
4.13 
PUBLICATIONS ......................................................................................................66 
5. 
ETHICS ...................................................................................................................67 
5.1 
ETHICAL CONDUCT OF THE STUDY ................................................................67 
5.2 
INSTITUTIONAL REVIEW BOARD .....................................................................67 
6. 
STUDY MANAGEMENT ......................................................................................68 
6.1 
MONITORING .........................................................................................................68 
6.1.1 
Monitoring the Study ................................................................................................68 
6.1.2 
Inspection of Records ...............................................................................................68 
6.2 
MANAGEMENT OF PROTOCOL AMENDMENTS  AND 
DEVIATIONS ...........................................................................................................68 
6.2.1 
Modification of the Protocol .....................................................................................68 
6.2.2 
Protocol Deviations ...................................................................................................68 
6.3 
STUDY TERMINATION .........................................................................................69 
6.4 
FINAL REPORT .......................................................................................................69 


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7. 
APPENDICES .........................................................................................................70 
7.1 
SCHEDULE OF EVENTS .......................................................................................71 
7.2 
EXAMPLES OF INHIBITORS AND INDUCERS OF CYP3A4 ...........................74 
7.3 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
(CTCAE) ...................................................................................................................75 
7.4 
CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS .............................76 
8. 
REFERENCES ........................................................................................................77 
 
 


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TABLE OF TABLES  
TABLE 
 
See Appendices, Section 7.  
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS 
AA 
arachidonic acid 
ACS 
acute coronary syndrome 
ADA 
anti-drug antibodies 
ADP 
adenosine diphosphate 
AE 
adverse event 
Ae48 
total amount of drug excreted in urine at 48 hours after dosing 
Ae24 
total amount of drug excreted in urine at 24 hours after dosing 
Aet1-t2 
Ae from time t1 to t2 hours 
Aet1-t2 
Ae from time t1 to t2 hours 
ALP 
alkaline phosphatase 
ALT 
aPTT 
alanine aminotransferase 
activated partial thromboplastin time 
ASA 
acetylsalicylic acid, aspirin 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC0-12 
AUC from time zero to 12 hours after dosing 
AUC0-24 
AUC0-48 
AUC from time zero to 24 hours after dosing 
AUC from time zero to 48 hours after dosing 
AUC0-∞ 
area under the plasma concentration versus time curve from time zero 
extrapolated to infinity 
AUC0-τ 
 
area under the concentration versus time curve from time zero to the time 
of the last quantifiable concentration 
bid 
twice daily 
BL 
baseline 
BLQ 
below the limit of quantification 
BMI 
BP 
body mass index 
Blood Pressure 
Bpm 
BUN 
CABG 
beats per minute 
Blood Urea Nitrogen 
coronary artery bypass graft 
CFR 
CL 
Code of Federal Regulations 
clearance 
CLr 
renal clearance 
Cmax 
observed maximum plasma concentration 
CrCl 
creatinine clearance 
CS 
clinically significant 
CSR 
Clinical Study Report 


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CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP3A 
cytochrome P450 3A4 
DAPT 
dual antiplatelet therapy 
DBP 
diastolic blood pressure 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
end of study 
FDA 
Fe24 
Food and Drug Administration 
Fraction excreted in urine from 1 to 24 hours after dosing 
Fe48 
fraction excreted in urine from 1 to 48 hours after dosing 
FSH 
follicle stimulating hormone 
GCP 
GGT 
Good Clinical Practice 
gamma-glutamyl transferase 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
HbA1c 
HBsAg 
glycosylated Hemoglobin Hgb 
hepatitis B surface antigen 
HCV 
HDL 
hepatitis C virus 
high-density lipoprotein 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
HR 
resting heart rate 
HTN 
hypertension 
IB 
Investigators’ Brochure 
ICF 
informed consent form 
ICH 
INR 
IPA 
International Council for Harmonisation 
international normalized ratio 
inhibition of platelet aggregation 
IRB 
institutional review board 
IRR 
infusion-related reaction 
IV 
LDH 
Intravenous- (ly) 
lactate dehydrogenase 
LDL 
low-density lipoprotein 


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LTA 
MAP 
MCH 
MCHC 
MCV 
MDMA 
light transmittance aggregometry 
mean arterial pressure 
mean corpuscular hemoglobin 
mean corpuscular hemoglobin concentration 
mean corpuscular volume 
methylenedioxymethamphetamine 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
MI 
MPV 
Medical Dictionary FOR Regulatory Activities 
Myocardial infarction 
Mean platelet volume 
msec 
millisecond 
MTD 
N 
maximum tolerated dose 
sample size 
NCS 
not clinically significant 
NOAEL 
OTC 
PD 
PEF 
no adverse effect level 
Over the counter 
Pharmacodynamic 
Peak expiratory flow 
PK 
pharmacokinetic 
PO 
by mouth 
PRI 
platelet reactivity index 
PRU 
P2Y12 reaction units 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QD 
once daily 
QTcF 
Fridericia-corrected QT interval 
RBC 
red blood cell(erythrocyte) 
RR 
respiration rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
System- organ- class 
SOP 
SpGr 
standard operating procedure 
specific gravity 
SRC 
Safety Review Committee 
t1/2 
terminal elimination half-life 
TAM 
ticagrelor active metabolite AR-C124910XX 
TEAE 
treatment-emergent adverse event 


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Tmax 
time to reach the observed maximum (peak) concentration 
TRAP 
thrombin receptor activating peptide 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
VASP 
vasodilator-stimulated phosphoprotein 
WBC 
white blood cell 
 


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1. 
INTRODUCTION 
1.1 PRODUCT AND BACKGROUND INFORMATION 
PB2452 (molecular weight 47.4 kDa) is a specific and selective recombinant human 
neutralizing antibody IgG1λ monoclonal fragment antigen-binding antibody that binds with 
high affinity to ticagrelor and to AR-C124910XX (TAM), the major active circulating 
ticagrelor metabolite. It is expressed in Escherichia coli cells. 
PB2452 is intended to reverse the antiplatelet effects of ticagrelor in patients who  
experience major bleeding or who require urgent surgery or intervention.  
Platelet transfusion has appeared to be inferior to standard care for those taking antiplatelet 
therapy.(Baharoglu, 2016)  
A strategy is needed to re-establish the integrity of the clotting cascade for the many patients 
who have abnormal coagulation due to pharmacological anticoagulation.(Beshay, 2010) 
Antiplatelet medications and anticoagulants pose a significant treatment dilemma since no 
direct reversal agents currently exist to reverse or mitigate antithrombotic properties.(Dornbos III, 
2018) Accordingly, the current lack of an effective therapy to mitigate ticagrelor-induced 
platelet inhibition in patients who have life-threatening bleeding or require urgent surgery or 
intervention represents a significant unmet need. 
Ticagrelor is an orally available, direct-acting cyclopentyltriazolopyrimidine, a selective and 
reversibly binding P2Y12 receptor antagonist.(Storey, 2007) TAM, the ticagrelor active metabolite 
(30% to 40% plasma exposure relative to parent in humans, (Storey, 2007) has potency similar to 
ticagrelor versus P2Y12. In addition to P2Y12, ticagrelor also inhibits the equilibrative 
nucleoside transporter-1, thereby providing an enhanced adenosine response.(Armstrong, 2014; 
Beshay JE, Morgan H, Madden C, Yu W, et al. Emergency reversal of anticoagulation and antiplatelet 
therapies in neurosurgical patients. J Neurosurg 2010 Feb;112(2):307-18. 
Catteneo, 2014) Ticagrelor in combination with low-dose aspirin (acetylsalicylic acid; ASA) is 
indicated for the prevention of thrombotic events (e.g., cardiovascular death, myocardial 
infarction [MI], and stroke) in patients with acute coronary syndrome (ACS) or a history of 
MI. Ticagrelor also reduces the rate of stent thrombosis in patients who have been stented for 
treatment of ACS. In the management of ACS, ticagrelor treatment is initiated with a 180 mg 
loading dose, followed by 90 mg twice daily (bid) during the first year after an ACS event. 
After one year, the prescribed dosage is decreased to 60 mg bid. 
Therapy with ASA plus an oral antiplatelet agent such as clopidogrel, prasugrel, or ticagrelor 
is known as dual antiplatelet therapy (DAPT). Although DAPT is strongly recommended in 
the early management of patients experiencing an ACS event, it also increases the risk of 
bleeding.(Storey, 2011) Patients with ACS may require urgent or emergent coronary artery bypass 


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graft (CABG) surgery. In such patients, DAPT is associated with a 2-fold increase in risk of 
blood transfusion, a 5-fold increase in risk of reoperation, and a 50% increased risk of wound 
infection.(Bell, 2011; Fitchett, 2011) Consequently, guidelines and guidance statements recommend 
the P2Y12 receptor antagonist be stopped ≥5 days prior to the procedure, a recommendation 
that is not possible in patients who require urgent surgery. 
There are no approved drugs or biological agents capable of reversing the P2Y12 inhibition 
produced by ticagrelor or other P2Y12 inhibitors; therefore, in the event of major bleeding in 
a patient on DAPT, there are limited treatment options. Although platelet transfusion restores 
platelet function in patients on ASA,(Taylor, 2013) it does not reverse the antiplatelet effect of 
ticagrelor in healthy volunteers and is unlikely to be of clinical benefit in patients with 
bleeding.(Teng, 2016)  
1.1.1 Non-clinical Pharmacology 
Non-clinical pharmacology studies have demonstrated that PB2452 binds with high affinity 
and selectivity to the P2Y12 receptor antagonist ticagrelor and its active metabolite, TAM, 
(equilibrium dissociation constant [KD] 20 pmol/L). PB2452 rapidly neutralizes the unbound 
plasma fraction of ticagrelor and TAM, thereby reversing ticagrelor- and TAM-mediated 
inhibition of adenosine diphosphate (ADP)-induced platelet aggregation in a concentration- 
and dose-dependent manner in vitro (in human platelet-rich plasma) and in vivo (mouse and 
pig, dose-dependency data in mouse only). In mice dosed with ticagrelor to a 
supratherapeutic plasma exposure, those dosed with PB2452 before a tail cut had reduced 
bleeding to a degree not statistically different from the observation in mice not treated with 
ticagrelor. The activity in vitro and the rapid onset of effect observed in vivo translated to a 
reduction of bleeding in ticagrelor-treated mice to a degree that was not statistically 
significantly different from mice not treated with ticagrelor. Detailed descriptions of the non-
clinical pharmacology of PB2452 may be found in the Investigators’ Brochure (IB) for 
PB2452.   
1.1.2 Summary of Human Data 
The first-in-human Phase 1 study (PB2452-PT-CL-0001) has been clinically completed, the 
database is locked, and final analyses are complete with the exception of exploratory 
endpoints. The safety, PK, and PD data described herein will be incorporated into a clinical 
study report. This study was a single-center, randomized, double-blind, placebo-controlled, 
single ascending dose study to evaluate the safety, tolerability, PK, and PD of PB2452 with 
and without ticagrelor pretreatment in healthy male and female subjects ages 18-50 years. 
Ten sequential dose cohorts were evaluated. Cohorts 1, 2, and 3 assessed 30 min IV infusions 
of PB2452 without ticagrelor pretreatment while Cohorts 4-10 assessed IV infusions of 


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PB2452 after ticagrelor pretreatment. Detailed descriptions of the clinical safety, PK, and PD 
profiles of PB2452 may be found in the Investigators’ Brochure (IB) for PB2452. 
PB2452 appeared generally safe and well tolerated across a dose range of 0.1 g to 18 g. A 
total of 30 adverse events occurred after initiation of PB2452 or placebo and were reported 
by 19 of the 64 volunteers (30%). Of the 48 volunteers who received PB2452, 17 (35%) 
reported 27 adverse events; of the 16 volunteers who received placebo, 2 (12%) reported 3 
adverse events. There were no dose-limiting toxicity (DLTs)effects or infusion-related 
reactions (IRRs). There were no deaths or adverse events that led to discontinuation of the 
trial drug. One volunteer had 2 serious adverse events (alcohol poisoning and acute 
respiratory failure) 4 days after discharge from the clinical site. Except for 2 volunteers, in 
cohorts 1 and 3, all volunteers with adverse events had received ticagrelor pretreatment. 
Changes in mean clinical laboratory test results, vital signs, and electrocardiographic results 
were similar across cohorts among volunteers who received different doses or regimens of 
PB2452 and were similar among those who received PB2452 and those who received 
placebo. Of the 48 volunteers who received PB2452, 21 (44%) had detectable anti-drug 
antibodies in blood obtained 7 and/or 28 days after exposure; 15 (31%) had been positive 
before they received PB2452 and 6 (12%) became positive after they received PB2452, albeit 
with low titers of 40 (in 5 volunteers) and 160 (in 1 volunteer). Of the 16 volunteers who 
received placebo, 3 (19%) were positive for anti-drug antibodies, with 2 (12%) having 
preexisting antibodies. The presence of these antibodies had no observed effect on the safety 
or efficacy of PB2452. 
The PK profile of PB2452 demonstrated that mean plasma concentrations of PB2452 rapidly 
declined following the end of infusion across all cohorts. In cohorts 1-3 when PB2452 was 
administered as a 30-minute intravenous infusion in the absence of ticagrelor, elimination 
appeared to be biphasic with half-life values ranging from 1.5 to 9.2 hours for the dose range 
0.1 g to 1 g. In the presence and absence of ticagrelor, geometric mean observed maximum 
plasma concentration (Cmax) values and geometric mean area under the plasma concentration 
versus time curve (AUC) from time zero extrapolated to infinity (AUC0-∞) )values of total 
PB2452 appeared to increase in a dose-proportional manner. The inter-individual variability 
(geometric mean coefficient of variation [CV%]) for Cmax and AUC0-∞ was low, ranging from 
4.8% to 28.9% across Cohorts 1-3. PB2452 appeared to increase mean total plasma 
concentrations of ticagrelor and TAM compared to placebo, and this effect was dependent on 
the dose of PB2452.  Additionally, PB2452 increased the renal CL of ticagrelor and TAM in a 
dose-dependent manner. 


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The PD profile of PB2452 demonstrated that for subjects receiving steady-state ticagrelor, IV 
infusion of PB2452 (3 to18 g) restored platelet activity to approximately 100% of baseline 
using multiple assays of platelet function. The onset of reversal was rapid, occurring at the 
first assessment of platelet function following initiation of PB2452 infusion (30 minutes in 
cohorts 4-6 and 5 minutes in cohorts 7-10). The duration of ticagrelor reversal appeared to be 
dependent on the total dose and infusion duration of PB2452.  
1.1.3 Benefit/Risk Assessment 
The first in human study of PB2452 in healthy volunteers (PB2452-PT-CL-0001) 
demonstrated that PB2452 appears to be generally safe and well tolerated when administered 
intravenously across a dose range of 0.1-18 g. The healthy volunteers who were 18-50 years 
in age were not expected to nor received any benefit from administration of PB2452. Platelet 
function analyses showed that PB2452 delivered immediate and sustained reversal of 
ticagrelor, occurring as early as 5 minutes after initiation of PB2452 infusions and lasting for 
20-24 hours. Rapid and sustained ticagrelor reversal by PB2452 may provide clinically 
significant benefit in patients taking ticagrelor who experience serious bleeding or require 
urgent surgical procedures by supporting rapid hemostasis or prevention of procedure-related 
bleeding. 
Although treatment emergent adverse events associated with PB2452 in the Phase 1 study 
were mostly mild and infrequent with no infusion-related or hypersensitivity reactions 
observed, in the older and elderly subjects in this Phase 2A study, there remain potential risks 
of infusion-related reactions (IRRs), infusion site reactions, and hypersensitivity-type 
reactions which can result from exposure to recombinant protein drugs administered 
intravenously (IV). These risks may be mitigated by predefined exclusion criteria and by 
close monitoring during and after administration. Risks may also be mitigated by 
premedication prior to receiving PB2452 which will be implemented if a study subject 
develops a Grade ≥2 IRR. 
The older and elderly subjects in this study will be administered dual anti-platelet therapy 
with ASA and ticagrelor which carries a risk of bleeding. The bleeding risk in study subjects 
is considered very low because the duration of dual antiplatelet therapy is only 48 hours. 
Among those patients taking ticagrelor for therapeutic benefit, the potential risk of disease-
related thrombosis upon reversal of the antiplatelet effect of ticagrelor will be evaluated in 
future clinical studies and by thorough monitoring of hemostasis parameters. In the current 
study, three platelet function assays and multiple platelet agonists will be used to monitor 
platelet function which will demonstrate both the reversal profile of PB2452 and also a 
potential prothrombotic rebound increase in platelet function. The risk of a platelet rebound 
effect is considered low and was not observed in the Phase 1 study. 


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Based on available information concerning the risks of PB2452 and the precautions included 
in this clinical study, the risks are considered acceptable. 
1.2 RATIONALE FOR STUDY 
Current recommendations for management of bleeding in patients treated with  
antiplatelet therapies are suboptimal; they are mostly supportive and non-specific.  
Platelet transfusion, while useful for some antiplatelet agents, exposes patients to the  
known risks of blood products. Further, the efficacy of transfused platelets may be  
limited by exposure to circulating antiplatelet drug or metabolites, if present. Moreover,  
it has been demonstrated that platelet transfusions do not reverse the effects of 
ticagrelor.(Dalen, 2013; Godier, 2015; Maillard, 2015; Teng, 2016) 
An agent to rapidly reduce the anti-platelet aggregation (IPA) associated with effects of 
ticagrelor, and the metabolite TAM, would fulfill an important unmet clinical need for those 
patients: 
• 
who have major bleeding with ticagrelor possibly contributing 
• 
who are taking ticagrelor and require urgent surgery or intervention associated with a 
high risk of bleeding 
• 
who are taking ticagrelor for conditions with a high risk of thrombosis, require major 
surgery, and/or need to minimize the time when they are not receiving ticagrelor 
1.3 RATIONALE FOR DOSE SELECTION 
In the first in human Phase 1 study of PB2452, 18 g administered as an initial 6 g bolus 
followed by a prolonged infusion of the remaining 12 g over 16 hours in healthy subjects 
aged 18-50 years old was considered generally safe and well tolerated. There were no 
PB2452-related adverse effects, injection site reaction (ISRs), or DLTs observed as 
determined by the study investigator and SRC. The profile of rapid and sustained ticagrelor 
reversal delivered by the 18 g dose level is potentially clinically meaningful and considered 
ideal for patients on ticagrelor with acute major bleeding or who need urgent surgery.  
The 18 g dose level and prolonged infusion regimen administered in the Phase 1 study will 
be repeated in the current study in older and elderly subjects who are more similar in age and 
background comorbidities to the actual patient population treated with ticagrelor. Potentially 
longer infusions of PB2452 may be investigated in this study, using potentially higher total 
doses of PB2452. To mitigate any risks related to dose escalation, a Safety Review 
Committee (SRC) will be assembled to review all emergent safety and tolerability data and 
available PK data after each cohort is completed to determine whether dose escalation and/or 
prolongation of infusion duration is warranted. PK/PD modeling will be used to simulate 
potential doses, infusion regimens, and Cmax and AUC exposure profiles prior to dose-
escalation or adjustment of infusion regimen to ensure that no dose or infusion regimen 


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investigated in this study will exceed Cmax or AUC exposures achieved at the no observed 
adverse effect level (NOAEL) in GLP toxicity study in rats.  
In the rat GLP toxicity study, there were no adverse effects observed following single doses 
of PB2452 at the highest dose level tested of 2000 mg/kg given IV, alone or in combination 
with oral ticagrelor (20 mg/kg). Therefore, 2000 mg/kg was considered NOAEL with a 
maximum plasma concentration (Cmax) of 18100 µg/mL and an area under the plasma 
concentration versus time curve from time zero extrapolated to infinity (AUC0-∞) of 23100 
µg*h/mL.  
 


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2. 
STUDY OBJECTIVES AND METHODOLOGY 
2.1 OBJECTIVES 
Primary: 
• 
To evaluate the safety and tolerability of intravenous (IV) doses of PB2452 vs matching 
placebo with oral ticagrelor plus acetylsalicylic acid (ASA) pretreatment in older and 
elderly subjects  
• 
To assess the efficacy/ pharmacodynamic (PD) of IV doses of PB2452 vs matching 
placebo in reversing ticagrelor antiplatelet activity by measuring P2Y12 reaction units 
(PRU) with VerifyNow® P2Y12 assay in older and elderly subjects    
Secondary: 
• 
To determine the pharmacokinetic (PK) of PB2452 in the presence of ticagrelor 
• 
To determine the PK of ticagrelor and TAM in the presence of PB2452  
• 
To evaluate the effect of PB2452 on ticagrelor antiplatelet activity by measuring platelet 
aggregation with light transmittance aggregometry (LTA) and platelet reactivity index 
(PRI) with vasodilator-stimulated phosphoprotein (VASP) assay by enzyme-linked 
immunosorbent assay (ELISA) 
• 
To evaluate the immunogenicity potential of PB2452 
Exploratory: 
• 
To evaluate the effect of PB2452 on the PK profile of unbound ticagrelor and unbound 
TAM plasma concentrations 
• 
To investigate the effect of PB2452 vs matching placebo on circulating biomarkers of 
platelet activation, such as P-selectin, in subjects pretreated with ticagrelor + ASA 
• 
To examine the correlation between estimated creatinine clearance (CrCl) and the PK of 
ticagrelor and TAM. 
2.2 EVALUATION CRITERIA 
2.2.1 Safety Endpoints 
Safety and tolerability will be assessed by monitoring and recording of Adverse Events 
(AEs), clinical laboratory test results (hematology, coagulation, serum chemistry, and 
urinalysis), vital sign measurements (systolic blood pressure [SBP] and diastolic blood 
pressure [DBP], oral body temperature, respiratory rate [RR], and resting heart rate [HR]), 
12-lead electrocardiogram (ECG), continuous 12-lead ECG (Holter monitoring), 
immunogenicity, and physical examination findings.  
2.2.2 Pharmacodynamic Endpoints 
VerifyNow®P2Y12: 


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• Minimum %inhibition of PRU within 4 hours after the initiation of study 
drug. %inhibition of PRU is calculated as 100 * [(PRUbsl – PRUtrt)/PRUbsl]. PRUbsl 
refers to the PRU value measured before treatment with ticagrelor and PRUtrt refers to 
the PRU value measured posttreatment with the study drug. 
• PRU AUC for the first 4 hours.  
• Proportion of patients with normalized platelet reactivity units within 4 hours after the 
initiation of study drug. Normalized platelet reactivity is defined as PRU ≥ 180. 
• Proportion of patients with ≥60%, ≥80%, and 100% of PRU response rate within 4 
hours after the initiation of study drug. A PRU response rate is defined as the 100 * 
(PRUtrt/PRUbsl). 
• Time to 60%, 80%, 100% of PRU response rate within 4 hours after the initiation of 
study drug  
• Duration of 80% and 100% of PRU response rate by PRU. 
LTA: 
• Minimum %inhibition of LTA within 4 hours after the initiation of study drug. 
• LTA AUC for the first 4 hours.  
• Proportion of patients with ≥60%, ≥80%, and 100% of LTA response rate within 4 hours 
after the initiation of study drug. LTA response rate is defined as the 100 * 
(LTAtrt/LTAbsl). 
• Time to 60%, 80%, 100% LTA response rate within 4 hours after the initiation of study 
drug. 
• Duration of 80% and 100% of LTA response rate. 
VASP by ELISA: 
• Minimum %inhibition of PRI within 4 hours after the initiation of study drug. 
• PRI AUC for the first 4 hours.  
• Proportion of patients with ≥60%, ≥80%, and 100% of PRI response rate within 4 hours 
after the initiation of study drug. A PRI response is defined as the 100 * (PRItrt/PRIbsl). 
•  Time to 60%, 80%, 100% PRI response rate within 4 hours after the initiation of study 
drug 
• Duration of 80% and 100% of PRI response rate 


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For Cohorts receiving a 6th dose of ticagrelor 24 hours following study drug, PD parameters 
will be calculated for Day 1 and Day 2 separately. Additional PD parameters may be 
generated, if needed. 
 
2.2.3 Pharmacokinetic Endpoints 
Plasma PK 
Plasma concentrations of total PB2452, unbound PB2452, total Ticagrelor, total TAM, 
unbound Ticagrelor, and unbound TAM, will be assessed at predetermined timepoints.  
PK parameters for PB2452 include:  
• Observed maximum plasma concentration (Cmax) 
• Area under the plasma concentration versus time curve (AUC) from time zero to the 
time of the last quantifiable concentration (AUC0-t) 
• Time to reach the observed maximum plasma concentration (Tmax) 
• AUC from time zero to 24 hours post-dose (AUC0-24) 
• AUC from time zero to 48 hours post-dose (AUC0-48)  
• Area under the plasma concentration versus time curve (AUC) from time zero to the 
time of the end of the dosing period(AUC0-tau) 
• AUC from time zero extrapolated to infinity (AUC0-∞; if data permit) 
• Terminal elimination half-life (t½; if data permit) 
• Clearance (CL; if data permit) 
• Volume of distribution (Vd)  
PK parameters for Ticagrelor/TAM include: 
• Cmax  
• AUC0-t 
• Tmax 
• AUC0-24 
• AUC0-48  
• AUC0-tau 
• AUC0-∞; if data permit 
• t½; if data permit 
For Cohorts receiving a 6th dose of ticagrelor 24 hours following study drug initiation, AUC0-
48 will not be calculated for neither plasma PB2452 nor ticagrelor/TAM. The remaining PK 


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parameters might be calculated for Days 1 and 2 separately. Additional PK parameters may 
be generated, if needed. Details will be provided in a separate document, the statistical 
analysis plan (SAP). 
Urine PK 
Pooled urine samples to assess urine PB2452, ticagrelor, and TAM concentrations will be 
collected over these intervals: before dosing (within 60 minutes prior to the first ticagrelor 
dose on Day -2) and 0 to 6, 6 to 12, and 12 to 24 hours. In patients receiving a 6th dose of 
ticagrelor, pooled urine samples to assess urine ticagrelor and TAM concentrations will be 
collected over these intervals beginning with the 6th ticagrelor dose: 0 to 6, 6 to 12, 12 to 
24 hours.  
Pharmacokinetics parameters for PB2452, ticagrelor, and TAM concentrations in urine for all 
subjects in the PK population to be calculated are: 
• 
Total amount of drug excreted in urine at 24 hours after dosing (Ae24) and at 48 hours 
after dosing (Ae48) 
• 
Ae from time t1 to t2 hours when the values of t1 to t2 are 0 to 6, 6 to 12, 12 to 24 and  
24 to 48 hours (Aet1-t2) 
• 
Fraction excreted in urine from 1 to 24 hours after dosing (Fe24) and from 1 to 48 hours 
after dosing (Fe48) 
• 
Renal clearance (CLr) for 24 hours after dosing 
For Cohorts receiving a 6th dose of ticagrelor 24 hours following study drug initiation, Fe48 
and Ae24-48 will not be calculated. Other urine PK parameters may be calculated for Days 1 
and 2 separately. 


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3. 
INVESTIGATION PLAN 
3.1 STUDY DESIGN AND METHODOLOGY 
This is Part A of a two-part Phase 2A, randomized, double-blind, placebo-controlled, single 
dose, sequential group study to evaluate the safety, tolerability, PK, and PD of PB2452 vs 
matching placebo. Part A investigates various dose levels and regimens of PB2452 
administered intravenously to older (ages 50 to 64 years) and elderly (ages 65 to 80 years) 
male and female subjects pretreated with ticagrelor + aspirin (ASA) as part of dual 
antiplatelet therapy. Part B investigates various dose levels and regimens of PB2452 
administered to healthy male and female subjects (ages 18-50) pretreated with a high dose of 
ticagrelor alone (180 mg BID). Part B is described in a separate protocol document.   
In Part A described herein, up to 5 dose levels and/or administration regimens will be 
evaluated in up to 5 cohorts. Each cohort will include approximately 8 to 12 subjects 
randomized in a 3:1 ratio, PB2452:placebo. All references to study drug within the content of 
the protocol apply to PB2452 or matching placebo. 
This initial cohort (Cohort 1) will include approximately 8 subjects ages 50 to 80 years 
pretreated with ASA + ticagrelor who will be randomized to 18 grams (g) of PB2452 or 
matching placebo administered as an initial 6 g bolus infused over 10 minutes, followed by 
12 g infused over the next 15 hours and 50 minutes to complete a 16 hour administration 
regimen. This initial regimen was shown to be safe and well tolerated in healthy young adults 
(18 to 50 years) in a prior Phase 1 study and provided immediate and sustained reversal of 
the antiplatelet effects of ticagrelor. Following completion of Cohort 1, subsequent cohort(s) 
may test the same, higher, or lower dose levels, and/or different infusion regimens of PB2452 
or matching placebo in the same population as in Cohort 1 or in different populations, such 
as, elderly subjects (65 to 80 years old) as determined by the Sponsor after examination of 
available PD and safety data from the prior cohort(s). A written Dosing Memo provided by 
the Sponsor to the clinical site will describe details of the dosing regimen, cohort population, 
cohort size, sampling schedules, and other cohort-specific study activities prior to initiation 
of each cohort. The maximum total dose of PB2452 administered to any subject will not 
exceed 30g. Duration of study drug infusions will not exceed 48 hours. The maximum 
administration rate of PB2452 will not exceed 18g over 30 minutes.     
A SRC will review all available safety data from ongoing or completed cohorts and will 
document their review and assessment in written SRC minutes prior to initiation of a 
subsequent cohort. Dose escalation may occur only if the SRC affirms the dose and regimen 
from the previously completed cohorts were safe and well tolerated and no DLTs were 
observed.  


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The study will consist of a Screening period (Days –45 to –4), a Check-in day (Day -3) and  
Pretreatment Period, an on-site Randomization/Treatment day (Day 1), 3 days on-site for 
treatment and safety monitoring, a Follow-up Visit (Day 7), and a Final Follow-up visit (Day 
28 [±2 days]). Seven days prior to Randomization (Day -7), subjects will be administered 
ASA 81 mg orally once daily (QD) until the final dose on the morning of Day 1 before 
receiving study drug. A ticagrelor 180 mg oral loading dose will be administered on the 
morning of Day -2 followed by 90 mg every 12 hours until the 5th dose has been 
administered on the morning of Day 1. After completion of Cohort 1, the Sponsor may 
choose to have a 6th dose of ticagrelor administered 24 hours after the initiation of study drug 
in a subsequent cohort.  
Subjects will check in to the clinical site (PPD) on Day -3. In the morning on Day -2, 
subjects will begin pretreatment with ticagrelor as described in the preceding paragraph. On 
Day 1, subjects who meet all the inclusion criteria and none of the exclusion criteria will be 
randomized in a ratio 3:1 (PB2452:placebo), to receive an IV dose of PB2452 or placebo 2 
hours following the 5th ticagrelor dose. Subjects may be discharged from the clinical site 
between Days 3 and 7 inclusive and will return for a Follow-up visit on Day 7, if already 
discharged, and on Day 28 (±2 days).  
Serum and plasma sampling times for PB2452, ticagrelor, and TAM PK and PD assessments 
and urine sampling times for urinary PB2452, ticagrelor, and TAM concentrations will be 
described in a detailed Dosing Memo for each cohort. Hour 0 will be the time for initiation of 
study drug infusion (2 hours following administration of the 5th ticagrelor dose). PK and PD 
time points for subsequent cohorts may be adjusted as needed based on available PK, PD, 
and safety data from prior cohorts. In any cohort subsequent to Cohort 1, there will be no 
more than 6 additional sampling time points.   
• 
For each cohort, the final dose level, administration regimen, PK/PD sampling and 
ECG schedule will be conveyed from the Sponsor to the clinical site in a written 
Dosing Memo 1 to 2 weeks prior to initiation of each cohort, including the following 
instructions Number of subjects to be randomized  
• 
Total PB2452 dose and administration regimen  
• 
Whether or not a 6th ticagrelor dose will be administered 24 hours after the 
5th ticagrelor dose 
• 
The PK and PD sampling schedule  
• 
Safety ECG schedule  
Hour 0 on Day 1 for all PK/PD and safety assessment will be the initiation of study drug 
infusion (2 hours following administration of the 5th ticagrelor dosing).  


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Safety and tolerability will be carefully monitored throughout the study. Immunogenicity 
samples will be collected from all subjects at Day -3, Randomization, Days 7 and 28 (±2 
days) following administration of study drug. 
3.2 SELECTION OF STUDY POPULATION 
Male or female subjects will be evaluated in up to 5 cohorts in the US, North America. To 
ensure the study clinic has sufficient subjects available for dosing for any cohort, additional 
subjects may be asked to present to the clinic for check in. The number of subjects brought in 
for check-in and pre-dosed with ticagrelor will be at the discretion of the study clinic 
personnel/ principal investigator to ensure there is a sufficient number of subjects available 
for dosing with study drug for a given cohort. Subjects who check in to the clinic may be 
dosed with ticagrelor in preparation for dosing with the study drug according to the Schedule 
of Events (Appendix 7.1). Extra subjects may be dosed with ticagrelor, so on the day of 
randomization there is a sufficient number of subjects available to fill the cohort. 
3.2.1 Inclusion Criteria 
Subjects must meet ALL the following criteria to be eligible for inclusion in the study: 
1. The subject provides written informed consent and agrees to comply with all 
protocol requirements. 
2. The subject is male or female between 50 and 80 years of age, inclusive.    
3. The subject has a body mass index (BMI) between 18 and 35 kg/m2 and a weight of 
≥50 kg but ≤120 kg, inclusive, at Screening. 
4. The subject is considered by the investigator to be in good general health, as determined 
by medical history, clinical laboratory test results, vital sign measurements, 12-lead ECG 
results, and physical examination findings at Screening. Subjects with chronic, stable, 
and well-controlled medical conditions are eligible provided they meet all other 
inclusion/exclusion criteria. Some examples of stable and well-controlled medical 
conditions include but are not limited to: 
• 
Hypertension (HTN) controlled with ≤2 antihypertensive drugs 
• 
Diabetes controlled with diet/exercise or treated with ≤2 oral diabetes medications  
• 
Subjects with diabetes must have a glycosylated hemoglobin HbA1c ≤8 mg/dL 
at Screening  
• 
Mild hepatic enzyme elevation (aspartate aminotransferase [AST] or alanine 
aminotransferase [ALT] <1.5 x upper limit of normal [ULN] or total bilirubin  
<1.2 x ULN) 


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• 
Controlled hyperlipidemia (defined as a Screening low density lipoprotein [LDL]  
<160 mg/dL) 
5. Specific inclusionary laboratory values at Screening and Check-in require:  
• 
White blood cell (WBC) count, platelet count, hemoglobin (Hgb) level within normal 
range as, defined by the clinical laboratory 
• 
Thyroid stimulating hormone (TSH) level within normal range, as defined by the 
clinical laboratory at Screening 
• 
Prothrombin time (PT) and partial thromboplastin time (PTT) level within normal 
range, as defined by the clinical laboratory  
6. Subjects taking medications for well-controlled medical conditions must have been on a 
stable dose (meaning no changes in dose) for at least 30 days prior to Screening visit. 
7. Subjects entering the study who are not already taking daily ASA must be willing to 
start an 81 mg daily dose of ASA on Day -7 and continue daily dosing until the final dose 
is administered on the morning of Day 1. Subjects entering the study who are already 
taking ASA daily will be administered a ASA 81 mg daily between Day -7 and Day 1 and 
must suspend further ASA dosing until discharge from the clinical facility. 
8. Female subjects of childbearing potential must not be pregnant, lactating, or planning to 
become pregnant for 3 months after the last dose of study drug, and have a negative 
serum pregnancy test at Screening and Check-in. Female subjects of childbearing 
potential must use 2 effective methods of birth control from 30 days before study drug 
administration through to the end of the study.  
• 
Effective birth control methods include oral, implantable, patch, or injectable 
contraceptive hormone treatment, hormone-containing intrauterine device that has 
been in place ≥2 months prior to Screening, sponge, diaphragm, or cervical cap with 
spermicidal gel or cream for female subjects or condom or vasectomy for male 
subjects.  
• 
Women are considered to not be of childbearing potential if they have fulfilled one of 
these criteria: documentation of irreversible surgical sterilization (i.e., hysterectomy 
or bilateral oophorectomy [not tubal ligation]) or are postmenopausal (defined as 
amenorrhea for 12 consecutive months following cessation of all exogenous 
hormonal treatments, and documented plasma follicle-stimulating hormone (FSH) 
level >40 IU/mL) or amenorrhea for 24 consecutive months.  
• 
Male subjects with partners of childbearing potential must agree to use appropriate 
and effective measures of contraception (e.g., condom plus diaphragm with 
spermicide, condom plus spermicide) during the study and for 30 days after the last 


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dose of study drug, and refrain from donating sperm for ≥90 days following the last 
dose of study drug.  
3.2.2 Exclusion Criteria 
Subjects will be excluded from this study if they meet ANY of the following criteria:  
1. Concern the subject may be unable to comply with study procedures and/or follow-up, or, 
in the opinion of the investigator, the subject is not suitable for entry into the study 
2. History of any acute or chronic medical disorder expected to decrease the life expectancy 
of the subject   
3. History or presence of gastrointestinal (GI), hepatic (with the exception of Gilbert’s 
syndrome), or any other condition known to interfere with absorption, distribution, 
metabolism, or excretion of drugs  
4. Significant renal insufficiency, as indicated by estimated glomerular filtration rate 
(eGFR) <30 mL/min/1.73m2 according to the Modification of Diet in Renal Disease  
(MDRD) equation   
5. Any clinically significant (CS) acute illness, medical/surgical procedure, or trauma within 
4 weeks of administration of study drug or any planned surgical procedure that will occur 
during the study (from Screening through the Day 28 [±2 days] Follow-up visit). 
6. Any CS abnormal findings in physical examination, vital signs, laboratory assessments, 
and ECG parameters identified during Screening or Check-in. Note: abnormal results 
may be repeated for confirmation immediately after the first out of range measurement. 
Abnormal vital signs may be repeated twice if needed, immediately after the first 
abnormal result and/or after the subject has rested for at least 10 minutes. 
Specific vital sign exclusionary criteria occurring after 10 minutes of supine rest are any 
of the following: 
• 
SBP <100 or >160 mm Hg 
• 
DBP <40 or >95 mm Hg 
• 
Resting HR <50 or >100 beats per minute (bpm) 
Specific exclusionary criteria for ECG parameters at Screening or Check-in include any 
of the following: 
• 
Prolonged Fridericia-corrected QT interval (QTcF) >450 milliseconds (msec), 
shortened QTcF <340 msec, or pause >3 seconds, or family history of long 
QT syndrome 


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7. Any specific contraindication to Brilinta® as described in the Brilinta prescribing 
information and: 
• 
History of intracranial hemorrhage, active bleeding, or hypersensitivity or allergic 
reaction to ticagrelor or any component of the product 
• 
Any history of severe head trauma, intracranial neoplasm, arteriovenous 
malformation, aneurysm, or proliferative retinopathy 
• 
Any history of intraocular, retroperitoneal, or spinal bleeding 
• 
Have taken, within 30 days of Screening, any oral or parenteral anticoagulant, 
including low molecular-weight heparin 
• 
Stool sample testing positive for occult blood within 3 months of Screening or at any 
time during the Screening Period. 
8. Receiving chronic treatment with nonsteroidal anti-inflammatory drugs (NSAIDS; 
including ASA [>100 mg daily]), anticoagulants, or other antiplatelet agents that cannot 
be discontinued 14 days prior to randomization (including clopidogrel, prasugrel, 
ticlopidine, dipyridamole, or cilostazol). 
9. Positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) 
antibody, or human immunodeficiency virus (HIV) types 1 or 2 antibodies at Screening. 
10. Concomitant oral or IV therapy with strong cytochrome P450 3A4 (CYP3A) inhibitors, 
CYP3A substrates with narrow therapeutic indices, or strong CYP3A inducers, which 
cannot be stopped within at least 5 half-lives, but not fewer than 10 days, before 
randomization (a list of examples may be found in Appendix 7.2). 
11. Consumption of grapefruit or grapefruit juice, Seville orange or Seville 
orange-containing products (e.g., marmalade), , or xanthine-containing products within 
48 hours before dosing with study drug. 
12. Prescription or over-the-counter (OTC) medications within 14 days before the first dose 
of study drug unless specifically allowed by protocol. (Permitted medications include 
multivitamins, paracetamol [up to 2g per day], and/or treatments for chronic stable 
diseases provided the drug and dose have been stable for ≥30 days prior to administration 
of study drug)   
13. Has received another investigational drug (defined as a small molecule or biologic 
compound which has not been approved for marketing) within 30 days of the 
administration of study drug in this study or within 5 half-lives of the experimental 
medication, whichever is longer.  
14. Positive test result for alcohol or drugs of abuse at Screening or Check-in. 


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15. Participated in strenuous activity or contact sports within 24 hours before the infusion of 
study drug or while confined in the clinical site. 
16. History of severe or ongoing allergy/hypersensitivity to any drug or biologic  
therapeutic agent.  
17. Involvement with any PhaseBio or study site employee or their close relatives (e.g., 
spouse, parents, siblings, or children whether biological or legally adopted). 
18. Previously received PB2452 or had been randomized to receive study drug in an earlier 
cohort for this study. 
3.2.3 Subject Restrictions During the Study 
If a subject is unable to comply with any of the following restrictions before study drug 
dosing on Day 1, the subject’s participation in the study will be re-evaluated by the 
investigator in consultation with the Sponsor and/or medical monitor on behalf of the 
Sponsor; the subject may not be eligible to participate in the study: 
• 
Subjects must be willing to remain at the study site from Day -3 through 48 hours 
following study drug dosing on Day 3.  
• 
Subjects must be willing to return to the clinic for Follow-up visits on Day 7 and  
Day 28 (±2 days).  
• 
Subjects must refrain from smoking or using nicotine or nicotine-containing products 
and from drinking alcohol-containing products   
• 
Subjects must refrain from strenuous exercise for 24 hours prior to Check-in and for 7 
days after discharge from the study 
• 
Subjects must be willing to maintain their usual caloric intake and to consume only 
food and beverages provided by the clinical site while confined to the study site. 
3.3 WITHDRAWAL OF SUBJECTS FROM THE STUDY 
3.3.1 Reasons for Withdrawal 
Subjects may withdraw consent and discontinue from the study at any time, for any reason, 
without prejudice to further treatment. Subject participation in the study may be stopped at 
any time at the discretion of the investigator or at the request of the Sponsor. The 
investigator may also withdraw a subject at the request of the Sponsor or if the Sponsor 
terminates the study.   
The investigator may withdraw a subject from the study if the subject:  
• 
Is non-compliant with the protocol;  


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• 
Experiences a serious adverse event (SAE) or intolerable adverse event (AE) that, in the 
investigator’s opinion, requires withdrawal from the study;  
• 
Has laboratory safety assessments that reveal CS hematological or biochemical changes 
from Baseline values;  
• 
During the course of the study and through the end of study (EOS) develops symptoms or 
conditions listed in the exclusion criteria;  
• 
Requires a medication prohibited by the protocol; or  
• 
Requests an early discontinuation for any reason.  
If a subject experiences an SAE or intolerable AE, the investigator will confer with the 
sponsor. If a subject is discontinued because of an AE, the event will be followed until it is 
resolved or until it is stable. 
3.3.2 Handling of Withdrawals 
When a subject withdraws from the study, the reason(s) for withdrawal will be recorded by 
the investigator on the relevant page of the electronic case report form (eCRF).  Whenever 
possible, any subject who withdraws from the study if willing, should continue to be 
followed according to the protocol. For example, if termination occurs earlier than planned 
(i.e., after a subject has received all or partial study drug infusion) all efforts should be made 
to ensure the remaining protocol visits are completed. If a subject refuses to return for the 
Follow-up visits, the Day 28 (±2 days) visit procedures should be completed. Any subject 
who fails to return for final assessments will be contacted by the site in an attempt to obtain 
compliance with the protocol. The status of subjects who fail to complete final assessments 
will be documented in the eCRF. 
3.3.3 Replacement of Subjects 
At the discretion of the investigator after consultation with the Sponsor, any subject who 
withdraws before completing the study, for reasons other than a DLT, may be replaced. Any 
replacement subject will be assigned to receive the same treatment as the subject he or she is 
replacing. 
3.4 STUDY TREATMENTS 
3.4.1 Method of Assigning Subjects to Treatment Groups 
On Study Day 1 eligible subjects will be randomly assigned to treatment with either PB2452 
or matching placebo in a 3:1 ratio, PB2452:placebo.  


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3.4.2 Treatments Administered 
PB2452: 
PB2452 IV infusion, prepared according to the Pharmacy Manual, will be administered on 
Day 1 for up to 48 hours. The total dose for each subject will not exceed 30g. The infusion 
rate will not exceed 18g over 30 minutes and the concentration will not exceed 24g in 
250mL. Subjects will not receive more than 250 mL of study drug infusion within any 1-hour 
period.  
For each cohort, the dose, infusion rate, and duration will be communicated from the Sponsor 
to the study site, PPD, in a Dosing Memo issued prior to initiation of each treatment cohort.  
Matching Placebo: 
0.9% sodium chloride single IV infusion, administered on Day 1, will be delivered at a rate 
and volume matching the active infusion.  
Ticagrelor: 
Ticagrelor 90 mg oral tablet (immediate release) administered as 180 mg  
(2 × 90 mg tablets) loading dose plus 90 mg every 12 hours for 4 additional doses. In 
successive cohorts following cohort 1, if indicated in a Dosing Memo from Sponsor to site, 
one or more cohorts may also receive an additional single oral dose of 90  
ASA: 
During Screening, starting on Study Day -7, subjects will receive ASA (enteric coated) 81 mg 
QD to be taken through to the morning of Day 1, prior to receiving study medication. 
Subjects who were already taking ASA daily before entering the study must be willing to 
document self-administered daily 81 mg dose of ASA between Day -7 and -3, accept ASA 81 
mg administered at the clinical site between Day -2 and Day 1, and suspend further ASA 
doses until discharge from the clinical facility.  
3.4.2.1 
Dose Escalation 
The SRC will conduct a blinded review of all safety and tolerability data from a cohort at 
least through Day 3 (e.g., clinical laboratory results, AEs, ECGs, Holter monitoring reports if 
available, vital signs, and available PK data) and available data for each completed dose 
cohort and will document their review and assessment in written SRC minutes prior to 
initiation of a subsequent cohort. Dose escalation may occur only if the SRC affirms the dose 
and regimen from the previously completed cohorts were safe and well tolerated and no 
DLTs were observed.  
The SRC will be minimally composed of the on-site PPD investigator/medical monitor, 
PhaseBio medical monitor, and PhaseBio clinical operations lead. Changes to the 
administration regimen (rate and duration) without escalation of the total dose or without 


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increases in the infusion rate will not require formal SRC approval. Similarly, reductions in 
the total dose or the infusion rate will not require SRC approval.  
The investigator may make a recommendation concerning whether the safety profile is 
sufficient to proceed to a higher dose level, whether a pause in dosing for review of 
additional safety and/or PK data is needed, or whether adjustment of the dose of the next 
dose cohort is needed. The decision to adjust or pause the dose or proceed to the next cohort 
will be made by the SRC.  
3.4.2.2 
Infusion-related or Allergic Reactions 
The administration of study drug infusion must be performed under supervision of trained 
medical staff and where facilities to handle allergic reactions are available. Should a subject 
experience symptoms typical of IRRs seen with some recombinant protein drugs  
e.g., lightheadedness, nausea, chills, fever(Doessegger 2015) the study drug infusion must be 
immediately and permanently discontinued. Should a subject experience symptoms typical of 
an allergic reaction (e.g., shortness of breath, anaphylaxis, urticaria, angioedema), the study 
drug administration must be immediately and permanently discontinued. Suspected IRRs 
will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.(NCI CTCAE, v5, 2017) Should any one subject develop a ≥Grade 2 IRR to 
study drug, all subsequent subjects in the study, inclusive of all dose cohorts, must be 
administered premedication (diphenhydramine 25 mg by mouth [PO] + acetaminophen 
650 mg PO) 30 to 60 minutes prior to receiving study drug to mitigate the risk of IRR. If any 
recipient of PB2452 (after unblinding) develops a ≥Grade 2 IRR in the absence of 
premedication, the entire dose level must be repeated as an additional cohort in which all 
subjects must be premedicated (as described above) 30 to 60 minutes prior to administration 
of study drug.  
To monitor for potential IRRs, vital signs, including BP, HR, Temp, RR, will be assessed at 
Baseline (prior to study drug infusion), every 10 minutes during the first 30 minutes of the 
infusion, and every 15 minutes thereafter for the first hour after initiation of the infusion. The 
remaining assessments of vital signs will be performed as described in the Schedule of 
Events (Appendix 7.1). Suspected allergic (hypersensitivity) reactions and anaphylaxis will 
be assessed according to the clinical diagnostic criteria outlined by the National Institute of 
Allergy and Infectious Diseases provided in the CTCAE v5 in Appendix 7.3 (Definition and 
Management of Anaphylaxis) and Appendix 7.4 (Clinical Criteria for Diagnosing 
Anaphylaxis). Subjects will receive appropriate medical treatment for these and other 
medical concerns at the discretion of the investigator. 


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3.4.2.3 
Dose-limiting Toxicities 
The SRC will review all AEs and all laboratory and ECG Holter monitoring abnormalities 
according to CTCAE v5 to determine whether DLT has been identified in a subject who is 
confirmed to have received PB2452. If the SRC determines an AE is related to administration 
of ticagrelor or another confirmed cause, the AE will not be considered a DLT. Definitions of 
DLT are:  
• 
Any AE assessed as ≥Grade 2 based on the CTCAE v5 grading scale and occurred in a 
subject confirmed to have received PB2452.  
• 
Any ≥Grade 2 laboratory abnormality (outside the clinical laboratory normal reference 
range) that occurs in a subject confirmed to have received PB2452.  
• 
Note: For a Grade 2 electrolyte abnormality that spontaneously resolves to ≤Grade 1 
without intervention within 24 hours, the SRC may decide to exempt the laboratory 
abnormality from being considered a DLT.  
• 
Any treatment-emergent adverse event (TEAE) that leads to study withdrawal of a 
subject confirmed to have received PB2452. 
3.4.2.4 
Stopping Criteria 
Dose escalation or ongoing infusions will be suspended, pending investigation by the SRC, if 
any of the following occur after confirmation the subject has received PB2452: 
• 
Any preclinical or clinical events that, in the opinion of the SRC, contraindicate further 
dosing of additional subjects with PB2452 
• 
Any serious AE (SAE) occurring prior to discharge from the clinical site 
• 
Data from previous cohorts indicate safety concerns for dosing at a higher level, such as 
unanticipated adverse responses (e.g., CS changes in clinical laboratory test data, ECGs 
Holter monitoring results, vital signs, physical examinations) 
• 
Two or more subjects in a cohort experience any DLT, or 1 subject experiences  
a ≥Grade 2 AE (DLT) that, in the opinion of the SRC, warrants suspension of dose 
escalation 
• 
Two or more subjects have >3 x ULN of either alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST), or >2 x ULN of bilirubin or alkaline phosphatase 
(ALP) when no other reason can be found to explain the increases 
• 
One or more subjects experiences a ≥Grade 2 IRR despite having been premedicated for 
IRRs. 
Continuation of dosing following suspension will be determined by the SRC and documented 
in an ad hoc SRC Safety Report. Dosing may also be suspended if, in the opinion of the SRC 
or Sponsor, any new or unexpected significant safety or tolerability issues related to 
ticagrelor or PB2452 are identified that warrant further evaluation before additional subjects 
are dosed. This may include emerging nonclinical data, clinically relevant AEs, or relevant 
data from other sources indicating safety concerns, even if the event(s) per se does not meet 
the protocol-specified definition of a DLT. 


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Dose-limiting toxicities identified during the study will be assessed as potential indicators of 
cumulative toxicity and provide rationale for defining the maximum tolerated dose (MTD). 
Although this study is not designed to dose to a MTD, the MTD may be reached if  
≥2 subjects in a dose cohort experience a DLT, as defined in Section 3.4.2.3. There will be no 
further dosing above the MTD. 
3.4.3 Identity of Investigational Product 
Study drug PB2452 is supplied as a sterile white to off-white lyophilized cake, free from 
visible foreign particles in a 20R glass vial at a nominal fill volume of 7.5 mL. PB2452 in the 
reconstituted state is formulated at 100 mg/mL in 25 mM histidine/histidine hydrochloride 
buffer, 290 mM sucrose, and 0.05% (w/v) polysorbate-80, pH 6.0. 
Matching placebo is a sterile, nonpyrogenic liquid product intended for IV administration 
composed of 0.9% sodium chloride in water for injection, USP. Separate instructions will be 
provided to the clinic for dose dilution, preparation, storage, and administration.  
3.4.4 Management of Clinical Supplies 
3.4.4.1 
Packaging and Storage 
PhaseBio Pharmaceuticals, Inc will provide the investigator and clinical site with adequate 
quantities of PB2452, and matching placebo. The study site will purchase commercially 
available ticagrelor 90 mg tablets and ASA 81 mg tablets. 
PB2452 will be supplied in a 20R glass vial at a nominal fill volume of 7.5 mL, stoppered 
with siliconized 20 mm chlorobutyl elastomer, flurotec-coated, single vent lyophilization 
stopper, and sealed with flip-off cap overseal. Following reconstitution with water for 
injection, PB2452 is further diluted into 0.9% saline for IV infusion.  
The clinical site pharmacy will prepare a single dose for each subject based on the dosing 
cohort and randomization assignment. The concentration will vary between 0.4 mg/mL up to 
72 mg/mL. Separate instructions will be provided to the clinic for dose dilution, preparation, 
storage, and administration. 
PB2452 must be stored in a secure area (e.g., a locked, temperature-controlled unit) at 2°C 
to 8°C (36°F to 46°F) protected from moisture and light with access restricted to necessary 
clinic personnel. with access restricted to necessary clinic personnel. The clinical site will be 
required to keep a temperature log to establish a record of compliance with these storage 
conditions.  
3.4.4.2 
Drug Accountability 
The investigator will maintain accurate records of receipt of all drug supplies used in this 
study including lot numbers (if applicable) and dates of receipt. In addition, accurate records 


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will be kept regarding when and how much drug is dispensed and used by each subject in the 
study. Reasons for departure from the expected dispensing regimen must also be recorded. At 
the completion of the study, to satisfy regulatory requirements regarding drug accountability, 
all drugs will be reconciled and retained or destroyed according to applicable regulations. 
3.4.5 Blinding 
This is a double-blind study. Neither the subjects nor the investigator will be aware of the 
treatment assignment. Blinding will be maintained throughout the study by use of active and 
placebo dose forms prepared to be similar in appearance. To maintain the blind, only 
designated pharmacy staff at the study site will have access to the randomization code and 
will prepare each dose for each subject. In order to prepare preliminary summaries of safety, 
PK, and/or PD data, as needed, to make timely decisions concerning adjustment of study 
procedures, dosing regimens, or potentially early termination of the study, certain designated 
staff at PhaseBio (e.g. study director, a single biostatistician, and bioanalytical scientist[s]) 
study drug accountability monitor, will receive unblinded data after each cohort completes 
Day 3 assessments. Except as noted above, all other members of PhaseBio will remain 
blinded. Access to the randomization code will be strictly controlled according to PPD SOPs.  
3.4.6 Treatment Compliance 
All doses of study drug, matching placebo, and ticagrelor will be administered at the clinical 
site under direct observation of clinic personnel and recorded in the eCRF.  
The date, time, and actual dose received of study drug and matching placebo infusion and 
ticagrelor dosing will be recorded on the appropriate pages of the eCRF. If a subject was 
scheduled to receive any of these drugs and did not, the reason for the missed or partial dose 
will be recorded in the eCRF pages. 
3.4.7 Breaking the Blind 
A subject may be unblinded in the event of a DLT, an SAE, or if there is a medical 
emergency when the identity of the drug must be known to properly treat a subject. A cohort 
may be unblinded to determine if dose escalation to the next dose level will or will not 
proceed. In the event of a medical emergency requiring identification of the study drug 
administered to an individual subject, the investigator will make every attempt to contact the 
medical monitor to explain the need for opening the code within 24 hours of performing that 
task. The investigator will be responsible for documenting the time, date, reason for the code 
break, and the names of the personnel involved.  


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3.4.8 Prior and Concomitant Medication 
Prior medications are defined as medications taken prior to the first dose of study medication, 
regardless of whether they are continued or not after the first dose of study medication. 
Concomitant medications are defined as medications taken on or after the first dose date of 
study medication, including those started before the first dose and continued into the 
treatment period. 
3.4.8.1 
Prior Medication and Therapies 
Information about prior medications taken by the subject within 30 days before he or she 
provides informed consent will be recorded in the subject’s eCRF. 
3.4.8.2 
Concomitant Medication and Therapies 
Subjects are prohibited from taking any additional prescription or OTC medications or 
nutritional supplements during their participation in the study (with the exception of protocol 
allowed medications, hormonal birth control and/or chronic medications). 
Paracetamol/acetaminophen or other medications may be administered at the discretion of 
the investigator at doses of up to 2 g/day. 
Subjects are prohibited from therapy with strong CYP3A inhibitors, CYP3A substrates with 
narrow therapeutic indices, or strong CYP3A inducers. A list of example inhibitors and 
inducers of CYP3A4 is presented in Appendix 7.2. 
Subjects are prohibited from taking NSAIDs (within 14 days of screening), anticoagulants, 
or other antiplatelet agents within 30 days of screening.  
Concomitant medications will be coded using the latest version of the World Health 
Organization Drug Dictionary (WHO-DD). With the exception of drug therapy specified in 
the protocol, if drug therapy is taken, a joint decision will be made by the investigator and 
the Sponsor whether to continue or discontinue the subject based on the time the 
medication was administered, its pharmacology and PK, and whether the use of the 
medication will compromise the subject’s safety or interpretation of the data. It is the 
investigator’s responsibility to ensure that details regarding the medication are accurately 
recorded in the eCRF. 
3.5 STUDY PROCEDURES 
After signing the ICF, subjects will have study procedures at the time points specified in the 
Schedule of Events (Appendix 7.1).  
Screening (Days -45 to -4) 
• 
Subjects sign informed consent 
• 
Inclusion/Exclusion criteria 


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• 
Demographics 
• 
Medical history 
• 
Urine drug screen, including cotinine 
• 
Urine alcohol screen 
• 
Serum pregnancy test for women of childbearing potential 
• 
Serology test 
• 
Stool occult blood test 
• 
Physical examination, full, including height, weight, and BMI calculation 
• 
Vital signs measured including SBP and DBP, oral body temperature, respiration rate 
(RR), and HR 
• 
12-lead ECG  
• 
Clinical laboratory tests including hematology, chemistry, coagulation, and urinalysis  
Screening (Day -7) 
• 
Subjects start receiving ASA 81mg QD (Subjects who enter the study already taking 
ASA daily will document a daily ASA 81 mg dose.) 
Screening (Day -6) 
• 
Subjects receive ASA 81mg QD 
Screening (Day -5) 
• 
Subjects receive ASA 81mg QD 
Screening (Day -4) 
• 
Subjects receive ASA 81mg QD 
Check-in/Pretreatment - Baseline (Day -3) 
• 
Subjects receive ASA 81mg QD 
• 
Inclusion/Exclusion criteria 
• 
Urine drug screen, including cotinine 
• 
Urine alcohol screen 
• 
Serum pregnancy test for women of childbearing potential 
• 
Admission to study site 
• 
Physical examination, full, including weight,  
• 
Vital signs measured including SBP and DBP, oral body temperature, RR, and HR  
• 
Clinical laboratory tests including hematology, chemistry, coagulation, and urinalysis 
• 
Blood sampling for PD (LTA/PRU/VASP) 
• 
Serum immunogenicity 
• 
AEs collected 
Pretreatment - Baseline (Day -2) 
• 
Subjects receive ASA 81mg QD 


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• 
Administration of ticagrelor begins in the morning, single dose oral ticagrelor 180 mg 
(2 x 90 mg), followed by oral ticagrelor 90 mg every 12 hours for 4 additional doses 
through to Day 1 (2 hours before study drug is initiated; for a total of 5 doses of 
ticagrelor) 
• 
Urine sampling, PK 
• 
Blood sampling for PD (LTA/PRU/VASP) 
• 
AEs collected 
Pretreatment - Baseline (Day -1) 
• 
Inclusion/Exclusion criteria 
• 
Subjects receive ASA 81mg QD 
• 
12-lead ECG  
• 
Biomarkers 
• 
Ticagrelor administered 
• 
Clinical laboratory tests including hematology, chemistry, coagulation, and urinalysis 
• 
AEs collected 
On-site Treatment – Randomization (Day 1) 
• 
Administration of ASA 81mg 2 hours prior to study drug administration 
• 
Administration of ticagrelor 2 hours prior to study drug administration 
• 
12-lead ECG before study drug is administered 
• 
Continuous 12-lead Holter monitor placed 2 hours before administration of study drug 
will remain in place for 24 hours after initiation of study drug. Subjects should be 
resting in the supine or semi-recumbent position depending upon Dosing Memo. 
• 
Vital signs (SBP, DBP, oral body temperature, RR, HR) measured 30 to 60 minutes 
prior to and during infusion of study drug according to Schedule of Events (Appendix 
7.1)   
• 
Randomization 
• 
Administration of PB2452 or matching placebo at Hour 0 
• 
Blood sampling for PK: plasma PB2452, ticagrelor, and TAM PK, collected within 10 
minutes before initiation of PB2452 infusion at Hour 0  
• 
Blood sampling for PK: plasma PB2452, ticagrelor, and TAM PK, collected according 
to the cohort-specific Dosing Memo                                    
• 
Blood sampling for PD: LTA/PRU/VASP according to the cohort-specific 
Dosing Memo  
• 
Urine sampling (PK) 
• 
Infusion site assessment 
• 
Serum immunogenicity prior to dosing 
• 
AEs collected 
 
On-site Treatment (Day 2) 


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• 
Vital signs measured 
• 
12-lead ECG  
• 
Continuous ECG recording (Holter) for ECG evaluation to remain in place for 24 
hours after initiation of study drug on Day 1 
• 
Administration of ticagrelor in cohorts specifying a 6th dose of ticagrelor 
• 
Blood sampling for plasma PB2452, ticagrelor, and TAM PK, collected according to 
the cohort-specific Dosing Memo 
• 
PK Urine sampling 
• 
Blood sampling for PD: LTA/PRU/VASP according to the cohort-specific Dosing 
Memo 
• 
Biomarkers 
• 
Infusion site assessment 
• 
Clinical laboratory tests including hematology, chemistry, coagulation, and urinalysis 
• 
AEs collected 
On-site Treatment (Day 3) 
• 
Physical examination, brief, includes querying the subject concerning any changes 
from Baseline 
• 
12-lead ECG  
• 
Vital signs measured 
• 
Blood sampling for PK: plasma PB2452, ticagrelor, and TAM PK collected according to 
the cohort-specific Dosing Memo 
• 
Urine sampling (PK) 
• 
Blood sampling for PD: LTA/PRU/VASP according to the cohort-specific Dosing Memo 
• 
Infusion site assessment 
• 
AEs collected 
• 
Subjects discharged from site 
Out-patient, Return to Study Site, Follow-up (Day 7) 
• 
Physical examination, brief, includes querying the subject concerning any changes 
from Baseline 
• 
Vital signs measured  
• 
12-lead ECG  
• 
Blood sampling for PK: plasma PB2452, ticagrelor, and TAM PK, collected according to 
the cohort-specific Dosing Memo 
• 
Biomarkers 
• 
Serum immunogenicity 
• 
Infusion site assessment  
• 
Clinical laboratory tests including hematology, chemistry, coagulation, and urinalysis 
• 
AEs collected 


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Out-patient, Return to Study Site, Follow-up, End of Study (Day 28 ±2 Days) 
• 
Serum pregnancy test 
• 
Physical examination, full, including height, weight, and BMI calculation 
• 
Vital signs measured 
• 
12-lead ECG  
• 
Blood sampling for PK: plasma PB2452, ticagrelor, and TAM PK, collected according to 
the cohort-specific Dosing Memo 
• 
Clinical laboratory tests including hematology, chemistry, coagulation, and urinalysis  
• 
Biomarkers 
• 
Serum immunogenicity 
• 
AEs collected 
3.5.1 Pharmacokinetic Sample Collection 
Samples for PK analyses should be collected after subjects has been resting supine for  
≥10 minutes. Additional details concerning the collection, preparation, and handling of PK 
blood and urine samples and sample shipping instructions will be provided to the clinical 
site. The clinical site will store all urine and plasma samples at the designated temperatures 
until shipped to the appropriate laboratories for analysis. Back-up samples will be maintained 
by the clinical site under the same conditions or at a designated storage facility until the 
Sponsor indicates the back-up samples should be shipped to the Sponsor. 
PB2452 PK and immunogenicity analysis will be performed by:  
PhaseBio Pharmaceuticals, Inc.  
1 Great Valley Parkway, Suite 30  
Malvern, PA 19355  
Telephone: 610-981-6500  
Ticagrelor and TAM concentration analysis will be performed by:  
Covance  
1121 East 3900 South, Suite C-110 
Salt Lake City, UT 84124  
Telephone: 801-313-6450 
3.5.1.1 
Bioanalytical Methods 
Pharmacokinetic samples for total and free ticagrelor and the metabolite TAM will be 
analyzed using a validated liquid chromatography coupled with tandem mass spectrometry 
assay in human plasma. Pharmacokinetic samples for PB2452 will be analyzed using an 
immunoassay. The methods will be validated according to ICH standards and fit for purpose. 
Details of the bioanalytical methods and validation will be available in a separate 
bioanalytical report. 


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3.5.1.2 
Pharmacodynamic Sample Collection 
Blood samples for PD analysis will be collected at the following times: Day -3, -2, Day 1 
(within 10 minutes prior to the initiation of study drug infusion [Hour 0] and per Dosing 
Memo), Day 2, and Day 3 if needed. 
Collection time points for each cohort will be specified in a Dosing Memo from the Sponsor 
to PPD prior to initiation of each cohort.   
Blood samples will be collected in collection tubes specific for each of the 3 PD assays. 
Specific instructions referring to the collection, processing, testing and, when applicable, the 
shipment of PD samples to CirQuest Labs, will be in the laboratory manual provided by 
CirQuest Labs and must be followed. If there is a discrepancy between the protocol and the 
lab manual, the lab manual should be followed. 
• 
LTA: 3.2% sodium citrate (blue-top) 
• 
VerifyNow® P2Y12: Greiner Bio-One Vacuette® partial fill blood collection tube 
containing 3.2% sodium citrate  
• 
VASP: 3.2% sodium citrate (blue-top) 
3.5.2 Adverse Events 
3.5.2.1 
Adverse Event Definitions 
The investigator is responsible for reporting all AEs observed or reported during the study, 
regardless of their relationship to study drug or their clinical significance. If there is any 
doubt whether a clinical observation is an AE, the event should be reported. For the purposes 
of AE recording when relationship to study drug is assessed, study drug refers to PB2452 or 
placebo. A separate line on the eCRF is for assessing whether or not an AE is related to the 
administration of ticagrelor.  
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not it is considered drug-related. Subjects will be instructed to contact 
the investigator at any time after randomization if any symptoms develop.  
A TEAE is defined as any AE not present before exposure to study drug or any AE already 
present that worsens in intensity or frequency after exposure to study drug. 
A suspected adverse reaction is any AE for which there is a reasonable possibility the study 
drug caused the AE. For the purposes of investigational new drug (IND) safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship between the 
study drug and the AE. A suspected adverse reaction implies a lesser degree of certainty 
about causality than “adverse reaction,” which means any AE caused by a study drug.  


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An adverse reaction is any AE caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions when there are reasons to conclude the drug caused the event.  
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the IB or 
at the specificity or severity that has been observed with the study drug; 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. For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the IB 
referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism 
and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the IB listed 
only cerebral vascular accidents. “Unexpected,” as used in this definition, also refers to AEs 
or suspected adverse reactions mentioned in the IB that occur with a certain class of drugs or 
as anticipated based on the pharmacological properties of the drug but are not specifically 
mentioned as having occurred with the specific drug under investigation.  
An AE or suspected adverse reaction is considered an SAE/suspected unexpected serious 
adverse reaction if, in the view of either the investigator or Sponsor, it results in any of the 
following outcomes:  
•  Death  
•  Life-threatening AE  
•  Inpatient hospitalization or prolongation of existing hospitalization  
•  Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
•  Congenital anomaly or birth defect  
Important medical events that may not result in death, may not be life threatening, or may not 
require hospitalization may be considered serious 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 in this definition. 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 hospitalization, or the 
development of drug dependency or drug abuse.  
An AE or suspected adverse reaction is considered “life threatening” if, in the opinion of 
either the investigator or Sponsor, its occurrence places the subject at immediate risk of 
death. It does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death.  
Special attention will be given to DLTs and the MTD, if applicable. DLT is defined in Section 
3.4.2.3. The overall safety profile, including but not limited to DLTs and MTDs will be used 
in the selection of the starting dose(s) in future studies of PB2452 administered by infusion. 


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3.5.2.2 
Eliciting and Documenting Adverse Events 
The investigator is responsible for ensuring that all AEs and SAEs are recorded in the eCRF 
and reported to PhaseBio Pharmaceuticals, Inc. From the time informed consent is signed 
through to completion of all study procedures and assessments at the Day 28 (±2 days) visit, 
all AEs will be assessed.  
Subjects may spontaneously report and/or will be asked a standard question to elicit any 
medically related changes in their well-being. They will also be asked if they have used any 
new medications or changed concomitant medication regimens (both prescription and 
OTC medications).  
In addition to subject observations, AEs will be documented from any data collected on the 
AE page of the eCRF (e.g., laboratory values, physical examination findings, ECG, Holter 
monitoring changes) or other documents relevant to subject safety. 
3.5.2.3 
Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page of the eCRF. 
Information to be collected includes drug treatment, type of event, time of onset, dosage, 
investigator-specified assessment of severity and relationship to study drug, time of 
resolution of the event, seriousness, as well as any required treatment or evaluations, and 
outcome. The AEs resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications, or progression of disease states must also be reported. 
All AEs will be followed until they are resolved or stable or judged by the investigator to be 
not clinically significant (NCS). The current version of the Medical Dictionary for 
Regulatory Activities (MedDRA) will be used to code all AEs.  
Any medical condition present at the time the subject is screened but does not deteriorate 
should not be reported as an AE. However, if the condition deteriorates at any time during the 
study, it should be recorded as an AE. 
Any AE considered serious by the investigator or that meets SAE criteria (Section 3.5.2.1) 
must be reported to the Sponsor immediately (after the investigator has confirmed the 
occurrence of the SAE). The investigator will assess whether there is a reasonable possibility 
the study drug caused the SAE. The Sponsor will be responsible for notifying the relevant 
regulatory authorities of any SAE, as outlined in the US Title 21 Code of Federal Regulations 
(CFR) Parts 312 and 320. The investigator is responsible for notifying the Institutional 
Review Board (IRB) directly. 
The following contact information is to be used for SAE reporting:  
PPD Medical Monitor: Rahul Bhatnagar, MD 
PPD 7551 Metro Center Drive, Suite 300  


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Austin, TX 78744  
Telephone (24 hour): 888-483-7729  
Fax: 888-529-3580  
email: rtpsafety@ppdi.com 
3.5.2.4 
Assessment of Severity 
The severity (or intensity) of an AE will be determined by the investigator and refers to the 
extent to which it affects the subject’s daily activities. Severity will be classified as mild, 
moderate, or severe using the following criteria:  
•  Mild: These events require minimal to no treatment and do not interfere with the 
subject’s daily activities.  
•  Moderate: These events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with normal 
functioning.  
•  Severe: These events interrupt a subject’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually incapacitating.  
Changes in the severity of an AE should be documented to allow assessment of the duration 
of the event at each level of intensity. An AE characterized as intermittent requires 
documentation of onset and duration of each episode. The CTCAE v5 grading scale will be 
used by the SRC to assess all IRRs to determine whether premedication is required to 
mitigate future potential IRRs for subsequent study subjects. Additionally, CTCAE v5 will be 
used by the SRC to assess all AEs and laboratory abnormalities to determine whether a DLT 
and/or stopping criteria have been reached.  
3.5.2.5 
Assessment of Causality 
The investigator’s assessment of the relationship between an AE and study drug or ticagrelor 
is part of the documentation process but is not a factor in determining what is or is not 
reported in the study. 
The investigator will assess causality of all AEs and SAEs (i.e., whether there is a reasonable 
certainty the study drug caused the event). The relationship between an AE and an SAE to 
study drug (and ticagrelor) will be characterized using the following classifications:   
•  Unrelated: This relationship suggests there is no association between study drug (or 
ticagrelor) and the reported event.  
•  Possible: This relationship is based on evidence suggesting a causal relationship between 
the study drug (or ticagrelor) and the AE (i.e., there is a reasonable possibility the drug 
caused the event). The event follows a reasonable temporal sequence from the time of 
drug administration or the event follows a known response pattern to study drug (or 
ticagrelor) but could also have been caused by other factors.  
•  Probable: This relationship suggests a reasonable temporal sequence of the event with 
drug administration exists and, based upon the known pharmacological action of the 


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drug, known or previously reported adverse reactions to the drug or class of drugs, or 
judgment based on the investigator’s clinical experience, the association of the event with 
study drug (or ticagrelor) seems likely.  
•  Definite: This relationship suggests that a definite causal relationship exists between 
study drug (or ticagrelor) administration and the AE, and other conditions (concurrent 
illness, progression/expression of disease state, or concurrent medication reaction) do not 
appear to explain the event.   
3.5.2.6 
Follow-up of Adverse Events 
All AEs must be reported in detail on the appropriate page of the eCRF and followed until it 
is resolved or stable or judged by the investigator to be not clinically significant (NCS). 
3.5.3 Clinical Laboratory Testing 
Clinical laboratory tests will be performed by PPD Central Laboratory. Blood will be 
collected at the time points indicated in the Schedule of Events (Appendix 7.1) and will be 
prepared using standard procedures. Repeat clinical laboratory tests may be performed at the 
discretion of the investigator, if necessary, to evaluate inclusion and exclusion criteria or 
clinical laboratory abnormalities. The clinical laboratory performing the tests will provide the 
reference ranges for all clinical laboratory parameters. 
The following clinical laboratory assessments will be performed:  
Hematology 
Complete blood count (CBC) with differential hematocrit (hct) 
hemoglobin (Hgb) 
mean corpuscular hemoglobin (MCH) 
mean corpuscular hemoglobin concentration (MCHC) 
mean corpuscular volume (MCV) 
mean platelet volume (MPV) 
platelet count 
erythrocyte (red blood cell [RBC]) count 
total and differential leukocyte (white blood cell [WBC]) count 
Serum Chemistry 
alanine aminotransferase (ALT) 
albumin 
alkaline phosphatase (ALP) 
aspartate aminotransferase (AST) 
bicarbonate 
bilirubin (total and direct) 
blood urea nitrogen (BUN) 
calcium 
chloride 
cholesterol 
 
total  
 
high-density lipoprotein (HDL) 
 
calculated low-density lipoprotein (LDL) 
creatine phosphokinase 
creatinine 
gamma-glutamyl transferase (GGT) 


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glucose 
Hgb A1C 
lactate dehydrogenase (LDH) 
magnesium 
phosphorus 
potassium 
sodium 
thyroid stimulating hormone (TSH; Screening only)  
total protein 
triglycerides (repeat fasting triglyceride if TG >500) 
uric acid 
Coagulation 
activated partial thromboplastin time (aPTT) 
international normalized ratio (INR) 
partial thromboplastin time (PTT) 
prothrombin time (PT) 
Urinalysis (should be aligned to  
PPD urinalysis) 
 
 
 
 
 
 
appearance 
bilirubin 
color 
glucose 
ketones 
leukocyte esterase 
reflex microscopy (at Screening and Check-in only, if dipstick is 
positive for protein or blood value ≥1+); includes  
 bacteria 
casts 
 crystals 
epithelial cells 
 RBCs 
WBCs 
 nitrites 
occult blood 
 pH  
protein 
 specific gravity (SpGr) 
turbidity 
 
 urobilinogen 
Serology 
hepatitis B surface antigen (HBsAg) 
hepatitis C virus (HCV) antibody 
human immunodeficiency virus (HIV)  
 types 1 and 2 antibodies (Screening only) 
Other analyses 
 urine drug screen (Screening and Check-in only): 
amphetamines 
barbiturates 
benzodiazepines 
cannabinoids 
cocaine 
cotinine 
methylenedioxymethamphetamine (MDMA) 
opiates 
phencyclidine 
propoxyphene 
tetrahydrocannabinol  
urine alcohol (Screening and Check-in only) 
female subjects: 
 
follicle-stimulating hormone (FSH; Screening only) 
 
serum pregnancy test (human chorionic gonadotropin  
 
 
[Screening, Check-in, and Day 28 (±2 days) only])  
 
 


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Abnormal clinical laboratory values will be flagged as either high or low (or normal or 
abnormal) based on the reference ranges for each laboratory parameter. The investigator 
will determine whether any of the abnormally high or low results are CS or NCS. Clinical 
significance is defined as any variation in results that has medical relevance and may result in 
an alteration in medical care (e.g., active observation, diagnostic measures, therapeutic 
measures). If a CS change from the Screening value is noted, the CS value and etiology or 
reason for clinical significance will be documented on the AE page of the eCRF. The 
investigator will continue to monitor the subject with additional assessments until the values 
have reached either the reference range or the values at Screening or until the investigator 
determines that follow-up is no longer medically necessary. 
When schedule procedures overlap at the same time point (see Schedule of Events  
(Appendix 7.1).  there must be planning to collect the specific information within the 
designated time window. Accordingly, the importance of these procedures is: 
1.  Blood collection (whether for PD, PK, immunology, or safety) should always be collected 
at the designated time point (if possible). However, multiple collections (PD, PK, 
immunology, and safety) may be required at the same time point. Therefore, the 
recommendation is for blood to be drawn in this order: PD, PK, immunology, and safety 
(see lab collection manual from CirQuest for additional information related to collection 
of PD samples).  
2.  The 12-lead ECG Holter monitoring has a ±10-minute window (unless otherwise 
 
designated in the Schedule of Events, [Appendix 7.1]) when this may be done, either 
 
before or after blood collection.  
3.  If time permits, vital sign measurements should be completed just prior to or just after 
 
blood collection; this may be still be done within the designated window in the Schedule 
 
of Events (Appendix 7.1). 
3.5.4 Vital Signs Measurements 
Vital signs will be measured at the time points indicated in the Schedule of Events  
(Appendix 7.1).   
Vital sign measurements will include SBP, DBP, oral body temperature, RR, and HR. The 
subject will have rested in a supine position for ≥10 minutes before all measurements are 
taken. Note: Vital signs collected during the initial 30 minutes of infusion of study drug 
require only the BP and HR. 
The investigator will determine whether any of the vital sign measurements are CS or NCS. 
Clinical significance is defined as any variation in results that has medical relevance and may 
result in an alteration in medical care (e.g., active observation, diagnostic measures, 
therapeutic measures). If a CS change from Screening values is noted, the CS value and 
reason for clinical significance will be documented on the AE page of the eCRF. The 
investigator will continue to monitor the subject with additional assessments until the value 


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has reached either the reference range or the value at Screening or until the investigator 
determines follow-up is no longer medically necessary. 
3.5.5 Twelve-lead Electrocardiogram 
Twelve-lead ECGs will be obtained after the subject has rested in the supine position for ≥10 
minutes or as clinically indicated based on reported AEs or laboratory findings, as necessary. 
The investigator should review and sign the ECG for any immediate issues. 
Electrocardiogram assessments will include comments concerning whether the tracings are 
normal or abnormal, rhythm, presence of arrhythmia or conduction defects, morphology, 
and any evidence of MI, or ST-segment, T-Wave, and U-Wave abnormalities. In addition, 
measurements of these intervals will be reported: RR interval, PR interval, QRS width,  
and and QTcF  
The investigator will determine whether any of the 12-lead ECG results are CS or NCS. 
Clinical significance is defined as any variation in results that has medical relevance and may 
result in an alteration in medical care (e.g., active observation, diagnostic measures, 
therapeutic measures). If a CS change from Screening is noted, the CS value and reason for 
CS will be documented on the AE page of the eCRF. The investigator will continue to 
monitor the subject with additional assessments until either the values have reached either 
reference range or the values at Screening or until the investigator determines follow-up is no 
longer medically necessary.  
3.5.6 Holter Monitoring (Continuous Twelve-lead ECG) 
Holter monitoring (continuous 12-lead ECG recording) for 24 hours will be performed at the 
time points indicated in the Schedule of Events (Appendix 7.1) to monitor HR and rhythm 
activity as standard safety measurements. The clinical research site will be responsible for 
providing trained study personnel for setting up and managing the Holter monitoring system 
to ensure that reports of Holter findings for each subject will be available for review at the 
safety review meeting for each cohort. The continuous ECG waveform data recorded by the 
Holter device will be stored for optional exposure-response QTc analysis. The Holter 
monitoring system used will be maintained in accordance with the clinical research site 
SOPs.  
The SRC will determine if any of the Holter findings are CS at the safety review meetings. 
Clinical significance is defined as any variation in results that has medical relevance and may 
result in an alteration in medical care (e.g., active observation, diagnostic measures, 
therapeutic measures).  


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If a CS finding from the Holter report is noted, the CS findings and etiology or reason for 
clinical significance will be documented in the AE page of the eCRF. The SRC may 
recommend repeat Holter monitoring during the 28-day safety period if clinically indicated.  
3.5.7 Physical Examinations 
A physical examination will be performed at the time points indicated in the Schedule of 
Events (Appendix 7.1).   
A full physical examination will include assessment of skin, head, ears, eyes, nose, throat, 
neck, thyroid, lungs, heart, cardiovascular system, abdomen, lymph nodes, and 
musculoskeletal system/extremities.  
A brief physical examination will include assessment of skin (including any signs of 
cutaneous erythema), lungs, cardiovascular system, and abdomen (liver, spleen). Interim 
physical examinations will be performed at the discretion of the investigator, if necessary, to 
evaluate AEs or clinical laboratory abnormalities. Height and weight will be measured, and 
BMI will be calculated at Screening and at Day 28 (±2 days).  
3.5.8 Infusion Site Assessments 
The infusion site will be examined by the investigator or designée concerning pain, 
tenderness, erythema/redness, and induration/swelling, as indicated in the Schedule of Events 
(Appendix 7.1). Infusion site reactions will be assessed according to the CTCAE v5 grading 
scale and will be recorded as AEs; these should be followed until resolution. 
3.5.9 Immunogenicity Assessments 
Immunogenicity (antibody) samples will be screened for the presence of binding anti-drug 
antibodies (ADA) at the time points indicated in the Schedule of Events (Appendix 7.1). 
Results of immunogenicity samples taken prior to administering study drug do not need to 
be available prior to dosing nor to confirm subject eligibility. A subject who tests positive for 
ADAs at the final scheduled visit (Day 28 ±2 days) will be asked to return for follow-up 
sampling approximately 3 months after the final visit and approximately every 6 months 
thereafter until ADAs no longer test positive or until levels return to a predose state. 
3.6 STATISTICAL CONSIDERATIONS 
3.6.1 Sample Size Calculations 
The sample size (N) of up to 5 cohorts of approximately for this study is based on clinical 
and practical considerations rather than on formal statistical power calculation. The sample 
size will provide preliminary safety, efficacy and PK information in a dose/regimen finding 
fashion.  


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3.6.2 Analysis Populations 
The Safety Population will include all subjects who receive any amount of study drug.  
The PK Population will include subjects in the safety population who have ≥1 measurable 
PK concentration. 
The PD Population will include subjects in the safety population who receive ≥1 dose of 
ticagrelor and have ≥1 measurable post dose PRU value. 
3.6.3 
Statistical Analysis 
Details concerning all statistical analyses will be described in a separate Statistical Analysis 
Plan (SAP). All data collected during the study will be presented in Data Listings.  
Data from subjects excluded from an analysis population will be presented in the Data 
Listings but will not be included in the calculation of summary statistics.  
Data from subjects who receive placebo will be pooled across cohorts for all presentations.  
For categorical variables, frequencies and percentages will be presented. Continuous 
variables will be summarized using descriptive statistics (number of subjects, mean, median, 
standard deviation [SD], minimum, and maximum).  
Demographic and baseline characteristics will be summarized. The number of subjects who 
enroll in the study and the number and percentage of subjects who complete the study will be 
presented. Frequency and percentage of subjects who withdraw or discontinue from the 
study, and the reason for withdrawal or discontinuation, will also be summarized. 
3.6.3.1 
Pharmacokinetic Analyses 
Plasma concentrations will be listed and summarized descriptively (number of subjects, 
arithmetic mean, SD, coefficient of variation [CV], median, minimum, and maximum). 
Plasma concentration versus time profiles for each subject will be presented graphically. 
The mean plasma concentration versus scheduled time profiles will be presented graphically 
by dose. 
Pharmacokinetic parameters will be summarized by time point for each dose level using 
descriptive statistics (number of subjects, mean, standard deviation (SD), CV, median, 
minimum, and maximum). Geometric means will be reported for AUCs and Cmax. For 
Cohorts receiving a 6th dose of ticagrelor 24 hours following study drug, PK parameters will 
be calculated for Days 1 and 2 separately. 
The PK parameters of PB2452, ticagrelor, and TAM will be determined with 
noncompartmental methods using Phoenix® WinNonlin® (Certara, L.P., Princeton, NJ) 
Version 6.4 or higher or SAS® Version 9.3 or higher (SAS Institute Inc., Cary, NC). Actual 


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sampling times, rather than scheduled sampling times, will be used in all calculations of PK 
parameters. However, for ease of presentation, scheduled sampling times will be used to 
present results in tables, listings, and figures.  
3.6.3.2 
Pharmacodynamic Analyses 
Pharmacodynamic data will be summarized for each time point using descriptive statistics 
(number of subjects, mean, SD, CV, median, minimum, and maximum). Pharmacodynamic 
parameters will also be summarized for each cohort. For Cohorts receiving a 6th dose of 
ticagrelor 24 hours following study drug, PD parameters will be calculated for Days 1 and 2 
separately.  
3.6.3.3 
Safety Analyses 
Adverse events will be coded by preferred term and system-organ-class (SOC) using the 
latest version of the Medical Dictionary for Regulatory Activities (MedDRA). All AE data 
will be presented in Data Listings. Treatment-emergent AEs (TEAEs) will be summarized by 
treatment and overall, as well as by severity and relationship to study drug. All SAEs and 
AEs leading to discontinuation of study drug will be presented in the Data Listings. 
Actual values and changes from Baseline in clinical laboratory test results, vital sign 
measurements, and 12-lead ECG results will be summarized by treatment at each time point 
using descriptive statistics (number of subjects, mean, standard deviation [SD], median, 
minimum, and maximum). Clinical laboratory test results, vital sign measurements, 12-lead 
ECG results, Holter monitor results, immunogenicity results, and physical examination 
findings will be presented in Data Listings. 
3.6.4 Handling of Missing Data 
Concentrations below the limit of quantification (BLQ) will be treated as zero for descriptive 
statistics. Mean BLQ concentrations will be presented as BLQ, and the SD and CV will be 
reported as not applicable. Missing concentrations will be excluded from the calculations. 
For the PK analysis, BLQ values will be treated as zero with the exception that a BLQ value 
between 2 quantifiable concentrations will be set as missing. Missing concentrations will be 
treated as missing from the PK parameter calculations. If consecutive BLQ concentrations 
are followed by quantifiable concentrations in the terminal phase, those concentrations after 
BLQ concentrations will be treated as missing. 
3.6.5 Interim Analyses 
There is no interim analysis planned for this study. 


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3.7 DATA QUALITY ASSURANCE 
This study will be conducted using quality processes described in applicable procedural 
documents. The quality management approach to be implemented will be documented and 
will comply with current ICH guidance on quality and risk management. All aspects of the 
study will be monitored for compliance with applicable government regulatory requirements, 
current GCP, the protocol, and SOPs. The monitor will maintain current personal knowledge 
of the study through observation, review of study records and source documents, and 
discussion of the conduct of the study with the investigator and staff.  
Electronic CRFs and electronic data capture will be used. The electronic data capture system 
is validated and compliant with US Title 21 CFR Part 11. Each person involved with the 
study will have an individual identification code and password that provides record 
traceability. There may be an internal quality review audit of the data and additional reviews 
by the clinical monitor. 


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4. 
INVESTIGATOR OBLIGATIONS 
Administrative items provided in this section are meant to guide the investigator in the 
conduct of the study and may be subject to change based on industry and government SOPs, 
working practice documents, or guidelines. Changes will be reported to the IRB but will not 
result in protocol amendments. 
4.1 CONFIDENTIALITY 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without written 
permission of the subject (or the subject’s legal guardian), except as necessary for monitoring 
and auditing by the Sponsor, designee, the US Food and Drug Administration, or the IRB.  
The investigator and all employees and coworkers involved in this study may not disclose or 
use for any purpose other than performance of the study, any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the Sponsor or designee must be obtained for the 
disclosure of any said confidential information to other parties. 
4.2 INSTITUTIONAL REVIEW 
Federal regulations and ICH guidelines require approval to be obtained from an IRB before 
human subjects participate in research studies. Before study onset, the protocol, ICF, 
advertisements to be used for recruitment of study subjects, and any other written 
information concerning this study must be provided to the subject must be approved by the 
IRB. Documentation of all IRB approvals and of the IRB compliance with the ICH E6(R2): 
GCP will be maintained by the site and will be available for review by the Sponsor or 
designee. All IRB approvals should be signed by the IRB chairman or designee and must 
identify the IRB name and address, the clinical protocol by title or protocol number or both, 
and the date approval or a favorable opinion was granted. 
4.3 SUBJECT CONSENT 
Written informed consent in compliance with US Title 21 CFR Part 50 will be obtained from 
each subject before he or she enters the study or before any unusual or non-routine procedure 
is performed that involves risk to the subject. If any institution-specific modifications to 
study-related procedures are proposed or made by the site, the consent should be reviewed by 
the Sponsor or designee or both before IRB submission. Once reviewed, the investigator will 
submit the ICF to the IRB for review and approval before the start of the study. If the ICF is 
revised during the course of the study, all active participating subjects must sign the 
revised form. 


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Before recruitment and enrollment, each prospective subject will be given a full explanation 
of the study and be allowed to read the approved ICF. Once the investigator is assured the 
subject understands the implications of participating in the study, the subject will be asked to 
give his/her consent to participate in the study by signing the ICF. A copy of the ICF will be 
provided to the subject/legal guardian. 
4.4 STUDY REPORTING REQUIREMENTS 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the time line and method outlined in this protocol. In addition, the investigator agrees to 
submit annual reports to his/her IRB, as appropriate. 
4.5 FINANCIAL DISCLOSURE AND OBLIGATIONS 
The investigator is required to provide financial disclosure information to allow the Sponsor 
to submit the complete and accurate certification or disclosure statements required under US 
Title 21 CFR Part 54. In addition, the investigator must provide the Sponsor with a 
commitment to promptly update this information if any relevant changes occur during the 
course of the investigation and for  
1 year following completion of the study. 
Neither the Sponsor nor PPD is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the Sponsor nor PPD is financially responsible for 
further treatment of the disease under study. 
4.6 INVESTIGATOR DOCUMENTATION 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R2) 
Section 8.2 and US Title 21 of the CFR by providing the following essential documents, 
including but not limited to:  
•  IRB approval 
•  The original signed investigator agreement page of the protocol 
•  Form FDA 1572, fully executed, and all updates on a new fully executed Form FDA 1572  
•  Curriculum vitae for the principal investigator and each sub-investigator listed on  
Form FDA 1572. Current licensure must be noted on the curriculum vitae. CVs will be 
signed and dated by the principal investigators and sub-investigators at study start-up, 
indicating they are accurate and current.  
•  Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under US Title 21 CFR Part 54. In 
addition, the investigators must provide to the Sponsor a commitment to promptly update 
this information if any relevant changes occur during the course of the investigation and 
for 1 year after the completion of the study.  


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•  An IRB-approved ICF, samples of site advertisements for recruitment for this study, 
and any other written information about this study to be provided to the subject or 
legal guardians  
•  Laboratory certifications and reference ranges for any local laboratories used by the site, 
in accordance with US Title 42 CFR Part 493. 
4.7 STUDY CONDUCT 
The investigator will agree to perform all aspects of this study in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, ICH E6(R2): GCP, the 
protocol, and all national, state, and local laws or regulations. 
4.8 DATA COLLECTION 
4.8.1 Case Report Forms and Source Documents 
Site personnel will maintain source documentation and enter subject data into the eCRF as 
accurately as possible and will rapidly respond to any reported discrepancies.  
Electronic CRFs and electronic data capture will be used. The electronic data capture system 
is validated and compliant with US Title 21 CFR Part 11. Each person involved in the study 
will have an individual identification code and password that provides record traceability. 
Therefore, the system, and subsequently any investigative reviews, can identify coordinators, 
investigators, and individuals who have entered or modified records, as well as the time and 
date of any modifications. There may be an internal quality review audit of the data and 
additional reviews by the clinical monitor. 
Each eCRF is presented as an electronic copy, allowing data entry by site personnel, who can 
add and edit data, add new subjects, identify and resolve discrepancies, and view records. 
This system provides immediate direct data transfer to the database, as well as immediate 
detection of discrepancies, enabling site coordinators to resolve and manage discrepancies in 
a timely manner.  
Paper copies of the eCRFs and other database reports may be printed and signed by the 
investigator. This system provides site personnel, monitors, and reviewers with access to 
hardcopy audits, discrepancy reviews, and investigator comment information. 
4.9 ADHERENCE TO PROTOCOL 
The investigator will agree to conduct the study as outlined in this protocol, in accordance 
with ICH E6(R2) and all applicable guidelines and regulations. 
4.10 REPORTING ADVERSE EVENTS 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the time line and method outlined in this protocol. In addition, the investigator agrees to 


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submit annual reports to his/her IRB, as appropriate. The investigator also agrees to provide 
the Sponsor with an adequate report, if applicable, shortly after completion of the 
investigator’s participation in the study. 
4.11 INVESTIGATOR’S FINAL REPORT 
Upon completion of the study, the investigator, when applicable, should inform the 
institution; the investigator/institution should provide the IRB with a summary of the study 
outcome and provide the Sponsor and regulatory authority(ies) with any reports required. 
4.12 RECORD RETENTION 
Essential documents should be retained until ≥2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or ≥2 years have elapsed since the formal discontinuation of 
clinical development of PB2452. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement with the 
Sponsor. It is the Sponsor’s responsibility to inform the investigator/institution when these 
documents no longer need to be retained. 
4.13 PUBLICATIONS 
After completion of the study, the study data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the Sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publications to which 
it will be submitted, and any other related issues. The Sponsor has final approval authority 
over all such issues.  
Data from this study are the property of the Sponsor and cannot be published without their 
prior authorization; however, data and any publication thereof will not be unduly withheld. 


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Protocol No. PB2452-PT-CL-0002 Part A 
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5. 
ETHICS 
5.1 ETHICAL CONDUCT OF THE STUDY 
PhaseBio Pharmaceuticals, Inc and designées carried out all aspects of this study in 
accordance with the US Code of Federal Regulations (CFR) governing the protection of 
human subjects (21 CFR 50), IRBs (21 CFR 56), and the obligations of clinical investigators 
(21 CFR 312). U.S. Title 21 CFR on Good Clinical Practice (GCP) is consistent with 
principles set forth by the Declaration of Helsinki and the International Conference on 
Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for 
Human Use. The study will be registered on Clinicaltrials.gov in accordance with Section 
801 of the FDA Amendments Act of 2007 (FDAAA). 
All Investigators were required to review and sign a Food and Drug Administration (FDA) 
Form 1572 and Sponsor-provided Study Operations Manual which described the 
Investigator’s responsibility according to ICH/GCP guidelines. 
5.2 INSTITUTIONAL REVIEW BOARD 
The study protocol and amendments, ICFs, advertisements, and other information given to 
study subjects and/or their guardians will be reviewed and approved by the Institutional 
Review Board (IRB) of each study center prior to use. Each investigator will be responsible 
for informing the IRB of the progress of the study and submitting annual reports. This study 
will be conducted in the US, North America.  


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Protocol No. PB2452-PT-CL-0002 Part A 
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6. 
STUDY MANAGEMENT 
6.1 MONITORING 
6.1.1 Monitoring the Study 
The clinical monitor, as a representative of the Sponsor, is obligated to follow the study 
closely. In doing so, the monitor will visit the investigator and study site at periodic intervals 
in addition to maintaining necessary telephone and email contact. The monitor will maintain 
current personal knowledge of the study through observation, review of study records and 
source documents, and discussion of the conduct of the study with the investigator and staff. 
All aspects of the study will be carefully monitored by the Sponsor or designee in 
compliance with applicable government regulation with respect to current ICH E6(R2) 
guidelines and SOPs. 
6.1.2 Inspection of Records 
The investigator and institution involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study records. 
In the event of an audit, the investigator agrees to allow the Sponsor, their representatives, 
the FDA, or other regulatory agency access to all study records.  
The investigator should promptly notify the Sponsor and study site(s) of any audits 
scheduled by any regulatory authorities and promptly forward to the Sponsor copies of any 
audit reports received. 
6.2 MANAGEMENT OF PROTOCOL AMENDMENTS  
AND DEVIATIONS 
6.2.1 Modification of the Protocol 
Any changes in this clinical study, except those necessary to remove an apparent immediate 
hazard to a subject, must be reviewed and approved by the Sponsor or designee. 
Amendments to the protocol must be submitted in writing to the investigator’s IRB and 
approved before subjects are enrolled into an amended protocol. 
6.2.2 Protocol Deviations  
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from or a change to the protocol without prior IRB approval to eliminate an 
immediate hazard to study subjects. As soon as possible after such an event, the implemented 
deviation or change, the reasons for it, and any proposed protocol amendments should be 


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submitted to the IRB for review and approval, to the Sponsor for agreement, and to the 
regulatory authorities, if required.  
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. An important protocol deviation (sometimes referred to as 
a protocol violation or a major protocol deviation) is a subset of protocol deviations that 
might significantly affect the reliability of study data or might significantly affect subject 
safety. An important deviation can include nonadherence to inclusion or exclusion criteria or 
nonadherence to FDA regulations or ICH E6(R2) guidelines.  
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. The investigator will be notified by the monitor of deviations in writing. 
The IRB should be notified of protocol deviations, if appropriate, in a timely manner. 
6.3 STUDY TERMINATION 
Although the Sponsor has every intention of completing the study, the Sponsor reserves the 
right to discontinue at any time for clinical or administrative reasons.  
The EOS is defined as the date on which the last subject completes the last visit; this includes 
the EOS visit and any additional long-term follow-up required for monitoring the resolution 
of an AE; the finding may be appended to the Clinical Study Report CSR. 
6.4 FINAL REPORT 
Whether the study is completed or prematurely terminated, the Sponsor will ensure CSRs are 
prepared and provided to regulatory agency(ies) according to the applicable regulatory 
requirement(s). The Sponsor will also ensure CSRs in marketing applications meet the 
standards of the ICH E3: Structure and Content of Clinical Study Reports.  
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for approval of the CSR. The investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have an opportunity to review 
complete study results. 
Upon completion of the CSR, the investigator(s) will be provided with the final approved 
CSR, as appropriate. 
 
 


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7. 
APPENDICES 
This section presents the following: 
Appendix 7.1 Schedule of Events 
Appendix 7.2 Examples of Inhibitors and Inducers of CYP3A4 
Appendix 7.3 Definition and Management of Anaphylaxis Summary Report 
Appendix 7.4 Clinical Criteria for Diagnosing Anaphylaxis 
 
 
 


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Protocol No. PB2452-PT-CL-0002 Part A 
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7.1 SCHEDULE OF EVENTS 
Procedure 
Screeninga 
Check-in/ 
Pretreatment 
Rand 
 
Subjects 
Discharged FUP 
FUP/End 
of Study 
(EOS) 
Study Day(s) 
–45 to –4 
-7 
–3 
-2 
–1 
1 
2 
3 
7 
28 (±2) 
Sign informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
X 
 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Urine drug screen  
X 
 
X 
 
 
 
 
 
 
 
Urine alcohol screen 
X 
 
X 
 
 
 
 
 
 
 
Serum pregnancy testb 
X 
 
X 
 
 
 
 
 
 
X 
Serology testing 
X 
 
 
 
 
 
 
 
 
 
Stool occult blood test 
X 
 
 
 
 
 
 
 
 
 
Admission to study site clinic 
 
 
X 
 
 
 
 
 
 
 
Physical examinationc,d 
Xc 
 
Xc 
 
 
 
 
Xd 
Xd 
Xc 
Vital sign measurementse 
X 
 
X 
 
 
X 
X 
X 
X 
X 
12-lead ECGf 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Continuous ECG recording (Holter)  
 
 
 
 
 
X 
Xj 
 
 
 
Clinical laboratory testing 
X 
 
X 
 
X 
 
X 
 
X 
X 
Randomization 
 
 
 
 
 
X 
 
 
 
 
Drug administration 
 
 
 
 
 
 
 
 
 
 
Ticagrelorg 
 
 
 
X 
X 
X 
(X)*  
 
 
 
PB2452/Placeboh 
 
 
 
 
 
X 
 
 
 
 
ASA 81 mg QDi 
X 
X 
X 
X 
X 
X 
 
 
 
 
PK blood sampling** 
 
 
 
 
 
 
 
 
 
 
Plasma PB2452 
 
 
 
 
 
X 
X 
X 
X 
X 
Plasma ticagrelor/TAM 
 
 
 
 
 
X 
X 
X 
X 
X 
Free plasma ticagrelor/TAM 
 
 
 
 
 
X 
X 
X 
X 
X 
PK urine sampling*** 
 
 
 
X 
 
X 
X 
X 
 
 
PD sampling (LTA/PRU/VASP)k 
 
 
X 
X 
 
X 
X 
X 
 
 
 Biomarkers** 
 
 
 
 
X 
 
X 
 
X 
X 
Infusion site assessmentl 
 
 
 
 
 
X 
X 
X 
X 
 
Serum immunogenicitym 
 
 
X 
 
 
Xm 
 
 
X 
X 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Discharge from clinical site 
 
 
 
 
 
 
 
Xn 
 
 
 
Abbreviations: ADA=anti-drug antibody; ASA=acetaminophen, aspirin; BMI=body mass index; DBP=diastolic 
blood pressure; ECG=electrocardiogram; EOS=end of study; FUP=follow-up; HR=heart rate; LTA=light 
transmittance aggregometry; PD=pharmacodynamics; PK=pharmacokinetics; PRU=P2Y12 reaction units; 
QD=once daily; Rand=Randomization; RR=respiratory rate; SBP=systolic blood pressure; TAM=ticagrelor 
active metabolite AR-C124910XX; VASP=vasodilator-stimulated phosphoprotein 
(Continued) 


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Protocol No. PB2452-PT-CL-0002 Part A 
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Schedule of Events (Cohort 1) (continued) 
* 
In successive cohorts following Cohort 1, if indicated in a Dosing Memo from Sponsor to site, one or more 
cohorts may also receive a 6th dose of ticagrelor 90 mg, 24 hours after initiation of PB2452 (or placebo) 
infusion on Day 1. 
** Modifications to this schedule may be made in a Dosing Memo from Sponsor to site prior to initiation of 
each cohort. For cohorts receiving a 6th ticagrelor dose only: Sampling times will be specified in a Dosing 
Memo from Sponsor to site. 
*** Modifications to this schedule may be made in a Dosing Memo from Sponsor to site prior to initiation of 
each cohort. For cohorts receiving a 6th ticagrelor dose only: Pooled urine samples to assess urine ticagrelor and 
TAM concentrations will be collected over the following intervals beginning with the 6th ticagrelor dose: 0 to 6, 
6 to 12, and 12 to 24 hours. 
a=Screening Period=Days -45 to -4 (including Day -7, when ASA is started).  
b=Serum pregnancy test for women of childbearing potential  
c= A full physical examination is conducted  at Screening, Day -3 and Day 28. Height and BMI calculation are 
completed at Screening and Day 28 only. Weight is collected at Screening, Day -3 and Day 28.   
d=Brief physical examination (querying the subject concerning any changes from Baseline) 
e= Vital sign measurements (SBP and DBP, oral body temp, RR, and HR) will be collected at screening, check-
in, before dosing (30 to 60 minutes prior to the initiation of the study drug infusion) and at 10, 20, 30, 45, 60 
min, 24 and 48 hours following initiation of study drug. Vital Signs are also collected on Day 7 and 28.  Vital 
signs at 10, 20 and 30 minutes following infusion require only SBP and DBP, and HR. 
f=12-lead ECGs will be obtained at Screening before initiation of PB2452 (or placebo), pre-treatment Day 1, 
and on treatment  
Days 1, 2, 3, 7 and 28. The specific time points for 12-lead ECG on Day 1 and 2 will be pre-dose, after bolus, 
end of infusion, and after 24 hours. If there is change to this schedule it will be communicated in a Dosing 
Memo. ECGs will be collected anytime on Day 3, 7, and 28.  
g=Beginning in the morning on Day –2, a single dose of oral ticagrelor 180 mg will be given, followed by oral 
ticagrelor 90 mg every 12 hours for 4 additional doses through to Day 1 (2 hours before study drug is 
initiated; this will be 5 total doses of ticagrelor). 
h=PB2452 (or placebo) will be administered at Hour 0 of Day 1. 
i=ASA will be taken on Days -7, -6, -5, -4, -3, -2, -1, and on Day 1 (2 hours before study drug is started). 
Subjects who enter the study already taking ASA daily must document a daily ASA 81 mg dose between Day 
-7 and Day -3. Patients will receive daily ASA 81 mg between Day -3 (or Day -2 if the patient took ASA 
81mg on Day -3 prior to Check-in) and Day 1 at the clinical facility and will suspend further ASA dosing 
until discharge from the clinical facility. 
j=Continuous 12-lead Holter monitor placed 2 hours before administration of study drug will remain in place 
for 24 hours after initiation of study drug to Day 2.  The resting schedule for Holter monitors will be aligned 
with PK draws 
k=PD samples may be tested for additional hematologic biomarkers, such as P-selectin. 
l=Infusion site assessments will be performed for all subjects within 15 minutes before initiation of PB2452 (or 
placebo) infusion at Hour 0, and at 1, 3, 24, and 48hours after initiation of PB2452 (or placebo) infusion, and 
on Day 7.   
m= Subjects may be required to return to the site for collection of additional follow-up samples, if the sample 
collected at Day 28 tests positive for treatment-emergent ADAs. These visits may occur approximately 3 
months after the final study visit and approximately every 6 months thereafter or until antibody levels return 
to Baseline level.  
 
 
 


PhaseBio Pharmaceuticals, Inc 
 
 
 
 
 
 
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Protocol No. PB2452-PT-CL-0002 Part A 
Clinical Study Protocol 
25July2019 
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Schedule of Events (Cohort 1) (continued) 
n=Subjects are discharged from the clinic on Day 3. Subjects are permitted, if necessary/convenient to the 
subject to remain housed at PPD following discharge through Day 7 visit. There are no study assessments to 
be completed on Days 4, 5, and 6.   
 


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Protocol No. PB2452-PT-CL-0002                                                        Clinical Study Protocol 
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   Page 74 
7.2 EXAMPLES OF INHIBITORS AND INDUCERS OF CYP3A4 
Strong Inhibitors (≥5-fold increase in AUC or >80% decrease in oral clearance):  
Boceprevir  
Clarithromycin  
Conivaptan  
Grapefruit juice  
Indinavir  
Itraconazole  
Ketoconazole  
Lopinavir/ritonavir  
Mibefradil  
Nefazodone  
Nelfinavir  
Posaconazole  
Ritonavir  
Saquinavir  
Telaprevir  
Telithromycin  
Voriconazole  
 
Strong Inducers (≥80% decrease in AUC):  
Avasimibe  
Carbamazepine  
Phenytoin  
Rifampin  
St John’s wort  
 
Note: This list is not all-inclusive. Please refer to the following website for further guidance: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractio 
nslabeling/ucm093664.htm  
 
 


PhaseBio Pharmaceuticals, Inc 
 
 
 
 
 
 
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Protocol No. PB2452-PT-CL-0002                                                        Clinical Study Protocol 
25July2019 
   Page 75 
7.3 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS (CTCAE) 
The common terminology criteria for adverse events, V5 can be found at the following link:  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
Clinical criteria for diagnosing anaphylaxis are presented in Appendix  7.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PhaseBio Pharmaceuticals, Inc 
 
 
 
 
 
 
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Protocol No. PB2452-PT-CL-0002                                                        Clinical Study Protocol 
25July2019 
   Page 76 
7.4 CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS 
Anaphylaxis is highly likely when any ONE of the following 3 criteria is fulfilled: 
1.  Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) AND 
AT LEAST ONE OF THE FOLLOWING:  
 
a.  Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced  
 
 
peak expiratory flow [PEF], hypoxemia)  
 
b.  Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (e.g.,  
 
 
hypotonia [collapse], syncope, incontinence)  
2.  Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours):  
 
 
a.  Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen  
 
 
lips-tongue-uvula)  
 
b.  Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced  
 
 
PEF, hypoxemia)  
 
c.  Reduced BP or associated symptoms (e.g., hypotonia [collapse],  
 
 
syncope, incontinence)  
 
d.  Persistent gastrointestinal (GI) symptoms (e.g., crampy abdominal pain, vomiting)  
3.  Reduced BP after exposure to known allergen for that patient (minutes to several hours):  
 
 
a.  Infants and children: low systolic blood pressure (SBP; age specific) or >30% decrease 
 
 
 
in SBP*  
 
 
b.  Adults: SBP <90 mm Hg or >30% decrease from that person’s Baseline 
*   Low SBP for children from 1 month to 1 year is defined as <70 mm Hg (<70  mmHg + [2 x age]); 
 
<70  mmHg + [2 x age] from 1 to 10 years; and <90 mm Hg from 11 to 17 years.  
 
 


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Protocol No. PB2452-PT-CL-0002                                                        Clinical Study Protocol 
25July2019 
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8. 
REFERENCES 
Armstrong D, Summers C, Ewart L, Nylander S, et al. Characterization of the adenosine 
pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside 
transporter 1. Journal of Cardiovascular Pharmacology and Therapeutics 2014;19(2):209-19. 
Baharoglu MI, Cordonnier C, Al-Shahi SR, de Gans K, et al. Platelet transfusion versus standard care 
after acute stroke due to spontaneous cerebral haemorrage associated with antiplatelet therapy 
(PATCH): a randomized, open-label, phase 3 trial. Lancet 2016 Jun 25;387(10038):2605-13. 
Bell AD, Roussin A, Cartier R, Chan WS, et al. The use of antiplatelet therapy in the outpatient 
setting: Canadian Cardiovascular Society guidelines. Can J Cardiol 2011;27(2):208-21. 
Beshay JE, Morgan H, Madden C, Yu W, et al. Emergency reversal of anticoagulation and 
antiplatelet therapies in neurosurgical patients. J Neurosurg 2010 Feb;112(2):307-18. 
Catteneo M, Schulz R, Nylander S. Adenosine-mediated effects of ticagrelor: evidence and potential 
clinical relevance. JACC 2014 Jun;63(23):2503-9. 
Dalén M, Ivert T, Lindvall G, van der Linden J. Ticagrelor-associated bleeding in a patient 
undergoing surgery for acute type A aortic dissection. J Cardiothorac Vasc Anesth 2013 
Oct;27(5):e55-7. 
Doessegger L, Banholzer ML. Clinical development methodology for infusion-related reactions with 
monoclonal antibodies. Clin Transl Immunology 2015 Jul 17;4(7):e39. 
Dornbos III D, Katz JS, Youssef P, Powers CJ, et al. Glycoprotein IIb/IIIa Inhibitors in Prevention 
and Rescue Treatment of Thromboembolic Complications during Endovascular Embolization of 
Intracranial Aneurysms. Neurosurgery 2018 Mar;82(3):268-77. 
FDA Website for complete lists of strong inhibitors and strong inducers of CYP3A4: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeli
ng/ucm093664.htm 
Fitchett DH, Theroux P, Brophy JM, Cantor WJ, et al. Assessment and management of acute 
coronary syndromes (ACS): a Canadian perspective on current guideline-recommended treatment--
part 1: non-ST-segment elevation ACS. Can J Cardiol 2011 Nov-Dec;27 Suppl A:S387-S401. 
Godier A, Taylor G, Gaussem P. Inefficacy of platelet transfusion to reverse ticagrelor. NEJM 2015 
Jan 8;372(2):196-7. 
ICH E3: Structure and Content of Clinical Study Reports 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_Guideline
.pdf 
Maillard J, Cartier Faessler V, Fontana P, Bonhomme F. Lack of effect of platelet transfusions and 
desmopressin on intracranial bleeding in a patient receiving ticagrelor. A Case Rep 2015 Jun 
15;4(12):169–71. 


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Protocol No. PB2452-PT-CL-0002                                                        Clinical Study Protocol 
25July2019 
   Page 78 
National Cancer Institute. Common Terminology Criteria for Adverse Events v5.0 (CTCAE). 
Bethesda, MD: National Cancer Institute, November 27, 2017. Available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50. Accessed 
March 16, 2018. 
Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G, et al. Inhibition of platelet 
aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in 
patients with acute coronary syndromes. JACC 2007 Nov 6;50(19):1852-6. 
Storey RF. New P2Y12 inhibitors. Heart 2011;97:1262-7. 
Taylor G, Osinski D, Thevenin A, Devys JM. Is platelet transfusion efficient to restore platelet 
reactivity in patients who are responders to aspirin and/or clopidogrel before emergency surgery? J 
Trauma Acute Care Surg 2013 May;74(5):1367-9. 
Teng R, Carlson GF, Nylander S, Andersson TL. Effects of autologous platelet transfusion on platelet 
inhibition in ticagrelor-treated and clopidogrel-treated subjects. J Thromb Haemost. 2016 Dec 14; 
14(12):2342-52. 
 


PhaseBio Pharmaceuticals, Inc 
PB2452 
Protocol No. PB2452-PT-CL-0002 Part B 
Clinical Study Protocol
25July2019 
Page 1
 
CLINICAL STUDY PROTOCOL: PB2452-PT-CL-0002 
Part B: A Phase 2A, Randomized, Double-Blind, Placebo-Controlled, Single 
Dose, Sequential Group Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of PB2452 with High-Dose 
Ticagrelor Pretreatment in Healthy Subjects 
 
Version Number: 2 Part B 
 Study Drug Name: PB2452 
Phase 2A 
IND #: 125267 
Sponsor:  
PhaseBio Pharmaceuticals Inc.  
1 Great Valley Parkway, Suite 30  
Malvern, PA 19355
Chief Medical Officer:  
 
John Lee, MD, PhD  
 
 
 
 
 
PhaseBio Pharmaceuticals Inc. 
 
 
 
 
 
Phone: 610-981-6505 
 
 
 
 
 
 
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 
 
 
 
 
 
 
     PB2452 
Protocol No. PB2452-PT-CL-0002 Part B 
Clinical Study Protocol 
25July2019 
Page 3 
 
AGREEMENT OF INVESTIGATOR 
STUDY TITLE: Part B: A Phase 2A, Randomized, Double-blind, Placebo-controlled, Single 
Dose, Sequential Group Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of PB2452 with Ticagrelor Pretreatment in Older and Elderly Subjects 
 
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), responsible for initial and continuing review 
and approval of the clinical study, complies with the requirements of 21 CFR §56; 
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: ____________________________________________ 
 


PhaseBio Pharmaceuticals, Inc 
 
 
 
 
 
 
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Protocol No. PB2452-PT-CL-0002 Part B 
Clinical Study Protocol 
25July2019 
Page 4 
PROTOCOL SYNOPSIS 
PROTOCOL NO.: PB2452-PT-CL-0002 
TITLE: Part B: A Phase 2A, Randomized, Double-Blind, Placebo-Controlled Single Dose, 
Sequential Group Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and 
Pharmacokinetics of PB2452 with High-Dose Ticagrelor Pretreatment in Healthy Subjects  
STUDY PHASE: 2A 
STUDY SITE: 1 clinical site in the United States: PPD Phase 1 Clinic, 7551 Metro Center Drive, 
Suite 200, Austin, Texas 78744 
INDICATION: Reversal of ticagrelor anti-platelet activity 
DURATION OF STUDY: The estimated duration of the study for each subject, excluding 
Screening, is approximately 35 days. 
OBJECTIVES: 
Primary: 
• 
To evaluate the safety and tolerability of intravenous (IV) doses of PB2452 vs matching placebo 
with a high-dose of oral ticagrelor (180 mg BID) pretreatment in healthy subjects 
• 
To assess the efficacy/pharmacodynamics (PD) of IV doses of PB2452 vs matching placebo in 
reversing a high dose of ticagrelor’s antiplatelet activity by measuring P2Y12 reaction units (PRU) 
with VerifyNow® P2Y12 assay in healthy subjects    
Secondary: 
• 
To determine the pharmacokinetics (PK) of PB2452 in the presence of a high dose of ticagrelor 
• 
To determine the PK of ticagrelor and the ticagrelor active metabolite AR-C124910XX (TAM) in 
the presence of PB2452  
• 
To evaluate the effect of PB2452 on ticagrelor antiplatelet activity by measuring platelet 
aggregation with light transmittance aggregometry (LTA) and platelet reactivity index (PRI)  
with vasodilator-stimulated phosphoprotein (VASP) assay by enzyme-linked immunosorbent 
assay (ELISA) 
• 
To evaluate the immunogenicity potential of PB2452 
Exploratory: 
• 
To evaluate the effect of PB2452 on the PK profile of unbound ticagrelor and unbound TAM 
plasma concentrations 
• 
To investigate the effect of PB2452 vs matching placebo on circulating biomarkers of platelet 
activation, such as P-selectin, in subjects pretreated with high-dose ticagrelor 
• 
To examine the correlation between estimated creatinine clearance (CrCl) and the PK of 
ticagrelor and TAM. 
STUDY DESIGN AND METHODOLOGY: 
This is Part B of a two-part Phase 2A, randomized, double-blind, placebo-controlled, single dose, 
sequential group study to evaluate the safety, tolerability, PK, and PD of PB2452 vs matching 
placebo. Part A investigated various dose regimens of PB2452 administered intravenously to older 
(ages 50 to 64 years) and elderly (ages 65 to 80 years) male and female subjects pretreated with 
ticagrelor + aspirin (ASA) as part of dual antiplatelet therapy. Part B investigates various dose levels 
and regimens of PB2452 administered to healthy male and female subjects (ages 18-50) pretreated 
with a high dose of ticagrelor alone (180 mg) twice daily (BID). Part A is described in a separate 
protocol document.  


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     PB2452 
Protocol No. PB2452-PT-CL-0002 Part B 
Clinical Study Protocol 
25July2019 
Page 5 
In Part B described herein, up to 3 dose levels and/or administration regimens of PB2452 will be 
evaluated in up to 3 cohorts. Each cohort will include up to 12 subjects randomized in a 3:1 ratio 
(PB2452:placebo). All references to study drug within the content of the protocol apply to PB2452 or 
matching placebo. 
This initial cohort of Part B will include healthy subjects pretreated with 180 mg of oral ticagrelor 
twice daily for 48 hours prior to randomization to a dose and regimen of PB2452 (or matching 
placebo) described in a cohort-specific Dosing Memo. The written Dosing Memo provided by the 
Sponsor to the clinical site will include details of the dosing regimen, cohort size, sampling schedules, 
and other cohort-specific study activities prior to initiation of each cohort. The dose level of the initial 
regimen in Part B will not exceed twice the total dose level (36 g) shown to be safe and well tolerated 
in older and elderly subjects (50-80 years) in Part A of this Phase 2A study and in the Phase 1 study 
of PB2452 in healthy subjects (PB2452-PT-CL-0001).  
Following completion of Cohort 3, subsequent cohort(s) may test the same, higher or lower dose 
levels, and/or different infusion regimens of PB2452 or matching placebo as determined by the 
Sponsor after examination of available PD and safety data from the prior cohort(s) and described in a 
subsequent Dosing Memo. Duration of study drug infusions will not exceed 48 hours.  
A Safety Review Committee (SRC) will review all available safety data from ongoing or completed 
cohorts and will document their review and assessment in written SRC minutes prior to initiation of a 
subsequent cohort. Dose escalation may occur only if the SRC affirms the dose and regimen from the 
previously completed cohorts were safe and well tolerated and no dose-limiting toxicities (DLTs) 
were observed.  
The study will consist of a Screening period (Days –45 to –4), a Check-in day (Day -3), a 48 hour 
Pretreatment Period starting on Day -2, an on-site Randomization/Treatment day (Day 1), 3 days on-
site for treatment and safety monitoring, a Follow-up Visit (Day 7), and a Final Follow-up Visit (Day 
28 [±2 days]). Two days prior to Randomization (Day -2), subjects will be administered ticagrelor 
180 mg orally twice daily (BID) until the final dose on the morning of Day 1 before receiving study 
drug. The first ticagrelor 180 mg oral dose will be administered on the morning of Day -2 followed by 
180 mg every 12 hours until the 5th dose has been administered on the morning of Day 1.   
Subjects will check in to the clinical site (PPD) on Day -3. In the morning on Day -2, subjects will 
begin pretreatment with ticagrelor as described in the preceding paragraph. On Day 1, subjects who 
meet all the inclusion criteria and none of the exclusion criteria will be randomized in a ratio 3:1 
(PB2452:placebo), to receive an IV dose of PB2452 or placebo 2 hours following the 5th ticagrelor 
dose. Subjects may be discharged from the clinical site between Days 3 and 7 inclusive and will 
return for a Follow-up visit on Day 7, if already discharged, and on Day 28 (±2 days).  
Serum and plasma sampling times for PB2452, ticagrelor, and TAM PK and PD assessments will be 
described in the detailed Dosing Memo for each cohort. Hour 0 will be the time for initiation of study 
drug infusion (2 hours following administration of the 5th ticagrelor dose). PK and PD time points for 
subsequent cohorts may be adjusted as needed based on available PK, PD, and safety data from prior 
cohorts. In any cohort subsequent to the initial cohort in Part B, there will be no more than 
6 additional sampling time points.  The written Dosing Memo provided by the Sponsor prior to 
initiation of each cohort will include the following instructions: 
• 
Number of subjects to be randomized  
• 
Total PB2452 dose and administration regimen  
• 
The PK and PD sampling schedule  
• 
Safety ECG schedule  
• 
Biomarkers schedule 


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     PB2452 
Protocol No. PB2452-PT-CL-0002 Part B 
Clinical Study Protocol 
25July2019 
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Safety and tolerability will be carefully monitored throughout the study. Immunogenicity samples 
will be collected from all subjects at Baseline and at Days 7 and 28 (±2 days) following 
administration of study drug.  
Dose Escalation 
The SRC will conduct a blinded review of all safety and tolerability data from a cohort at least 
through Day 3 (e.g., clinical laboratory test results, adverse events [AEs], ECGs, Holter monitoring 
report, vital signs) prior to initiation of a subsequent cohort. Escalation to a higher total dose of 
PB2452 will occur only if the SRC affirms the safety, tolerability, and absence of DLTs in the 
preceding cohort(s).  
The SRC will be minimally composed of the on-site PPD investigator/medical monitor, PhaseBio 
medical monitor, and PhaseBio clinical operations lead. Changes to the administration regimen (rate 
and duration) without escalation of the total dose or without increasing the infusion rate will not 
require formal SRC approval. Similarly, reductions in the total dose or the infusion rate will not 
require SRC approval.  
Stopping Criteria 
Dose escalation or ongoing infusions will be suspended, pending investigation by the SRC, if any of 
the following occur after confirmation the subject has received PB2452: 
• 
Any preclinical or clinical events that, in the opinion of the SRC, contraindicate further dosing of 
additional subjects with PB2452 
• 
Any serious AE (SAE) occurring prior to discharge from the clinical site  
• 
Data from previous cohorts indicate safety concerns for dosing at a higher level, such as 
unanticipated adverse responses (e.g., clinically significant [CS] changes in clinical 
laboratory test data, 12 lead ECGs, continuous 12-lead electrocardiogram (Holter monitor) 
results, vital signs, physical examinations) 
• 
Two or more subjects in a cohort experience any DLT, or 1 subject experiences a  
≥Grade 2 AE (DLT) that, in the opinion of the SRC, warrants suspension of dose escalation 
• 
Two or more subjects have >3 x upper limit of normal (ULN) of either alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST), or >2 x ULN of bilirubin or alkaline phosphatase 
(ALP) when no other reason can be found to explain the increases 
• 
One or more subjects experiences a ≥Grade 2 infusion-related reaction (IRR) despite having been 
premedicated for IRRs 
Continuation of dosing following suspension will be determined by the SRC and documented in an ad 
hoc SRC Safety Report. Dosing may also be suspended if, in the opinion of the SRC or Sponsor, any 
new or unexpected significant safety or tolerability issues related to ticagrelor or PB2452 are 
identified that warrant further evaluation before additional subjects are dosed. This may include 
emerging nonclinical data, clinically relevant AEs, or relevant data from other sources indicating 
safety concerns, even if the event(s) per se does not meet the protocol-specified definition of a DLT. 
INCLUSION CRITERIA: 
1. The subject provides written informed consent and agrees to comply with all 
protocol requirements. 
2. The subject is male or female between 18 and 50 years of age, inclusive.    
3. The subject has a body mass index (BMI) between 18 and 35 kg/m2 and a weight of ≥50 kg but 
≤120 kg, inclusive, at Screening. 


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Protocol No. PB2452-PT-CL-0002 Part B 
Clinical Study Protocol 
25July2019 
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4. The subject is considered by the investigator to be in good general health, as determined by 
medical history, clinical laboratory test results, vital sign measurements, 12-lead ECG results, and 
physical examination findings at Screening.  
5. Specific inclusionary laboratory values at Screening and Check-in require:  
• 
White blood cell (WBC) count, platelet count, hemoglobin (Hgb) level within normal range, 
as defined by the clinical laboratory 
• 
Thyroid stimulating hormone (TSH) level within normal range, as defined by the clinical 
laboratory at Screening 
• 
Prothrombin time (PT) and partial thromboplastin time (PTT) level within normal range, as 
defined by the clinical laboratory  
6. Female subjects of childbearing potential must not be pregnant, lactating, or planning to become 
pregnant for 3 months after the last dose of study drug, and have a negative serum pregnancy test 
at Screening and Check-in. Female subjects of childbearing potential must use 2 effective 
methods of birth control from 30 days before study drug administration through to the end of 
the study.  
• 
Effective birth control methods include oral, implantable, patch, or injectable contraceptive 
hormone treatment, hormone-containing intrauterine device that has been in place ≥2 months 
prior to Screening, sponge, diaphragm, or cervical cap with spermicidal gel or cream for 
female subjects or condom or vasectomy for male subjects.  
• 
Women are considered to not be of childbearing potential if they have fulfilled one of these 
criteria: documentation of irreversible surgical sterilization (i.e., hysterectomy or bilateral 
oophorectomy [not tubal ligation]) or are postmenopausal (defined as amenorrhea for 
12 consecutive months following cessation of all exogenous hormonal treatments, and 
documented plasma follicle-stimulating hormone (FSH) level >40 IU/mL) or amenorrhea for 
24 consecutive months.  
• 
Male subjects with partners of childbearing potential must agree to use appropriate and 
effective measures of contraception (e.g., condom plus diaphragm with spermicide, condom 
plus spermicide) during the study and for 30 days after the last dose of study drug, and refrain 
from donating sperm for ≥90 days following the last dose of study drug.  
EXCLUSION CRITERIA: 
1. Concern the subject may be unable to comply with study procedures and/or follow-up, or, in the 
opinion of the investigator, the subject is not suitable for entry into the study 
2. History of any acute or chronic medical disorder expected to decrease the life expectancy of 
the subject   
3. History or presence of gastrointestinal (GI), hepatic (with the exception of Gilbert’s syndrome), 
or any other condition known to interfere with absorption, distribution, metabolism, or excretion 
of drugs  
4. Significant renal insufficiency, as indicated by estimated glomerular filtration rate 
(eGFR) <30 mL/min/1.73m2 according to the Modification of Diet in Renal Disease  
(MDRD) equation   
5. Any CS acute illness, medical/surgical procedure, or trauma within 4 weeks of administration of 
study drug or any planned surgical procedure that will occur during the study (from Screening 
through the Day 28 [±2 days] Follow-up visit) 
6. Any CS abnormal findings in physical examination, vital signs, laboratory assessments, and ECG 
parameters identified during Screening or Check-in. Note: abnormal results may be repeated for 


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Protocol No. PB2452-PT-CL-0002 Part B 
Clinical Study Protocol 
25July2019 
Page 8 
confirmation immediately after the first out of range measurement. Abnormal vital signs may be 
repeated twice if needed, immediately after the first abnormal result and/or after the subject has 
rested for at least 10 minutes. 
Specific vital sign exclusionary criteria occurring after 10 minutes of supine rest are any of the 
following: 
• 
Systolic blood pressure (SBP) <100 or >160 mm Hg 
• 
Diastolic blood pressure (DBP) <40 or >95 mm Hg 
• 
Resting heart rate (HR) <50 or >100 beats per minute (bpm) 
Specific exclusionary criteria for ECG parameters at Screening or Check-in include any of the 
following: 
• 
Prolonged Fridericia-corrected QT interval (QTcF) >450 milliseconds (msec), shortened 
QTcF <340 msec, or pause >3 seconds, or family history of long QT syndrome 
7. Any specific contraindication to Brilinta® as described in the Brilinta® prescribing 
information and: 
• 
History of intracranial hemorrhage, active bleeding, or hypersensitivity or allergic reaction to 
ticagrelor or any component of the product 
• 
Any history of severe head trauma, intracranial neoplasm, arteriovenous malformation, 
aneurysm, or proliferative retinopathy 
• 
Any history of intraocular, retroperitoneal, or spinal bleeding 
• 
Have taken, within 30 days of Screening, any oral or parenteral anticoagulant, including low 
molecular-weight heparin 
• 
Stool sample testing positive for occult blood within 3 months of Screening or at any time 
during the Screening Period 
8. Receiving chronic treatment with nonsteroidal anti-inflammatory drugs (NSAIDS; [including 
ASA >100 mg daily]), anticoagulants, or other antiplatelet agents that cannot be discontinued 
14 days prior to randomization (including clopidogrel, prasugrel, ticlopidine,  dipyridamole, 
or cilostazol) 
9. Positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or 
human immunodeficiency virus (HIV) types 1 or 2 antibodies at Screening 
10. Concomitant oral or IV therapy with strong or moderate cytochrome P450 3A4 (CYP3A) 
inhibitors, CYP3A substrates with narrow therapeutic indices, or strong CYP3A inducers, which 
cannot be stopped within at least 5 half-lives, but not fewer than 10 days, before randomization (a 
list of examples may be found in Appendix 7.2) 
11. Consumption of grapefruit or grapefruit juice, Seville orange or Seville orange-containing 
products (e.g., marmalade), or xanthine-containing products within 48 hours before dosing with 
study drug 
12. Prescription or over-the-counter (OTC) medications within 14 days before the first dose of study 
drug unless specifically allowed by protocol. (Permitted medications include multivitamins, 
paracetamol [up to 2g per day], and/or treatments for chronic stable diseases, provided the drug 
and dose have been stable for ≥30 days prior to administration of study drug)   
13. Has received another investigational drug (defined as a small molecule or biologic compound 
which has not been approved for marketing) within 30 days of the administration of study drug in 
this study or within 5 half-lives of the prior study drug, whichever is longer       
14. Positive test result for alcohol or drugs of abuse at Screening or Check-in 


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Protocol No. PB2452-PT-CL-0002 Part B 
Clinical Study Protocol 
25July2019 
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15. Participated in strenuous activity or contact sports within 24 hours before the infusion of study 
drug or while confined in the clinical site 
16. History of severe or ongoing allergy/hypersensitivity to any drug or biologic therapeutic agent 
17. Involvement with any PhaseBio or study site employee or their close relatives (e.g., spouse, 
parents, siblings, or children whether biological or legally adopted) 
18. Previously received PB2452 or had been randomized to receive study drug in an earlier cohort for 
this study 
 
EVALUATION CRITERIA 
Safety Endpoints: 
Safety and tolerability will be assessed by monitoring and recording of Adverse Events (AEs), 
clinical laboratory test results (hematology, coagulation, serum chemistry, and urinalysis), vital sign 
measurements (SBP and DBP, oral body temperature, respiratory rate [RR], and HR), 12-lead ECG, 
immunogenicity, biomarkers and physical examination findings. 
Pharmacodynamic Endpoints 
VerifyNow®P2Y12: 
• 
Minimum %inhibition of PRU within 4 hours after the initiation of study drug. %inhibition of 
PRU is calculated as 100 * [(PRUbsl – PRUtrt)/PRUbsl]. PRUbsl refers to the PRU value measured 
before treatment with ticagrelor and PRUtrt refers to the PRU value measured posttreatment 
with the study drug. 
• 
PRU AUC for the first 4 hours.  
• 
Proportion of patients with normalized platelet reactivity units within 4 hours after the initiation 
of study drug. Normalized platelet reactivity is defined as PRU ≥ 180. 
• 
Proportion of patients with ≥60%, ≥80%, and 100% of PRU response rate within 4 hours after 
the initiation of study drug. A PRU response rate is defined as the 100 * (PRUtrt/PRUbsl). 
• 
Time to 60%, 80%, 100% of PRU response rate within 4 hours after the initiation of study drug  
• 
Duration of 80% and 100% of PRU response rate by PRU. 
LTA: 
• 
Minimum %inhibition of LTA within 4 hours after the initiation of study drug. 
• 
LTA AUC for the first 4 hours.  
• 
Proportion of patients with ≥60%, ≥80%, and 100% of LTA response rate within 4 hours after 
the initiation of study drug. LTA response rate is defined as the 100 * (LTAtrt/LTAbsl). 
• 
Time to 60%, 80%, 100% LTA response rate within 4 hours after the initiation of study drug. 
• 
Duration of 80% and 100% of LTA response rate. 
VASP by ELISA: 
• 
Minimum %inhibition of PRI within 4 hours after the initiation of study drug. 
• 
PRI AUC for the first 4 hours.  
• 
Proportion of patients with ≥60%, ≥80%, and 100% of PRI response rate within 4 hours after 
the initiation of study drug. A PRI response is defined as the 100 * (PRItrt/PRIbsl). 
• 
 Time to 60%, 80%, 100% PRI response rate within 4 hours after the initiation of study drug 
• 
Duration of 80% and 100% of PRI response rate 
 


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Protocol No. PB2452-PT-CL-0002 Part B 
Clinical Study Protocol 
25July2019 
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Additional PD parameters may be generated, if needed. 
Pharmacokinetic Endpoints:   
Plasma PK 
Plasma concentrations of total PB2452, unbound PB2452, total Ticagrelor, total TAM, unbound 
Ticagrelor, and unbound TAM, will be assessed at predetermined timepoints.  
PK parameters for PB2452 include:  
• 
Observed maximum plasma concentration (Cmax) 
• 
Area under the plasma concentration versus time curve (AUC) from time zero to the time of the 
last quantifiable concentration (AUC0-t) 
• 
Time to reach the observed maximum plasma concentration (Tmax) 
• 
AUC from time zero to 24 hours post-dose (AUC0-24) 
• 
AUC from time zero to 48 hours post-dose (AUC0-48)  
• 
Area under the plasma concentration versus time curve (AUC) from time zero to the time of the 
end of the dosing period(AUC0-tau) 
• 
AUC from time zero extrapolated to infinity (AUC0-∞; if data permit) 
• 
Terminal elimination half-life (t½; if data permit) 
• 
Clearance (CL; if data permit) 
• 
Volume of distribution (Vd)  
PK parameters for Ticagrelor/TAM include: 
• 
Cmax  
• 
AUC0-t 
• 
Tmax 
• 
AUC0-24 
• 
AUC0-48  
• 
AUC0-tau 
• 
AUC0-∞; if data permit 
• 
t½; if data permit 
Urine PK 
Pooled urine samples to assess urine PB2452, ticagrelor, and TAM concentrations will be collected 
over these intervals: before dosing (within 60 minutes prior to the first ticagrelor dose on Day -2) and 
0 to 6, 6 to 12, and 12 to 24 hours.  
Pharmacokinetic parameters for PB2452, ticagrelor, and TAM concentrations in urine for all subjects 
in the PK population to be calculated are: 
• 
Total amount of drug excreted in urine at 24 hours after dosing (Ae24) and at 48 hours after 
dosing (Ae48)  
• 
Total amount of drug excreted in urine from time t1 to t2 (Aet1-t2) hours when the values of t1 to 
t2 are 0 to 6, 6 to 12, 12 to 24 and 24 to 48 hours  
• 
Fraction excreted in urine from 1 to 24 hours after dosing (Fe24) and from 1 to 48 hours after 
dosing (Fe48) 


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Protocol No. PB2452-PT-CL-0002 Part B 
Clinical Study Protocol 
25July2019 
Page 11 
• 
Renal clearance (CLr) for 24 hours after dosing 
Additional PK parameters may be generated, if needed. Details will be provided in a separate 
document, the SAP. 
STUDY DRUG, DOSAGE, AND ROUTE OF ADMINISTRATION: 
PB2452: 
PB2452 IV infusion, prepared according to the Pharmacy Manual, will be administered on Day 1 for 
up to 48 hours. The total dose for each subject will not exceed 30 g. The infusion rate will not exceed 
18 g over 30 minutes and the concentration will not exceed 24g in 250mL. Subjects will not receive 
more than 250 mL of study drug infusion within any 1-hour period.  
For each cohort, the dose, infusion rate, and duration will be communicated from the Sponsor to PPD 
in a Dosing Memo issued prior to initiation of each treatment cohort.  
Matching Placebo: 
0.9% sodium chloride single IV infusion, to be delivered at a rate and volume matching the 
active infusion.  
Ticagrelor: 
Ticagrelor 90 mg oral tablets (immediate release) will be administered as a 180 mg (2 × 90 mg 
tablets) oral dose every 12 hours for 5 total doses.  
 
STATISTICAL METHODS: 
Sample Size: 
The sample size (N) of up to 3 cohorts for Part B of this study is based on clinical and practical 
considerations and not on a formal statistical power calculation. The sample size will provide 
preliminary safety, efficacy and PK information in a dose/regimen finding fashion.  
Analysis Populations: 
• 
The Safety Population will include all subjects who receive any amount of study drug. 
• 
The PK Population will include subjects in the safety population who have ≥1 measurable PK 
concentration. 
• 
The PD Population will include subjects in the safety population who receive ≥1 dose of 
ticagrelor and have ≥1 measurable post dose PRU value. 
Safety Analyses:  
Adverse events will be coded by preferred term and system-organ-class (SOC) using the latest 
version of the Medical Dictionary for Regulatory Activities (MedDRA). All AE data will be 
presented in Data Listings. Treatment-emergent AEs (TEAEs) will be summarized by treatment and 
overall, as well as by severity and relationship to study drug. All SAEs and AEs leading to 
discontinuation of study drug will be presented in the Data Listings. 
Actual values and changes from Baseline in clinical laboratory test results, vital sign measurements, 
and 12-lead ECG results will be summarized by treatment at each time point using descriptive 
statistics (number of subjects, mean, standard deviation [SD], median, minimum, and maximum). 
Clinical laboratory test results, vital sign measurements, 12-lead ECGs, Holter monitor report data, 
immunogenicity results, and physical examination findings will be presented in Data Listings.  
Efficacy Analyses: 
Pharmacodynamic data will be summarized using descriptive statistics (number of subjects, mean, 
SD, CV, median, minimum, and maximum) for each treatment group or by cohort at each time point 


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Protocol No. PB2452-PT-CL-0002 Part B 
Clinical Study Protocol 
25July2019 
Page 12 
if applicable. Inferential analysis maybe carried out to compare the % inhibition of PRU, LTA, PRI 
between PB2452 vs Placebo individually. However due to the limited sample size, efficacy analysis 
results will be considered descriptive.   
Pharmacokinetic Analyses: 
Plasma concentrations will be listed and summarized descriptively (number of subjects, arithmetic 
mean, SD, coefficient of variation [CV], median, minimum, and maximum). Plasma concentration 
versus time profiles for each subject will be presented graphically. The mean plasma concentration 
versus scheduled time profiles will be presented graphically by dose. 
Pharmacokinetic parameters will be summarized by time point for each dose level using descriptive 
statistics (number of subjects, mean, SD, CV, median, minimum, and maximum). Geometric means 
will be reported for AUCs and Cmax.  
 
 
 


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Protocol No. PB2452-PT-CL-0002 Part B 
Clinical Study Protocol 
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TABLE OF CONTENTS 
Section 
Page 
SIGNATURE PAGE ................................................................................................................2 
PROTOCOL SYNOPSIS ........................................................................................................4 
TABLE OF CONTENTS .......................................................................................................13 
TABLE OF TABLES .............................................................................................................17 
LIST OF ABBREVIATIONS AND DEFINITIONS ...........................................................18 
1. 
INTRODUCTION...................................................................................................22 
1.1 
PRODUCT AND BACKGROUND INFORMATION .............................................22 
1.1.1 
Non-clinical Pharmacology ......................................................................................23 
1.1.2 
Summary of Human Data .........................................................................................23 
1.1.3 
Benefit/Risk Assessment ...........................................................................................25 
1.2 
RATIONALE FOR STUDY .....................................................................................26 
1.3 
RATIONALE FOR DOSE SELECTION .................................................................26 
2. 
STUDY OBJECTIVES AND METHODOLOGY ...............................................28 
2.1 
OBJECTIVES ...........................................................................................................28 
2.2 
EVALUATION CRITERIA ......................................................................................28 
2.2.1 
Safety Endpoints .......................................................................................................28 
2.2.2 
Pharmacodynamic Endpoints ....................................................................................28 
2.2.3 
Pharmacokinetic Endpoints ......................................................................................29 
3. 
INVESTIGATION PLAN ......................................................................................31 
3.1 
STUDY DESIGN AND METHODOLOGY ............................................................31 
3.2 
SELECTION OF STUDY POPULATION ...............................................................32 
3.2.1 
Inclusion Criteria ......................................................................................................33 
3.2.2 
Exclusion Criteria .....................................................................................................33 
3.2.3 
Subject Restrictions During the Study ......................................................................35 
3.3 
WITHDRAWAL OF SUBJECTS FROM THE STUDY ..........................................36 
3.3.1 
Reasons for Withdrawal ............................................................................................36 
3.3.2 
Handling of Withdrawals ..........................................................................................36 
3.3.3 
Replacement of Subjects ...........................................................................................37 
3.4 
STUDY TREATMENTS ..........................................................................................37 
3.4.1 
Method of Assigning Subjects to Treatment Groups ................................................37 
3.4.2 
Treatments Administered ..........................................................................................37 


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3.4.2.1 Dose Escalation ........................................................................................................ 37 
3.4.2.2 Infusion-related or Allergic Reactions ..................................................................... 38 
3.4.2.3 Dose-limiting Toxicities ........................................................................................... 39 
3.4.2.4 Stopping Criteria ...................................................................................................... 39 
3.4.3 
Identity of Investigational Product............................................................................40 
3.4.4 
Management of Clinical Supplies .............................................................................40 
3.4.4.1 Packaging and Storage ............................................................................................. 40 
3.4.4.2 Drug Accountability ................................................................................................. 40 
3.4.5 
Blinding.....................................................................................................................41 
3.4.6 
Treatment Compliance ..............................................................................................41 
3.4.7 
Breaking the Blind ....................................................................................................41 
3.4.8 
Prior and Concomitant Medication ...........................................................................42 
3.4.8.1 Prior Medication and Therapies ............................................................................... 42 
3.4.8.2 Concomitant Medication and Therapies .................................................................. 42 
3.5 
STUDY PROCEDURES ..........................................................................................42 
3.5.1 
Pharmacokinetic Sample Collection .........................................................................45 
3.5.1.1 Bioanalytical Methods ............................................................................................. 46 
3.5.1.2 Pharmacodynamic Sample Collection ..................................................................... 46 
3.5.2 
Adverse Events .........................................................................................................47 
3.5.2.1 Adverse Event Definitions ....................................................................................... 47 
3.5.2.2 Eliciting and Documenting Adverse Events ............................................................ 48 
3.5.2.3 Reporting Adverse Events........................................................................................ 48 
3.5.2.4 Assessment of Severity ............................................................................................ 49 
3.5.2.5 Assessment of Causality .......................................................................................... 50 
3.5.2.6 Follow-up of Adverse Events................................................................................... 50 
3.5.3 
Clinical Laboratory Testing ......................................................................................50 
3.5.4 
Vital Signs Measurements.........................................................................................53 
3.5.5 
Twelve-lead Electrocardiogram ................................................................................53 
3.5.6 
Holter Monitoring (Continuous Twelve-lead ECG) .................................................54 
3.5.7 
Physical Examinations ..............................................................................................54 
3.5.8 
Infusion Site Assessments .........................................................................................55 
3.5.9 
Immunogenicity Assessments ...................................................................................55 
3.6 
STATISTICAL CONSIDERATIONS .......................................................................55 
3.6.1 
Sample Size Calculations ..........................................................................................55 
3.6.2 
Analysis Populations .................................................................................................55 
3.6.3 
Statistical Analysis ....................................................................................................55 
3.6.3.1 Pharmacokinetic Analyses ....................................................................................... 56 


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Protocol No. PB2452-PT-CL-0002 Part B 
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3.6.3.2 Pharmacodynamic Analyses .................................................................................... 56 
3.6.3.3 Safety Analyses ........................................................................................................ 56 
3.6.4 
Handling of Missing Data .........................................................................................57 
3.6.5 
Interim Analyses .......................................................................................................57 
3.7 
DATA QUALITY ASSURANCE .............................................................................57 
4. 
INVESTIGATOR OBLIGATIONS .......................................................................59 
4.1 
CONFIDENTIALITY...............................................................................................59 
4.2 
INSTITUTIONAL REVIEW ....................................................................................59 
4.3 
SUBJECT CONSENT ..............................................................................................59 
4.4 
STUDY REPORTING REQUIREMENTS ..............................................................60 
4.5 
FINANCIAL DISCLOSURE AND OBLIGATIONS ...............................................60 
4.6 
INVESTIGATOR DOCUMENTATION ..................................................................60 
4.7 
STUDY CONDUCT .................................................................................................61 
4.8 
DATA COLLECTION ..............................................................................................61 
4.8.1 
Case Report Forms and Source Documents..............................................................61 
4.9 
ADHERENCE TO PROTOCOL ..............................................................................61 
4.10 
REPORTING ADVERSE EVENTS .........................................................................61 
4.11 
INVESTIGATOR’S FINAL REPORT .....................................................................62 
4.12 
RECORD RETENTION ...........................................................................................62 
4.13 
PUBLICATIONS ......................................................................................................62 
5. 
ETHICS ...................................................................................................................63 
5.1 
ETHICAL CONDUCT OF THE STUDY ................................................................63 
5.2 
INSTITUTIONAL REVIEW BOARD .....................................................................63 
6. 
STUDY MANAGEMENT ......................................................................................64 
6.1 
MONITORING .........................................................................................................64 
6.1.1 
Monitoring the Study ................................................................................................64 
6.1.2 
Inspection of Records ...............................................................................................64 
6.2 
MANAGEMENT OF PROTOCOL AMENDMENTS  AND 
DEVIATIONS ...........................................................................................................64 
6.2.1 
Modification of the Protocol .....................................................................................64 
6.2.2 
Protocol Deviations ...................................................................................................64 
6.3 
STUDY TERMINATION .........................................................................................65 
6.4 
FINAL REPORT .......................................................................................................65 


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7. 
APPENDICES .........................................................................................................66 
7.1 
PART B SCHEDULE OF EVENTS .........................................................................67 
7.2 
EXAMPLES OF INHIBITORS AND INDUCERS OF CYP3A4 ...........................70 
7.3 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
(CTCAE) ...................................................................................................................72 
7.4 
CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS .............................73 
8. 
REFERENCES ........................................................................................................74 
 
 


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TABLE OF TABLES  
TABLE 
 
See Appendices, Section 7.  
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS 
AA 
arachidonic acid 
ACS 
acute coronary syndrome 
ADA 
anti-drug antibodies 
ADP 
adenosine diphosphate 
AE 
adverse event 
Ae48 
total amount of drug excreted in urine at 48 hours after dosing 
Ae24 
total amount of drug excreted in urine at 24 hours after dosing 
Aet1-t2 
Ae from time t1 to t2 hours 
Aet1-t2 
Ae from time t1 to t2 hours 
ALP 
alkaline phosphatase 
ALT 
aPTT 
alanine aminotransferase 
activated partial thromboplastin time 
ASA 
acetylsalicylic acid, aspirin 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC0-12 
AUC from time zero to 12 hours after dosing 
AUC0-24 
AUC0-48 
AUC from time zero to 24 hours after dosing 
AUC from time zero to 48 hours after dosing 
AUC0-∞ 
area under the plasma concentration versus time curve from time zero 
extrapolated to infinity 
AUC0-τ 
 
area under the concentration versus time curve from time zero to the time 
of the last quantifiable concentration 
bid 
twice daily 
BL 
baseline 
BLQ 
below the limit of quantification 
BMI 
BP 
body mass index 
Blood Pressure 
Bpm 
BUN 
CABG 
beats per minute 
Blood Urea Nitrogen 
coronary artery bypass graft 
CFR 
CL 
Code of Federal Regulations 
clearance 
CLr 
renal clearance 
Cmax 
observed maximum plasma concentration 
CrCl 
creatinine clearance 
CS 
clinically significant 
CSR 
Clinical Study Report 


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CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP3A 
cytochrome P450 3A4 
DAPT 
dual antiplatelet therapy 
DBP 
diastolic blood pressure 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
end of study 
FDA 
Fe24 
Food and Drug Administration 
Fraction excreted in urine from 1 to 24 hours after dosing 
Fe48 
fraction excreted in urine from 1 to 48 hours after dosing 
FSH 
follicle stimulating hormone 
GCP 
GGT 
Good Clinical Practice 
gamma-glutamyl transferase 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
HbA1c 
HBsAg 
glycosylated Hemoglobin Hgb 
hepatitis B surface antigen 
HCV 
HDL 
hepatitis C virus 
high-density lipoprotein 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
HR 
resting heart rate 
HTN 
hypertension 
IB 
Investigators’ Brochure 
ICF 
informed consent form 
ICH 
INR 
IPA 
International Council for Harmonisation 
international normalized ratio 
inhibition of platelet aggregation 
IRB 
institutional review board 
IRR 
infusion-related reaction 
IV 
LDH 
Intravenous- (ly) 
lactate dehydrogenase 
LDL 
low-density lipoprotein 


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LTA 
MAP 
MCH 
MCHC 
MCV 
MDMA 
light transmittance aggregometry 
mean arterial pressure 
mean corpuscular hemoglobin 
mean corpuscular hemoglobin concentration 
mean corpuscular volume 
methylenedioxymethamphetamine 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
MI 
MPV 
Medical Dictionary FOR Regulatory Activities 
Myocardial infarction 
Mean platelet volume 
msec 
millisecond 
MTD 
N 
maximum tolerated dose 
sample size 
NCS 
not clinically significant 
NOAEL 
OTC 
PD 
PEF 
no adverse effect level 
Over the counter 
Pharmacodynamic 
Peak expiratory flow 
PK 
pharmacokinetic 
PO 
by mouth 
PRI 
platelet reactivity index 
PRU 
P2Y12 reaction units 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QD 
once daily 
QTcF 
Fridericia-corrected QT interval 
RBC 
red blood cell(erythrocyte) 
RR 
respiration rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
System- organ- class 
SOP 
SpGr 
standard operating procedure 
specific gravity 
SRC 
Safety Review Committee 
t1/2 
terminal elimination half-life 
TAM 
ticagrelor active metabolite AR-C124910XX 
TEAE 
treatment-emergent adverse event 


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Tmax 
time to reach the observed maximum (peak) concentration 
TRAP 
thrombin receptor activating peptide 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
VASP 
vasodilator-stimulated phosphoprotein 
WBC 
white blood cell 
 


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1. 
INTRODUCTION 
1.1 PRODUCT AND BACKGROUND INFORMATION 
PB2452 (molecular weight 47.4 kDa) is a specific and selective recombinant human 
neutralizing antibody IgG1λ monoclonal fragment antigen-binding antibody that binds with 
high affinity to ticagrelor and to AR-C124910XX (TAM), the major active circulating 
ticagrelor metabolite. It is expressed in Escherichia coli cells. 
PB2452 is intended to reverse the antiplatelet effects of ticagrelor in patients who  
experience major bleeding or who require urgent surgery or intervention.  
Platelet transfusion has appeared to be inferior to standard care for those taking antiplatelet 
therapy.(Baharoglu, 2016)  
A strategy is needed to re-establish the integrity of the clotting cascade for the many patients 
who have abnormal coagulation due to pharmacological anticoagulation.(Beshay, 2010) 
Antiplatelet medications and anticoagulants pose a significant treatment dilemma since no 
direct reversal agents currently exist to reverse or mitigate antithrombotic properties.(Dornbos III, 
2018) Accordingly, the current lack of an effective therapy to mitigate ticagrelor-induced 
platelet inhibition in patients who have life-threatening bleeding or require urgent surgery or 
intervention represents a significant unmet need. 
Ticagrelor is an orally available, direct-acting cyclopentyltriazolopyrimidine, a selective and 
reversibly binding P2Y12 receptor antagonist.(Storey, 2007) TAM, the ticagrelor active metabolite 
(30% to 40% plasma exposure relative to parent in humans, (Storey, 2007) has potency similar to 
ticagrelor versus P2Y12. In addition to P2Y12, ticagrelor also inhibits the equilibrative 
nucleoside transporter-1, thereby providing an enhanced adenosine response.(Armstrong, 2014; 
Beshay JE, Morgan H, Madden C, Yu W, et al. Emergency reversal of anticoagulation and antiplatelet 
therapies in neurosurgical patients. J Neurosurg 2010 Feb;112(2):307-18. 
Catteneo, 2014) Ticagrelor in combination with low-dose aspirin (acetylsalicylic acid; ASA) is 
indicated for the prevention of thrombotic events (e.g., cardiovascular death, myocardial 
infarction [MI], and stroke) in patients with acute coronary syndrome (ACS) or a history of 
MI. Ticagrelor also reduces the rate of stent thrombosis in patients who have been stented for 
treatment of ACS. In the management of ACS, ticagrelor treatment is initiated with a 180 mg 
loading dose, followed by 90 mg twice daily (bid) during the first year after an ACS event. 
After one year, the prescribed dosage is decreased to 60 mg bid. 
Therapy with ASA plus an oral antiplatelet agent such as clopidogrel, prasugrel, or ticagrelor 
is known as dual antiplatelet therapy (DAPT). Although DAPT is strongly recommended in 
the early management of patients experiencing an ACS event, it also increases the risk of 
bleeding.(Storey, 2011) Patients with ACS may require urgent or emergent coronary artery bypass 


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graft (CABG) surgery. In such patients, DAPT is associated with a 2-fold increase in risk of 
blood transfusion, a 5-fold increase in risk of reoperation, and a 50% increased risk of wound 
infection.(Bell, 2011; Fitchett, 2011) Consequently, guidelines and guidance statements recommend 
the P2Y12 receptor antagonist be stopped ≥5 days prior to the procedure, a recommendation 
that is not possible in patients who require urgent surgery. 
There are no approved drugs or biological agents capable of reversing the P2Y12 inhibition 
produced by ticagrelor or other P2Y12 inhibitors; therefore, in the event of major bleeding in 
a patient on DAPT, there are limited treatment options. Although platelet transfusion restores 
platelet function in patients on ASA,(Taylor, 2013) it does not reverse the antiplatelet effect of 
ticagrelor in healthy volunteers and is unlikely to be of clinical benefit in patients with 
bleeding.(Teng, 2016)  
1.1.1 Non-clinical Pharmacology 
Non-clinical pharmacology studies have demonstrated that PB2452 binds with high affinity 
and selectivity to the P2Y12 receptor antagonist ticagrelor and its active metabolite, TAM, 
(equilibrium dissociation constant [KD] 20 pmol/L). PB2452 rapidly neutralizes the unbound 
plasma fraction of ticagrelor and TAM, thereby reversing ticagrelor- and TAM-mediated 
inhibition of adenosine diphosphate (ADP)-induced platelet aggregation in a concentration- 
and dose-dependent manner in vitro (in human platelet-rich plasma) and in vivo (mouse and 
pig, dose-dependency data in mouse only). In mice dosed with ticagrelor to a 
supratherapeutic plasma exposure, those dosed with PB2452 before a tail cut had reduced 
bleeding to a degree not statistically different from the observation in mice not treated with 
ticagrelor. The activity in vitro and the rapid onset of effect observed in vivo translated to a 
reduction of bleeding in ticagrelor-treated mice to a degree that was not statistically 
significantly different from mice not treated with ticagrelor. Detailed descriptions of the non-
clinical pharmacology of PB2452 may be found in the Investigators’ Brochure (IB) for 
PB2452.   
1.1.2 Summary of Human Data 
The first-in-human Phase 1 study (PB2452-PT-CL-0001) has been clinically completed, the 
database is locked, and final analyses are complete with the exception of exploratory 
endpoints. The safety, PK, and PD data described herein will be incorporated into a clinical 
study report. This study was a single-center, randomized, double-blind, placebo-controlled, 
single ascending dose study to evaluate the safety, tolerability, PK, and PD of PB2452 with 
and without ticagrelor pretreatment in healthy male and female subjects ages 18-50 years. 
Ten sequential dose cohorts were evaluated. Cohorts 1, 2, and 3 assessed 30 min IV infusions 
of PB2452 without ticagrelor pretreatment while Cohorts 4-10 assessed IV infusions of 


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PB2452 after ticagrelor pretreatment. Detailed descriptions of the clinical safety, PK, and PD 
profiles of PB2452 may be found in the Investigators’ Brochure (IB) for PB2452. 
PB2452 appeared generally safe and well tolerated across a dose range of 0.1 g to 18 g. A 
total of 30 adverse events occurred after initiation of PB2452 or placebo and were reported 
by 19 of the 64 volunteers (30%). Of the 48 volunteers who received PB2452, 17 (35%) 
reported 27 adverse events; of the 16 volunteers who received placebo, 2 (12%) reported 3 
adverse events. There were no dose-limiting toxicity (DLTs)effects or infusion-related 
reactions (IRRs). There were no deaths or adverse events that led to discontinuation of the 
trial drug. One volunteer had 2 serious adverse events (alcohol poisoning and acute 
respiratory failure) 4 days after discharge from the clinical site. Except for 2 volunteers, in 
cohorts 1 and 3, all volunteers with adverse events had received ticagrelor pretreatment. 
Changes in mean clinical laboratory test results, vital signs, and electrocardiographic results 
were similar across cohorts among volunteers who received different doses or regimens of 
PB2452 and were similar among those who received PB2452 and those who received 
placebo. Of the 48 volunteers who received PB2452, 21 (44%) had detectable anti-drug 
antibodies in blood obtained 7 and/or 28 days after exposure; 15 (31%) had been positive 
before they received PB2452 and 6 (12%) became positive after they received PB2452, albeit 
with low titers of 40 (in 5 volunteers) and 160 (in 1 volunteer). Of the 16 volunteers who 
received placebo, 3 (19%) were positive for anti-drug antibodies, with 2 (12%) having 
preexisting antibodies. The presence of these antibodies had no observed effect on the safety 
or efficacy of PB2452. 
The PK profile of PB2452 demonstrated that mean plasma concentrations of PB2452 rapidly 
declined following the end of infusion across all cohorts. In cohorts 1-3 when PB2452 was 
administered as a 30-minute intravenous infusion in the absence of ticagrelor, elimination 
appeared to be biphasic with half-life values ranging from 1.5 to 9.2 hours for the dose range 
0.1 g to 1 g. In the presence and absence of ticagrelor, geometric mean observed maximum 
plasma concentration (Cmax) values and geometric mean area under the plasma concentration 
versus time curve (AUC) from time zero extrapolated to infinity (AUC0-∞) )values of total 
PB2452 appeared to increase in a dose-proportional manner. The inter-individual variability 
(geometric mean coefficient of variation [CV%]) for Cmax and AUC0-∞ was low, ranging from 
4.8% to 28.9% across Cohorts 1-3. PB2452 appeared to increase mean total plasma 
concentrations of ticagrelor and TAM compared to placebo, and this effect was dependent on 
the dose of PB2452.  Additionally, PB2452 increased the renal CL of ticagrelor and TAM in a 
dose-dependent manner. 


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The PD profile of PB2452 demonstrated that for subjects receiving steady-state ticagrelor, IV 
infusion of PB2452 (3 to18 g) restored platelet activity to approximately 100% of baseline 
using multiple assays of platelet function. The onset of reversal was rapid, occurring at the 
first assessment of platelet function following initiation of PB2452 infusion (30 minutes in 
cohorts 4-6 and 5 minutes in cohorts 7-10). The duration of ticagrelor reversal appeared to be 
dependent on the total dose and infusion duration of PB2452.  
1.1.3 Benefit/Risk Assessment 
The first in human study of PB2452 in healthy volunteers (PB2452-PT-CL-0001) 
demonstrated that PB2452 appears to be generally safe and well tolerated when administered 
intravenously across a dose range of 0.1-18 g. The healthy volunteers who were 18-50 years 
in age were not expected to receive any benefit from administration of PB2452. Platelet 
function analyses showed that PB2452 delivered immediate and sustained reversal of 
ticagrelor, occurring as early as 5 minutes after initiation of PB2452 infusions and lasting for 
20-24 hours. Rapid and sustained ticagrelor reversal by PB2452 may provide clinically 
significant benefit in patients taking ticagrelor who experience serious bleeding or require 
urgent surgical procedures by supporting rapid hemostasis or prevention of procedure-related 
bleeding. 
Although treatment emergent adverse events associated with PB2452 in the Phase 1 study 
were mostly mild and infrequent with no infusion-related or hypersensitivity reactions 
observed, in the older and elderly subjects in this Phase 2A study, there remain potential risks 
of infusion-related reactions (IRRs), infusion site reactions, and hypersensitivity-type 
reactions which can result from exposure to recombinant protein drugs administered 
intravenously (IV). These risks may be mitigated by predefined exclusion criteria and by 
close monitoring during and after administration. Risks may also be mitigated by 
premedication prior to receiving PB2452 which will be implemented if a study subject 
develops a Grade ≥2 IRR. 
The healthy subjects in Part B of this study will be administered a high-dose of ticagrelor 
(180 mg BID) which is expected to cause a dose-dependent increase in exposure compared to 
the 90 mg BID ticagrelor dose tested in Part A of this study and in the previous Phase 1 study 
of PB2452. Treatment with ticagrelor in any subject carries a risk of bleeding. However, in a 
ticagrelor study in atherosclerosis patients, the elevated exposures from 180 mg BID of 
ticagrelor demonstrated no apparent increase in bleeding compared to patients treated with 
ticagrelor 90 mg BID (Storey et al. DISPERSE-2 JACC 2007; 50: 1852-6). Based on the 
patient data and because the duration of high-dose ticagrelor treatment in Part B of this study 
is only 48 hours and will be administered without aspirin, the bleeding risk in study subjects 
is considered low.   


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Among those patients taking ticagrelor for therapeutic benefit, the potential risk of disease-
related thrombosis upon reversal of the antiplatelet effect of ticagrelor will be evaluated in 
future clinical studies and by thorough monitoring of hemostasis parameters. In the current 
study, three platelet function assays and multiple platelet agonists will be used to monitor 
platelet function which will demonstrate both the reversal profile of PB2452 and also a 
potential prothrombotic rebound increase in platelet function. The risk of a platelet rebound 
effect is considered low and was not observed in the Phase 1 study. 
Based on available information concerning the risks of PB2452 and the precautions included 
in this clinical study, the risks are considered acceptable. 
1.2 RATIONALE FOR STUDY 
Current recommendations for management of bleeding in patients treated with  
antiplatelet therapies are suboptimal; they are mostly supportive and non-specific.  
Platelet transfusion, while useful for some antiplatelet agents, exposes patients to the  
known risks of blood products. Further, the efficacy of transfused platelets may be  
limited by exposure to circulating antiplatelet drug or metabolites, if present. Moreover,  
it has been demonstrated that platelet transfusions do not reverse the effects of 
ticagrelor.(Dalen, 2013; Godier, 2015; Maillard, 2015; Teng, 2016) 
An agent to rapidly reduce the anti-platelet aggregation (IPA) associated with effects of 
ticagrelor, and the metabolite TAM, would fulfill an important unmet clinical need for those 
patients: 
• 
who have major bleeding with ticagrelor possibly contributing 
• 
who are taking ticagrelor and require urgent surgery or intervention associated with a 
high risk of bleeding 
• 
who are taking ticagrelor for conditions with a high risk of thrombosis, require major 
surgery, and/or need to minimize the time when they are not receiving ticagrelor 
1.3 RATIONALE FOR DOSE SELECTION 
In the first in human Phase 1 study of PB2452, 18 g administered as an initial 6 g bolus 
followed by a prolonged infusion of the remaining 12 g over 16 hours in healthy subjects 
aged 18-50 years old was considered generally safe and well tolerated. There were no 
PB2452-related adverse effects, ISRs, or DLTs observed as determined by the study 
investigator and SRC. The profile of rapid and sustained ticagrelor reversal delivered by the 
18 g dose level is potentially clinically meaningful and considered ideal for patients on 
ticagrelor with acute major bleeding or who need urgent surgery.  
The 18 g dose level and prolonged infusion regimen administered in the Phase 1 study will 
be repeated in the current study in older and elderly subjects who are more similar in age and 
background comorbidities to the actual patient population treated with ticagrelor. Potentially 


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longer infusions of PB2452 may be investigated in this study, using potentially high total 
doses of PB2452. To mitigate any risks related to dose escalation, a Safety Review 
Committee (SRC) will be assembled to review all emergent safety and tolerability data and 
available PK data after each cohort is completed to determine whether dose escalation and/or 
prolongation of infusion duration is warranted. PK/PD modeling will be used to simulate 
potential doses, infusion regimens, and Cmax and AUC exposure profiles prior to dose-
escalation or adjustment of infusion regimen to ensure that no dose or infusion regimen 
investigated in this study will exceed Cmax or AUC exposures achieved at the no observed 
adverse effect level (NOAEL) in GLP toxicity study in rats.  
In the rat GLP toxicity study, there were no adverse effects observed following single doses 
of PB2452 at the highest dose level tested of 2000 mg/kg given IV, alone or in combination 
with oral ticagrelor (20 mg/kg). Therefore, 2000 mg/kg was considered NOAEL with a 
maximum plasma concentration (Cmax) of 18100 µg/mL and an area under the plasma 
concentration versus time curve from time zero extrapolated to infinity (AUC0-∞) of 23100 
µg*h/mL.  
One or more doses and administration regimens of PB2452 will be tested in Part B to identify 
an approach to reverse a high oral dose of ticagrelor (180 mg BID). In a previous study of 
ticagrelor, co-administration of ticagrelor with CYP3A inhibitors resulted in higher exposure 
to ticagrelor and lower exposure to its active metabolite (Teng et al 2013). Similar increases 
in exposure were reported in ACS patients who were treated with oral 180 mg ticagrelor 
twice daily. In the patient population, the elevated exposures from this high dose of ticagrelor 
resulted in a dose-dependent increase in inhibition of platelet aggregation but no apparent 
increase in bleeding compared to patients treated with ticagrelor 90 mg BID (Cannon et al. 
2007 and Storey et al. 2007). 


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2. 
STUDY OBJECTIVES AND METHODOLOGY 
2.1 OBJECTIVES 
Primary: 
• 
To evaluate the safety and tolerability of intravenous (IV) doses of PB2452 vs matching 
placebo with a high dose of oral ticagrelor (180 mg BID) in healthy subjects  
• 
To assess the efficacy/ pharmacodynamic (PD) of IV doses of PB2452 vs matching 
placebo in reversing a high dose of ticagrelor’s antiplatelet activity by measuring P2Y12 
reaction units (PRU) with VerifyNow® P2Y12 assay in healthy subjects    
Secondary: 
• 
To determine the pharmacokinetics (PK) of PB2452 in the presence of a high dose of 
ticagrelor 
• 
To determine the PK of ticagrelor and TAM in the presence of PB2452  
• 
To evaluate the effect of PB2452 on ticagrelor antiplatelet activity by measuring platelet 
aggregation with light transmittance aggregometry (LTA) and platelet reactivity index 
(PRI) with vasodilator-stimulated phosphoprotein (VASP) assay by enzyme-linked 
immunosorbent assay (ELISA) 
• 
To evaluate the immunogenicity potential of PB2452 
Exploratory: 
• 
To evaluate the effect of PB2452 on the PK profile of unbound ticagrelor and unbound 
TAM plasma concentrations 
• 
To investigate the effect of PB2452 vs matching placebo on circulating biomarkers of 
platelet activation, such as P-selectin, in subjects pretreated with high-dose ticagrelor 
• 
To examine the correlation between estimated creatinine clearance (CrCl) and the PK of 
ticagrelor and TAM. 
2.2 EVALUATION CRITERIA 
2.2.1 Safety Endpoints 
Safety and tolerability will be assessed by monitoring and recording of Adverse Events 
(AEs), clinical laboratory test results (hematology, coagulation, serum chemistry, and 
urinalysis), vital sign measurements (systolic blood pressure [SBP] and diastolic blood 
pressure [DBP], oral body temperature, respiratory rate [RR], and resting heart rate [HR]), 
12-lead electrocardiogram (ECG), continuous 12-lead ECG (Holter monitoring), 
immunogenicity, and physical examination findings.  
2.2.2 Pharmacodynamic Endpoints 
VerifyNow®P2Y12: 


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• Minimum %inhibition of PRU within 4 hours after the initiation of study 
drug. %inhibition of PRU is calculated as 100 * [(PRUbsl – PRUtrt)/PRUbsl]. PRUbsl 
refers to the PRU value measured before treatment with ticagrelor and PRUtrt refers to 
the PRU value measured posttreatment with the study drug. 
• PRU AUC for the first 4 hours.  
• Proportion of patients with normalized platelet reactivity units within 4 hours after the 
initiation of study drug. Normalized platelet reactivity is defined as PRU ≥ 180. 
• Proportion of patients with ≥60%, ≥80%, and 100% of PRU response rate within 4 
hours after the initiation of study drug. A PRU response rate is defined as the 100 * 
(PRUtrt/PRUbsl). 
• Time to 60%, 80%, 100% of PRU response rate within 4 hours after the initiation of 
study drug  
• Duration of 80% and 100% of PRU response rate by PRU. 
LTA: 
• Minimum %inhibition of LTA within 4 hours after the initiation of study drug. 
• LTA AUC for the first 4 hours.  
• Proportion of patients with ≥60%, ≥80%, and 100% of LTA response rate within 4 hours 
after the initiation of study drug. LTA response rate is defined as the 100 * 
(LTAtrt/LTAbsl). 
• Time to 60%, 80%, 100% LTA response rate within 4 hours after the initiation of study 
drug. 
• Duration of 80% and 100% of LTA response rate. 
VASP by ELISA: 
• Minimum %inhibition of PRI within 4 hours after the initiation of study drug. 
• PRI AUC for the first 4 hours.  
• Proportion of patients with ≥60%, ≥80%, and 100% of PRI response rate within 4 hours 
after the initiation of study drug. A PRI response is defined as the 100 * (PRItrt/PRIbsl). 
•  Time to 60%, 80%, 100% PRI response rate within 4 hours after the initiation of study 
drug 
• Duration of 80% and 100% of PRI response rate 
 
Additional PD parameters may be generated, if needed. 
 
2.2.3 Pharmacokinetic Endpoints 
Plasma PK 
Plasma concentrations of total PB2452, unbound PB2452, total Ticagrelor, total TAM, 
unbound Ticagrelor, and unbound TAM, will be assessed at predetermined timepoints.  
PK parameters for PB2452 include:  
• 
Observed maximum plasma concentration (Cmax) 


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• 
Area under the plasma concentration versus time curve (AUC) from time zero to the time 
of the last quantifiable concentration (AUC0-t) 
• 
Time to reach the observed maximum plasma concentration (Tmax) 
• 
AUC from time zero to 24 hours post-dose (AUC0-24) 
• 
AUC from time zero to 48 hours post-dose (AUC0-48)  
• 
Area under the plasma concentration versus time curve (AUC) from time zero to the time 
of the end of the dosing period(AUC0-tau) 
• 
AUC from time zero extrapolated to infinity (AUC0-∞; if data permit) 
• 
Terminal elimination half-life (t½; if data permit) 
• 
Clearance (CL; if data permit) 
• 
Volume of distribution (Vd)  
PK parameters for Ticagrelor/TAM include: 
• 
Cmax  
• 
AUC0-t 
• 
Tmax 
• 
AUC0-24 
• 
AUC0-48  
• 
AUC0-tau 
• 
AUC0-∞; if data permit 
• 
t½; if data permit 
Urine PK 
Pooled urine samples to assess urine PB2452, ticagrelor, and TAM concentrations will be 
collected over these intervals: before dosing (within 60 minutes prior to the first ticagrelor 
dose on Day -2) and 0 to 6, 6 to 12, and 12 to 24 hours.  
Pharmacokinetics parameters for PB2452, ticagrelor, and TAM concentrations in urine for all 
subjects in the PK population to be calculated are: 
• 
Total amount of drug excreted in urine at 24 hours after dosing (Ae24) and at 48 hours 
after dosing (Ae48) 
• 
Ae from time t1 to t2 hours when the values of t1 to t2 are 0 to 6, 6 to 12, 12 to 24 and  
24 to 48 hours (Aet1-t2) 
• 
Fraction excreted in urine from 1 to 24 hours after dosing (Fe24) and from 1 to 48 hours 
after dosing (Fe48) 
• 
Renal clearance (CLr) for 24 hours after dosing 
Additional PK parameters may be generated, if needed. Details will be provided in a separate 
document, the SAP. 


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3. 
INVESTIGATION PLAN 
3.1 STUDY DESIGN AND METHODOLOGY 
This is Part B of a Phase 2A, randomized, double-blind, placebo-controlled, single dose, 
sequential group study to evaluate the safety, tolerability, PK, and PD of PB2452 vs matching 
placebo with ticagrelor pretreatment. Various dose levels and/or administration regimens of 
PB2452 may be administered to healthy male and female subjects 18-50 years old. All 
references to study drug within the content of the protocol apply to PB2452 or 
matching placebo.  
In Part B up to 3 dose levels and/or administration regimens of PB2452 will be evaluated in 
up to 3 cohorts. Each cohort will include up to 12 subjects randomized in a 3:1 ratio 
(PB2452:placebo).  
This initial cohort of Part B (Cohort 3) will pretreat subjects with 180 mg of oral ticagrelor 
twice daily for 48 hours prior to randomization to a dose and regimen of PB2452 or matching 
placebo described in a cohort-specific Dosing Memo. The written Dosing Memo provided by 
the Sponsor to the clinical site will describe details of the dosing regimen, cohort size, 
sampling schedules, and other cohort-specific study activities prior to initiation of each 
cohort. The dose level of the initial regimen in Part B will not exceed twice the total dose 
level (36 g) shown to be safe and well tolerated in older and elderly subjects (50-80 years) in 
Part A of this Phase 2A study and in the Phase 1 study of PB2452 in healthy subjects 
(PB2452-PT-CL-0001). 
Following completion of Cohort 3, subsequent cohort(s) may test the same, higher or lower 
dose levels, and/or different infusion regimens of PB2452 or matching placebo in the same 
population as in Cohort 3, or in different populations such as elderly subjects (65 to 80 years 
old), as determined by the Sponsor after examination of available PD and safety data from 
the prior cohort(s) and described in a subsequent Dosing Memo. Duration of study drug 
infusions will not exceed 48 hours.  
A Safety Review Committee (SRC) will review all available safety data from ongoing or 
completed cohorts and will document their review and assessment in written SRC minutes 
prior to initiation of a subsequent cohort. Dose escalation may occur only if the SRC affirms 
the dose and regimen from the previously completed cohorts were safe and well tolerated and 
no dose-limiting toxicities (DLTs) were observed.  
The study will consist of a Screening period (Days –45 to –4), a Check-in day (Day -3), a 48 
hour Pretreatment Period starting on Day -2, an on-site Randomization/Treatment day (Day 
1), 3 days on-site for treatment and safety monitoring, a Follow-up Visit (Day 7), and a Final 
Follow-up visit (Day 28 [±2 days]). Two days prior to Randomization (Day -2), subjects will 
be administered ticagrelor 180 mg orally twice daily (BID) until the final dose on the 
morning of Day 1 before receiving study drug. The first ticagrelor 180 mg oral dose will be 


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administered on the morning of Day -2 followed by 180 mg every 12 hours until the 5th dose 
has been administered on the morning of Day 1.   
Subjects will check in to the clinical site (PPD) on Day -3. In the morning on Day -2, 
subjects will begin pretreatment with ticagrelor as described in the preceding paragraph. On 
Day 1, subjects who meet all the inclusion criteria and none of the exclusion criteria will be 
randomized in a ratio 3:1 (PB2452:placebo), to receive an IV dose of PB2452 or placebo 2 
hours following the 5th ticagrelor dose. Subjects may be discharged from the clinical site 
between Days 3 and 7 inclusive and will return for a Follow-up visit on Day 7, if already 
discharged, and on Day 28 (±2 days).  
Serum and plasma sampling times for PB2452, ticagrelor, and TAM PK and PD assessments 
will be described in the detailed Dosing Memo for each cohort. Hour 0 will be the time for 
initiation of study drug infusion (2 hours following administration of the 5th ticagrelor dose). 
PK and PD time points for subsequent cohorts may be adjusted as needed based on available 
PK, PD, and safety data from prior cohorts. In any cohort subsequent to Cohort 3, there will 
be no more than 6 additional sampling time points.  The written Dosing Memo provided by 
the Sponsor prior to initiation of each cohort will include the following instructions: 
• 
Number of subjects to be randomized  
• 
Total PB2452 dose and administration regimen  
• 
The PK and PD sampling schedule  
• 
Safety ECG schedule  
• 
Biomarkers schedule 
Safety and tolerability will be carefully monitored throughout the study. Immunogenicity 
samples will be collected from all subjects at Day -3, Randomization , Days 7 and 28 (±2 
days) following administration of study drug. 
3.2 SELECTION OF STUDY POPULATION 
Male or female subjects will be evaluated in up to 3 cohorts in the US, North America. To 
ensure the study clinic has sufficient subjects available for dosing for any cohort, additional 
subjects may be asked to present to the clinic for check in. The number of subjects brought in 
for check-in and pre-dosed with ticagrelor will be at the discretion of the study clinic 
personnel/principal investigator to ensure there is a sufficient number of subjects available 
for dosing with study drug for a given cohort. Subjects who check in to the clinic may be 
dosed with ticagrelor in preparation for dosing with the study drug according to the Schedule 
of Events (Appendix 7.1). Extra subjects may be dosed with ticagrelor, so on the day of 
randomization there is a sufficient number of subjects available to fill the cohort. 


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3.2.1 Inclusion Criteria 
Subjects must meet ALL the following criteria to be eligible for inclusion in the study: 
1. The subject provides written informed consent and agrees to comply with all 
protocol requirements. 
2. The subject is male or female between 18 and 50 years of age, inclusive.    
3. The subject has a body mass index (BMI) between 18 and 35 kg/m2 and a weight of 
≥50 kg but ≤120 kg, inclusive, at Screening. 
4. The subject is considered by the investigator to be in good general health, as determined 
by medical history, clinical laboratory test results, vital sign measurements, 12-lead ECG 
results, and physical examination findings at Screening.  
5. Specific inclusionary laboratory values at Screening and Check-in require:  
• 
White blood cell (WBC) count, platelet count, hemoglobin (Hgb) level within normal 
range, as, defined by the clinical laboratory 
• 
Thyroid stimulating hormone (TSH) level within normal range, as defined by the 
clinical laboratory at Screening 
• 
Prothrombin time (PT) and partial thromboplastin time (PTT) level within normal 
range, as defined by the clinical laboratory  
6. Female subjects of childbearing potential must not be pregnant, lactating, or planning to 
become pregnant for 3 months after the last dose of study drug, and have a negative 
serum pregnancy test at Screening and Check-in. Female subjects of childbearing 
potential must use 2 effective methods of birth control from 30 days before study drug 
administration through to the end of the study.  
• 
Effective birth control methods include oral, implantable, patch, or injectable 
contraceptive hormone treatment, hormone-containing intrauterine device that has 
been in place ≥2 months prior to Screening, sponge, diaphragm, or cervical cap with 
spermicidal gel or cream for female subjects or condom or vasectomy for male 
subjects.  
• 
Women are considered to not be of childbearing potential if they have fulfilled one of 
these criteria: documentation of irreversible surgical sterilization (i.e., hysterectomy 
or bilateral oophorectomy [not tubal ligation]) or are postmenopausal (defined as 
amenorrhea for 12 consecutive months following cessation of all exogenous 
hormonal treatments, and documented plasma follicle-stimulating hormone (FSH) 
level >40 IU/mL) or amenorrhea for 24 consecutive months.  
• 
Male subjects with partners of childbearing potential must agree to use appropriate 
and effective measures of contraception (e.g., condom plus diaphragm with 
spermicide, condom plus spermicide) during the study and for 30 days after the last 
dose of study drug, and refrain from donating sperm for ≥90 days following the last 
dose of study drug.  
3.2.2 Exclusion Criteria 
Subjects will be excluded from this study if they meet ANY of the following criteria:  


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1. Concern the subject may be unable to comply with study procedures and/or follow-up, or, 
in the opinion of the investigator, the subject is not suitable for entry into the study 
2. History of any acute or chronic medical disorder expected to decrease the life expectancy 
of the subject   
3. History or presence of gastrointestinal (GI), hepatic (with the exception of Gilbert’s 
syndrome), or any other condition known to interfere with absorption, distribution, 
metabolism, or excretion of drugs  
4. Significant renal insufficiency, as indicated by estimated glomerular filtration rate 
(eGFR) <30 mL/min/1.73m2 according to the Modification of Diet in Renal Disease  
(MDRD) equation   
5. Any CS acute illness, medical/surgical procedure, or trauma within 4 weeks of 
administration of study drug or any planned surgical procedure that will occur during the 
study (from Screening through the Day 28 [±2 days] Follow-up visit). 
6. Any CS abnormal findings in physical examination, vital signs, laboratory assessments, 
and ECG parameters identified during Screening or Check-in. Note: abnormal results 
may be repeated for confirmation immediately after the first out of range measurement. 
Abnormal vital signs may be repeated twice if needed, immediately after the first 
abnormal result and/or after the subject has rested for at least 10 minutes. 
Specific vital sign exclusionary criteria occurring after 10 minutes of supine rest are any 
of the following: 
• 
SBP <100 or >160 mm Hg 
• 
DBP <40 or >95 mm Hg 
• 
Resting HR <50 or >100 beats per minute (bpm) 
Specific exclusionary criteria for ECG parameters at Screening or Check-in include any 
of the following: 
• 
Prolonged Fridericia-corrected QT interval (QTcF) >450 milliseconds (msec), 
shortened QTcF <340 msec, or pause >3 seconds, or family history of long 
QT syndrome 
7. Any specific contraindication to Brilinta® as described in the Brilinta prescribing 
information and: 
• 
History of intracranial hemorrhage, active bleeding, or hypersensitivity or allergic 
reaction to ticagrelor or any component of the product 
• 
Any history of severe head trauma, intracranial neoplasm, arteriovenous 
malformation, aneurysm, or proliferative retinopathy 
• 
Any history of intraocular, retroperitoneal, or spinal bleeding 
• 
Have taken, within 30 days of Screening, any oral or parenteral anticoagulant, 
including low molecular-weight heparin 
• 
Stool sample testing positive for occult blood within 3 months of Screening or at any 
time during the Screening Period. 
8. Receiving chronic treatment with nonsteroidal anti-inflammatory drugs (NSAIDS; 
including ASA [>100 mg daily]), anticoagulants, or other antiplatelet agents that cannot 


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be discontinued 14 days prior to randomization (including clopidogrel, prasugrel, 
ticlopidine, dipyridamole, or cilostazol). 
9. Positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) 
antibody, or human immunodeficiency virus (HIV) types 1 or 2 antibodies at Screening. 
10. Concomitant oral or IV therapy with strong or moderate cytochrome P450 3A4 (CYP3A) 
inhibitors, CYP3A substrates with narrow therapeutic indices, or strong CYP3A inducers, 
which cannot be stopped within at least 5 half-lives, but not fewer than 10 days, before 
randomization (a list of examples may be found in Appendix 7.2). 
11. Consumption of grapefruit or grapefruit juice, Seville orange or Seville 
orange-containing products (e.g., marmalade), or xanthine-containing products within 
48 hours before dosing with study drug. 
12. Prescription or over-the-counter (OTC) medications within 14 days before the first dose 
of study drug unless specifically allowed by protocol. (Permitted medications include 
multivitamins, paracetamol [up to 2g per day], and/or treatments for chronic stable 
diseases provided the drug and dose have been stable for ≥30 days prior to administration 
of study drug)   
13. Has received another investigational drug (defined as a small molecule or biologic 
compound which has not been approved for marketing) within 30 days of the 
administration of study drug in this study or within 5 half-lives of the experimental 
medication, whichever is longer.  
14. Positive test result for alcohol or drugs of abuse at Screening or Check-in. 
15. Participated in strenuous activity or contact sports within 24 hours before the infusion of 
study drug or while confined in the clinical site. 
16. History of severe or ongoing allergy/hypersensitivity to any drug or biologic  
therapeutic agent.  
17. Involvement with any PhaseBio or study site employee or their close relatives (e.g., 
spouse, parents, siblings, or children whether biological or legally adopted). 
18. Previously received PB2452 or had been randomized to receive study drug in an earlier 
cohort for this study. 
3.2.3 Subject Restrictions During the Study 
If a subject is unable to comply with any of the following restrictions before study drug 
dosing on Day 1, the subject’s participation in the study will be re-evaluated by the 
investigator in consultation with the Sponsor and/or medical monitor on behalf of the 
Sponsor; the subject may not be eligible to participate in the study: 
• 
Subjects must be willing to remain at the study site from Day -3 through 48 hours 
following study drug dosing on Day 3.  
•  Subjects must be willing to return to the clinic for Follow-up visits on Day 7 and  
Day 28 (±2 days).  
•  Subjects must refrain from smoking or using nicotine or nicotine-containing products and 
from drinking alcohol-containing products   


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•  Subjects must refrain from strenuous exercise for 24 hours prior to Check-in and for 7 
days after discharge from the study 
• 
Subjects must be willing to maintain their usual caloric intake and to consume only food 
and beverages provided by the clinical site while confined to the study site. 
3.3 WITHDRAWAL OF SUBJECTS FROM THE STUDY 
3.3.1 Reasons for Withdrawal 
Subjects may withdraw consent and discontinue from the study at any time, for any reason, 
without prejudice to further treatment. Subject participation in the study may be stopped at 
any time at the discretion of the investigator or at the request of the Sponsor. The 
investigator may also withdraw a subject at the request of the Sponsor or if the Sponsor 
terminates the study.   
The investigator may withdraw a subject from the study if the subject:  
• 
Is non-compliant with the protocol;  
• 
Experiences a serious adverse event (SAE) or intolerable adverse event (AE) that, in the 
investigator’s opinion, requires withdrawal from the study;  
• 
Has laboratory safety assessments that reveal CS hematological or biochemical changes 
from Baseline values;  
• 
During the course of the study and through the end of study (EOS) develops symptoms or 
conditions listed in the exclusion criteria;  
• 
Requires a medication prohibited by the protocol; or  
• 
Requests an early discontinuation for any reason.  
If a subject experiences an SAE or intolerable AE, the investigator will confer with the 
sponsor. If a subject is discontinued because of an AE, the event will be followed until it is 
resolved or until it is stable. 
3.3.2 Handling of Withdrawals 
When a subject withdraws from the study, the reason(s) for withdrawal will be recorded by 
the investigator on the relevant page of the electronic case report form (eCRF).  Whenever 
possible, any subject who withdraws from the study if willing, should continue to be 
followed according to the protocol. For example, if termination occurs earlier than planned 
(i.e., after a subject has received all or partial study drug infusion) all efforts should be made 
to ensure the remaining protocol visits are completed. If a subject refuses to return for the 
Follow-up visits, the Day 28 (±2 days) visit procedures should be completed. Any subject 
who fails to return for final assessments will be contacted by the site in an attempt to obtain 
compliance with the protocol. The status of subjects who fail to complete final assessments 
will be documented in the eCRF. 


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3.3.3 Replacement of Subjects 
At the discretion of the investigator after consultation with the Sponsor, any subject who 
withdraws before completing the study, for reasons other than a DLT, may be replaced. Any 
replacement subject will be assigned to receive the same treatment as the subject he or she is 
replacing. 
3.4 STUDY TREATMENTS 
3.4.1 Method of Assigning Subjects to Treatment Groups 
On Study Day 1 eligible subjects will be randomly assigned to treatment with either PB2452 
or matching placebo in a 3:1 ratio, PB2452:placebo.  
3.4.2 Treatments Administered 
PB2452: 
PB2452 IV infusion, prepared according to the Pharmacy Manual, will be administered on 
Day 1 for up to 48 hours. For each cohort, the dose, infusion rate, and duration will 
be communicated from the Sponsor to the study site, PPD, in a Dosing Memo issued prior to 
initiation of each treatment cohort.  
Matching Placebo: 
0.9% sodium chloride single IV infusion, administered on Day 1, will be delivered at a rate 
and volume matching the active infusion.  
Ticagrelor: 
Ticagrelor 90 mg oral tablets (immediate release) administered as 180 mg  
(2 × 90 mg tablets) every 12 hours for 5 total doses.   
3.4.2.1 
Dose Escalation 
The SRC will conduct a blinded review of all safety and tolerability data from a cohort at 
least through Day 3 (e.g., clinical laboratory results, AEs, ECGs, Holter monitoring reports if 
available, vital signs, and available PK data) and available data for each completed dose 
cohort and will document their review and assessment in written SRC minutes prior to 
initiation of a subsequent cohort. Dose escalation may occur only if the SRC affirms the dose 
and regimen from the previously completed cohorts were safe and well tolerated and no 
DLTs were observed.  
The SRC will be minimally composed of the on-site PPD investigator/medical monitor, 
PhaseBio medical monitor, and PhaseBio clinical operations lead. Changes to the 
administration regimen (rate and duration) without escalation of the total dose or without 


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increases in the infusion rate will not require formal SRC approval. Similarly, reductions in 
the total dose or the infusion rate will not require SRC approval.  
The investigator may make a recommendation concerning whether the safety profile is 
sufficient to proceed to a higher dose level, whether a pause in dosing for review of 
additional safety and/or PK data is needed, or whether adjustment of the dose of the next 
dose cohort is needed. The decision to adjust or pause the dose or proceed to the next cohort 
will be made by the SRC.  
3.4.2.2 
Infusion-related or Allergic Reactions 
The administration of study drug infusion must be performed under supervision of trained 
medical staff and where facilities to handle allergic reactions are available. Should a subject 
experience symptoms typical of IRRs seen with some recombinant protein drugs  
e.g., lightheadedness, nausea, chills, fever(Doessegger 2015) the study drug infusion must be 
immediately and permanently discontinued. Should a subject experience symptoms typical of 
an allergic reaction (e.g., shortness of breath, anaphylaxis, urticaria, angioedema), the study 
drug administration must be immediately and permanently discontinued. Suspected IRRs 
will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.(NCI CTCAE, v5, 2017) Should any one subject develop a ≥Grade 2 IRR to 
study drug, all subsequent subjects in the study, inclusive of all dose cohorts, must be 
administered premedication (diphenhydramine 25 mg by mouth [PO] + acetaminophen 
650 mg PO) 30 to 60 minutes prior to receiving study drug to mitigate the risk of IRR. If any 
recipient of PB2452 (after unblinding) develops a ≥Grade 2 IRR in the absence of 
premedication, the entire dose level must be repeated as an additional cohort in which all 
subjects must be premedicated (as described above) 30 to 60 minutes prior to administration 
of study drug.  
To monitor for potential IRRs, vital signs, including BP, HR, Temp, RR, will be assessed at 
Baseline (prior to study drug infusion), every 10 minutes during the first 30 minutes of the 
infusion, and every 15 minutes thereafter for the first hour after initiation of the infusion. The 
remaining assessments of vital signs will be performed as described in the Schedule of 
Events (Appendix 7.1). Suspected allergic (hypersensitivity) reactions and anaphylaxis will 
be assessed according to the clinical diagnostic criteria outlined by the National Institute of 
Allergy and Infectious Diseases provided in the CTCAE v5 in Appendix 0 (Definition and 
Management of Anaphylaxis) and Appendix 7.4 (Clinical Criteria for Diagnosing 
Anaphylaxis). Subjects will receive appropriate medical treatment for these and other 
medical concerns at the discretion of the investigator. 


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3.4.2.3 
Dose-limiting Toxicities 
The SRC will review all AEs and all laboratory and ECG Holter monitoring abnormalities 
according to CTCAE v5 to determine whether DLT has been identified in a subject who is 
confirmed to have received PB2452. If the SRC determines an AE is related to administration 
of ticagrelor or another confirmed cause, the AE will not be considered a DLT. Definitions of 
DLT are:  
• 
Any AE assessed as ≥Grade 2 based on the CTCAE v5 grading scale and occurred in a 
subject confirmed to have received PB2452.  
• 
Any ≥Grade 2 laboratory abnormality (outside the clinical laboratory normal reference 
range) that occurs in a subject confirmed to have received PB2452.  
• 
Note: For a Grade 2 electrolyte abnormality that spontaneously resolves to ≤Grade 1 
without intervention within 24 hours, the SRC may decide to exempt the laboratory 
abnormality from being considered a DLT.  
• 
Any treatment-emergent adverse event (TEAE) that leads to study withdrawal of a 
subject confirmed to have received PB2452. 
3.4.2.4 
Stopping Criteria 
Dose escalation or ongoing infusions will be suspended, pending investigation by the SRC, if 
any of the following occur after confirmation the subject has received PB2452: 
• 
Any preclinical or clinical events that, in the opinion of the SRC, contraindicate further 
dosing of additional subjects with PB2452 
• 
Any serious AE (SAE) occurring prior to discharge from the clinical site 
• 
Data from previous cohorts indicate safety concerns for dosing at a higher level, such as 
unanticipated adverse responses (e.g., CS changes in clinical laboratory test data, ECGs 
Holter monitoring results, vital signs, physical examinations) 
• 
Two or more subjects in a cohort experience any DLT, or 1 subject experiences  
a ≥Grade 2 AE (DLT) that, in the opinion of the SRC, warrants suspension of dose 
escalation 
• 
Two or more subjects have >3 x ULN of either alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST), or >2 x ULN of bilirubin or alkaline phosphatase 
(ALP) when no other reason can be found to explain the increases 
• 
One or more subjects experiences a ≥Grade 2 IRR despite having been premedicated for 
IRRs. 
Continuation of dosing following suspension will be determined by the SRC and documented 
in an ad hoc SRC Safety Report. Dosing may also be suspended if, in the opinion of the SRC 
or Sponsor, any new or unexpected significant safety or tolerability issues related to 
ticagrelor or PB2452 are identified that warrant further evaluation before additional subjects 
are dosed. This may include emerging nonclinical data, clinically relevant AEs, or relevant 
data from other sources indicating safety concerns, even if the event(s) per se does not meet 
the protocol-specified definition of a DLT. 


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Dose-limiting toxicities identified during the study will be assessed as potential indicators of 
cumulative toxicity and provide rationale for defining the maximum tolerated dose (MTD). 
Although this study is not designed to dose to a MTD, the MTD may be reached if  
≥2 subjects in a dose cohort experience a DLT, as defined in Section 3.4.2.3. There will be no 
further dosing above the MTD. 
3.4.3 Identity of Investigational Product 
Study drug PB2452 is supplied as a sterile white to off-white lyophilized cake, free from 
visible foreign particles in a 20R glass vial at a nominal fill volume of 7.5 mL. PB2452 in the 
reconstituted state is formulated at 100 mg/mL in 25 mM histidine/histidine hydrochloride 
buffer, 290 mM sucrose, and 0.05% (w/v) polysorbate-80, pH 6.0. 
Matching placebo is a sterile, nonpyrogenic liquid product intended for IV administration 
composed of 0.9% sodium chloride in water for injection, USP. Separate instructions will be 
provided to the clinic for dose dilution, preparation, storage, and administration.  
3.4.4 Management of Clinical Supplies 
3.4.4.1 
Packaging and Storage 
PhaseBio Pharmaceuticals, Inc will provide the investigator and clinical site with adequate 
quantities of PB2452, and matching placebo. The study site will purchase commercially 
available ticagrelor 90 mg tablets. 
PB2452 will be supplied in a 20R glass vial at a nominal fill volume of 7.5 mL, stoppered 
with siliconized 20 mm chlorobutyl elastomer, flurotec-coated, single vent lyophilization 
stopper, and sealed with flip-off cap overseal. Following reconstitution with water for 
injection, PB2452 is further diluted into 0.9% saline for IV infusion.  
The clinical site pharmacy will prepare a single dose for each subject based on the dosing 
cohort and randomization assignment. The concentration will vary between 0.4 mg/mL up to 
72 mg/mL. Separate instructions will be provided to the clinic for dose dilution, preparation, 
storage, and administration. 
PB2452 must be stored in a secure area (e.g., a locked, temperature-controlled unit) at 2°C 
to 8°C (36°F to 46°F) protected from moisture and light with access restricted to necessary 
clinic personnel. with access restricted to necessary clinic personnel. The clinical site will be 
required to keep a temperature log to establish a record of compliance with these storage 
conditions.  
3.4.4.2 
Drug Accountability 
The investigator will maintain accurate records of receipt of all drug supplies used in this 
study including lot numbers (if applicable) and dates of receipt. In addition, accurate records 


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will be kept regarding when and how much drug is dispensed and used by each subject in the 
study. Reasons for departure from the expected dispensing regimen must also be recorded. At 
the completion of the study, to satisfy regulatory requirements regarding drug accountability, 
all drugs will be reconciled and retained or destroyed according to applicable regulations. 
3.4.5 Blinding 
This is a double-blind study. Neither the subjects nor the investigator will be aware of the 
treatment assignment. Blinding will be maintained throughout the study by use of active and 
placebo dose forms prepared to be similar in appearance. To maintain the blind, only 
designated pharmacy staff at the study site will have access to the randomization code and 
will prepare each dose for each subject. In order to prepare preliminary summaries of safety, 
PK, and/or PD data, as needed, to make timely decisions concerning adjustment of study 
procedures, dosing regimens, or potentially early termination of the study, certain designated 
staff at PhaseBio (e.g. study director, a single biostatistician, and bioanalytical scientist[s]) 
study drug accountability monitor, will receive unblinded data after each cohort completes 
Day 3 assessments. Except as noted above, all other members of PhaseBio will remain 
blinded. Access to the randomization code will be strictly controlled according to PPD SOPs.  
3.4.6 Treatment Compliance 
All doses of study drug, matching placebo, and ticagrelor will be administered at the clinical 
site under direct observation of clinic personnel and recorded in the eCRF.  
The date, time, and actual dose received of study drug and matching placebo infusion and 
ticagrelor dosing will be recorded on the appropriate pages of the eCRF. If a subject was 
scheduled to receive any of these drugs and did not, the reason for the missed or partial dose 
will be recorded in the eCRF pages. 
3.4.7 Breaking the Blind 
A subject may be unblinded in the event of a DLT, an SAE, or if there is a medical 
emergency when the identity of the drug must be known to properly treat a subject. A cohort 
may be unblinded to determine if dose escalation to the next dose level will or will not 
proceed. In the event of a medical emergency requiring identification of the study drug 
administered to an individual subject, the investigator will make every attempt to contact the 
medical monitor to explain the need for opening the code within 24 hours of performing that 
task. The investigator will be responsible for documenting the time, date, reason for the code 
break, and the names of the personnel involved.  


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3.4.8 Prior and Concomitant Medication 
Prior medications are defined as medications taken prior to the first dose of study medication, 
regardless of whether they are continued or not after the first dose of study medication. 
Concomitant medications are defined as medications taken on or after the first dose date of 
study medication, including those started before the first dose and continued into the 
treatment period. 
3.4.8.1 
Prior Medication and Therapies 
Information about prior medications taken by the subject within 30 days before he or she 
provides informed consent will be recorded in the subject’s eCRF. 
3.4.8.2 
Concomitant Medication and Therapies 
Subjects are prohibited from taking any additional prescription or OTC medications or 
nutritional supplements during their participation in the study (with the exception of protocol 
allowed medications, hormonal birth control and/or chronic medications). 
Paracetamol/acetaminophen or other medications may be administered at the discretion of 
the investigator at doses of up to 2 g/day. 
Subjects are prohibited from therapy with strong or moderate CYP3A inhibitors, CYP3A 
substrates with narrow therapeutic indices, or strong CYP3A inducers. A list of example 
inhibitors and inducers of CYP3A4 is presented in Appendix 7.2. 
Subjects are prohibited from taking NSAIDs (within 14 days of screening), anticoagulants, 
or other antiplatelet agents within 30 days of screening.  
Concomitant medications will be coded using the latest version of the World Health 
Organization Drug Dictionary (WHO-DD). With the exception of drug therapy specified in 
the protocol, if drug therapy is taken, a joint decision will be made by the investigator and 
the Sponsor whether to continue or discontinue the subject based on the time the 
medication was administered, its pharmacology and PK, and whether the use of the 
medication will compromise the subject’s safety or interpretation of the data. It is the 
investigator’s responsibility to ensure that details regarding the medication are accurately 
recorded in the eCRF. 
3.5 STUDY PROCEDURES 
After signing the ICF, subjects will have study procedures at the time points specified in the 
Schedule of Events (Appendix 7.1).  
Screening (Days -45 to -4) 
• 
Subjects sign informed consent 
• 
Inclusion/Exclusion criteria 


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• 
Demographics 
• 
Medical history 
• 
Urine screen, including cotinine 
• 
Urine alcohol screen 
• 
Serum pregnancy test for women of childbearing potential 
• 
Serology test 
• 
Stool occult blood test 
• 
Physical examination, full, including height, weight, and BMI calculation 
• 
Vital signs measured including SBP and DBP, oral body temperature, respiration rate 
(RR), and HR 
• 
12-lead ECG  
• 
Clinical laboratory tests including hematology, chemistry, coagulation, and urinalysis  
Check-in/Pretreatment - Baseline (Day -3) 
• 
Inclusion/Exclusion criteria 
• 
Urine drug screen, including cotinine 
• 
Urine alcohol screen 
• 
Serum pregnancy test for women of childbearing potential 
• 
Admission to study site 
• 
Physical examination, full, including weight,  
• 
Vital signs measured including SBP and DBP, oral body temperature, RR, and HR  
• 
Clinical laboratory tests including hematology, chemistry, coagulation, and urinalysis 
• 
Blood sampling for PD (LTA/PRU/VASP) 
• 
Serum immunogenicity 
• 
AEs collected 
Pretreatment - Baseline (Day -2) 
• 
Administration of high-dose ticagrelor begins in the morning, single dose oral 
ticagrelor 180 mg (2 x 90 mg), followed by oral ticagrelor 180 mg every 12 hours for 
4 additional doses through to Day 1 (2 hours before study drug is initiated; for a total 
of 5 doses of ticagrelor) 
• 
Urine sampling, PK 
• 
Blood sampling for PD (LTA/PRU/VASP) 
• 
AEs collected 
Pretreatment - Baseline (Day -1) 
• 
Inclusion/Exclusion criteria 
• 
12-lead ECG  
• 
Biomarkers 
• 
Ticagrelor administered 
• 
Clinical laboratory tests including hematology, chemistry, coagulation, and urinalysis 


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• 
AEs collected 
On-site Treatment – Randomization (Day 1) 
• 
Administration of ticagrelor 2 hours prior to study drug administration 
• 
12-lead ECG before study drug is administered 
• 
Continuous 12-lead Holter monitor placed 2 hours before administration of study drug 
will remain in place for 24 hours after initiation of study drug. Subjects should be 
resting in the supine or semi-recumbent position depending upon Dosing Memo. 
• 
Vital signs (SBP, DBP, oral body temperature, RR, HR) measured 30 to 60 minutes 
prior to and during infusion of study drug according to Schedule of Events (Appendix 
7.1)   
• 
Randomization 
• 
Administration of PB2452 or matching placebo at Hour 0 
• 
Blood sampling for PK: plasma PB2452, ticagrelor, and TAM PK, collected within 10 
minutes before initiation of PB2452 infusion at Hour 0  
• 
Blood sampling for PK: plasma PB2452, ticagrelor, and TAM PK, collected according 
to the cohort-specific Dosing Memo                                    
• 
Blood sampling for PD: LTA/PRU/VASP according to the cohort-specific 
Dosing Memo  
• 
Urine sampling (PK) 
• 
Infusion site assessment 
• 
Serum immunogenicity prior to dosing 
• 
AEs collected 
 
On-site Treatment (Day 2) 
• 
Vital signs measured 
• 
12-lead ECG  
• 
Continuous ECG recording (Holter) for ECG evaluation to remain in place for 24 
hours after initiation of study drug on Day 1 
• 
Blood sampling for plasma PB2452, ticagrelor, and TAM PK, collected according to 
the cohort-specific Dosing Memo 
• 
PK Urine sampling 
• 
Blood sampling for PD: LTA/PRU/VASP according to the cohort-specific Dosing 
Memo 
• 
Biomarkers 
• 
Infusion site assessment 
• 
Clinical laboratory tests including hematology, chemistry, coagulation, and urinalysis 
• 
AEs collected 
On-site Treatment (Day 3) 


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• 
Physical examination, brief, includes querying the subject concerning any changes 
from Baseline 
• 
12-lead ECG  
• 
Vital signs measured 
• 
Blood sampling for PK: plasma PB2452, ticagrelor, and TAM PK collected according to 
the cohort-specific Dosing Memo 
• 
Urine sampling (PK) 
• 
Blood sampling for PD: LTA/PRU/VASP according to the cohort-specific Dosing Memo 
• 
Infusion site assessment 
• 
AEs collected 
• 
Subjects discharged from site 
Out-patient, Return to Study Site, Follow-up (Day 7) 
• 
Physical examination, brief, includes querying the subject concerning any changes 
from Baseline 
• 
Vital signs measured  
• 
12-lead ECG  
• 
Blood sampling for PK: plasma PB2452, ticagrelor, and TAM PK, collected according to 
the cohort-specific Dosing Memo 
• 
Biomarkers 
• 
Serum immunogenicity 
• 
Infusion site assessment  
• 
Clinical laboratory tests including hematology, chemistry, coagulation, and urinalysis 
• 
AEs collected 
Out-patient, Return to Study Site, Follow-up, End of Study (Day 28 ±2 Days) 
• 
Serum pregnancy test 
• 
Physical examination, full, including height, weight, and BMI calculation 
• 
Vital signs measured 
• 
12-lead ECG  
• 
Blood sampling for PK: plasma PB2452, ticagrelor, and TAM PK, collected according to 
the cohort-specific Dosing Memo 
• 
Clinical laboratory tests including hematology, chemistry, coagulation, and urinalysis  
• 
Biomarkers 
• 
Serum immunogenicity 
• 
AEs collected 
3.5.1 Pharmacokinetic Sample Collection 
Samples for PK analyses should be collected after subjects has been resting supine for  
≥10 minutes. Additional details concerning the collection, preparation, and handling of PK 


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blood and urine samples and sample shipping instructions will be provided to the clinical 
site. The clinical site will store all urine and plasma samples at the designated temperatures 
until shipped to the appropriate laboratories for analysis. Back-up samples will be maintained 
by the clinical site under the same conditions or at a designated storage facility until the 
Sponsor indicates the back-up samples should be shipped to the Sponsor. 
PB2452 PK and immunogenicity analysis will be performed by:  
PhaseBio Pharmaceuticals, Inc.  
1 Great Valley Parkway, Suite 30  
Malvern, PA 19355  
Telephone: 610-981-6500  
Ticagrelor and TAM concentration analysis will be performed by:  
Covance  
1121 East 3900 South, Suite C-110 
Salt Lake City, UT 84124  
Telephone: 801-313-6450 
3.5.1.1 
Bioanalytical Methods 
Pharmacokinetic samples for total and free ticagrelor and the metabolite TAM will be 
analyzed using a validated liquid chromatography coupled with tandem mass spectrometry 
assay in human plasma. Pharmacokinetic samples for PB2452 will be analyzed using an 
immunoassay. The methods will be validated according to ICH standards and fit for purpose. 
Details of the bioanalytical methods and validation will be available in a separate 
bioanalytical report. 
3.5.1.2 
Pharmacodynamic Sample Collection 
Blood samples for PD analysis will be collected at the following times: Day -3, -2, Day 1 
(within 10 minutes prior to the initiation of study drug infusion [Hour 0] and per Dosing 
Memo), Day 2, and Day 3 if needed. 
Collection time points for each cohort will be specified in a Dosing Memo from the Sponsor 
to PPD prior to initiation of each cohort.   
Blood samples will be collected in collection tubes specific for each of the 3 PD assays. 
Specific instructions referring to the collection, processing, testing and, when applicable, the 
shipment of PD samples to CirQuest Labs, will be in the laboratory manual provided by 
CirQuest Labs and must be followed. If there is a discrepancy between the protocol and the 
lab manual, the lab manual should be followed. 
• 
LTA: 3.2% sodium citrate (blue-top) 
• 
VerifyNow® P2Y12: Greiner Bio-One Vacuette® partial fill blood collection tube 
containing 3.2% sodium citrate  


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• 
VASP: 3.2% sodium citrate (blue-top) 
3.5.2 Adverse Events 
3.5.2.1 
Adverse Event Definitions 
The investigator is responsible for reporting all AEs observed or reported during the study, 
regardless of their relationship to study drug or their clinical significance. If there is any 
doubt whether a clinical observation is an AE, the event should be reported. For the purposes 
of AE recording when relationship to study drug is assessed, study drug refers to PB2452 or 
placebo. A separate line on the eCRF is for assessing whether or not an AE is related to the 
administration of ticagrelor.  
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not it is considered drug-related. Subjects will be instructed to contact 
the investigator at any time after randomization if any symptoms develop.  
A TEAE is defined as any AE not present before exposure to study drug or any AE already 
present that worsens in intensity or frequency after exposure to study drug. 
A suspected adverse reaction is any AE for which there is a reasonable possibility the study 
drug caused the AE. For the purposes of investigational new drug (IND) safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship between the 
study drug and the AE. A suspected adverse reaction implies a lesser degree of certainty 
about causality than “adverse reaction,” which means any AE caused by a study drug.  
An adverse reaction is any AE caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions when there are reasons to conclude the drug caused the event.  
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the IB or 
at the specificity or severity that has been observed with the study drug; 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. For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the IB 
referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism 
and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the IB listed 
only cerebral vascular accidents. “Unexpected,” as used in this definition, also refers to AEs 
or suspected adverse reactions mentioned in the IB that occur with a certain class of drugs or 
as anticipated based on the pharmacological properties of the drug but are not specifically 
mentioned as having occurred with the specific drug under investigation.  
An AE or suspected adverse reaction is considered an SAE/suspected unexpected serious 
adverse reaction if, in the view of either the investigator or Sponsor, it results in any of the 
following outcomes:  


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•  Death  
•  Life-threatening AE  
•  Inpatient hospitalization or prolongation of existing hospitalization  
•  Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
•  Congenital anomaly or birth defect  
Important medical events that may not result in death, may not be life threatening, or may not 
require hospitalization may be considered serious 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 in this definition. 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 hospitalization, or the 
development of drug dependency or drug abuse.  
An AE or suspected adverse reaction is considered “life threatening” if, in the opinion of 
either the investigator or Sponsor, its occurrence places the subject at immediate risk of 
death. It does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death.  
Special attention will be given to DLTs and the MTD, if applicable. DLT is defined in Section 
3.4.2.3. The overall safety profile, including but not limited to DLTs and MTDs will be used 
in the selection of the starting dose(s) in future studies of PB2452 administered by infusion. 
3.5.2.2 
Eliciting and Documenting Adverse Events 
The investigator is responsible for ensuring that all AEs and SAEs are recorded in the eCRF 
and reported to PhaseBio Pharmaceuticals, Inc. From the time informed consent is signed 
through to completion of all study procedures and assessments at the Day 28 (±2 days) visit, 
all AEs will be assessed.  
Subjects may spontaneously report and/or will be asked a standard question to elicit any 
medically related changes in their well-being. They will also be asked if they have used any 
new medications or changed concomitant medication regimens (both prescription and 
OTC medications).  
In addition to subject observations, AEs will be documented from any data collected on the 
AE page of the eCRF (e.g., laboratory values, physical examination findings, ECG, Holter 
monitoring changes) or other documents relevant to subject safety. 
3.5.2.3 
Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page of the eCRF. 
Information to be collected includes drug treatment, type of event, time of onset, dosage, 


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investigator-specified assessment of severity and relationship to study drug, time of 
resolution of the event, seriousness, as well as any required treatment or evaluations, and 
outcome. The AEs resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications, or progression of disease states must also be reported. 
All AEs will be followed until they are resolved or stable or judged by the investigator to be 
not clinically significant (NCS). The current version of the Medical Dictionary for 
Regulatory Activities (MedDRA) will be used to code all AEs.  
Any medical condition present at the time the subject is screened but does not deteriorate 
should not be reported as an AE. However, if the condition deteriorates at any time during the 
study, it should be recorded as an AE. 
Any AE considered serious by the investigator or that meets SAE criteria (Section 3.5.2.1) 
must be reported to the Sponsor immediately (after the investigator has confirmed the 
occurrence of the SAE). The investigator will assess whether there is a reasonable possibility 
the study drug caused the SAE. The Sponsor will be responsible for notifying the relevant 
regulatory authorities of any SAE, as outlined in the US Title 21 Code of Federal Regulations 
(CFR) Parts 312 and 320. The investigator is responsible for notifying the Institutional 
Review Board (IRB) directly. 
The following contact information is to be used for SAE reporting:  
PPD Medical Monitor: Rahul Bhatnagar, MD 
PPD 7551 Metro Center Drive, Suite 300  
Austin, TX 78744  
Telephone (24 hour): 888-483-7729  
Fax: 888-529-3580  
email: rtpsafety@ppdi.com 
3.5.2.4 
Assessment of Severity 
The severity (or intensity) of an AE will be determined by the investigator and refers to the 
extent to which it affects the subject’s daily activities. Severity will be classified as mild, 
moderate, or severe using the following criteria:  
•  Mild: These events require minimal to no treatment and do not interfere with the 
subject’s daily activities.  
•  Moderate: These events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with normal 
functioning.  
•  Severe: These events interrupt a subject’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually incapacitating.  
Changes in the severity of an AE should be documented to allow assessment of the duration 
of the event at each level of intensity. An AE characterized as intermittent requires 


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documentation of onset and duration of each episode. The CTCAE v5 grading scale will be 
used by the SRC to assess all IRRs to determine whether premedication is required to 
mitigate future potential IRRs for subsequent study subjects. Additionally, CTCAE v5 will be 
used by the SRC to assess all AEs and laboratory abnormalities to determine whether a DLT 
and/or stopping criteria have been reached.  
3.5.2.5 
Assessment of Causality 
The investigator’s assessment of the relationship between an AE and study drug or ticagrelor 
is part of the documentation process but is not a factor in determining what is or is not 
reported in the study. 
The investigator will assess causality of all AEs and SAEs (i.e., whether there is a reasonable 
certainty the study drug caused the event). The relationship between an AE and an SAE to 
study drug (and ticagrelor) will be characterized using the following classifications:   
•  Unrelated: This relationship suggests there is no association between study drug (or 
ticagrelor) and the reported event.  
•  Possible: This relationship is based on evidence suggesting a causal relationship between 
the study drug (or ticagrelor) and the AE (i.e., there is a reasonable possibility the drug 
caused the event). The event follows a reasonable temporal sequence from the time of 
drug administration or the event follows a known response pattern to study drug (or 
ticagrelor) but could also have been caused by other factors.  
•  Probable: This relationship suggests a reasonable temporal sequence of the event with 
drug administration exists and, based upon the known pharmacological action of the 
drug, known or previously reported adverse reactions to the drug or class of drugs, or 
judgment based on the investigator’s clinical experience, the association of the event with 
study drug (or ticagrelor) seems likely.  
•  Definite: This relationship suggests that a definite causal relationship exists between 
study drug (or ticagrelor) administration and the AE, and other conditions (concurrent 
illness, progression/expression of disease state, or concurrent medication reaction) do not 
appear to explain the event.   
3.5.2.6 
Follow-up of Adverse Events 
All AEs must be reported in detail on the appropriate page of the eCRF and followed until it 
is resolved or stable or judged by the investigator to be NCS. 
3.5.3 Clinical Laboratory Testing 
Clinical laboratory tests will be performed by PPD Central Laboratory. Blood will be 
collected at the time points indicated in the Schedule of Events (Appendix 7.1) and will be 
prepared using standard procedures. Repeat clinical laboratory tests may be performed at the 
discretion of the investigator, if necessary, to evaluate inclusion and exclusion criteria or 


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clinical laboratory abnormalities. The clinical laboratory performing the tests will provide the 
reference ranges for all clinical laboratory parameters. 
The following clinical laboratory assessments will be performed:  
Hematology 
Complete blood count (CBC) with differential hematocrit (hct) 
hemoglobin (Hgb) 
mean corpuscular hemoglobin (MCH) 
mean corpuscular hemoglobin concentration (MCHC) 
mean corpuscular volume (MCV) 
mean platelet volume (MPV) 
platelet count 
erythrocyte (red blood cell [RBC]) count 
total and differential leukocyte (white blood cell [WBC]) count 
Serum Chemistry 
alanine aminotransferase (ALT) 
albumin 
alkaline phosphatase (ALP) 
aspartate aminotransferase (AST) 
bicarbonate 
bilirubin (total and direct) 
blood urea nitrogen (BUN) 
calcium 
chloride 
cholesterol 
 
total  
 
high-density lipoprotein (HDL) 
 
calculated low-density lipoprotein (LDL) 
creatine phosphokinase 
creatinine 
gamma-glutamyl transferase (GGT) 
glucose 
Hgb A1C 
lactate dehydrogenase (LDH) 
magnesium 
phosphorus 
potassium 
sodium 
thyroid stimulating hormone (TSH; Screening only)  
total protein 
triglycerides (repeat fasting triglyceride if TG >500) 
uric acid 
Coagulation 
activated partial thromboplastin time (aPTT) 
international normalized ratio (INR) 
partial thromboplastin time (PTT) 
prothrombin time (PT) 
Urinalysis (should be aligned to  
PPD urinalysis) 
 
 
 
 
 
appearance 
bilirubin 
color 
glucose 
ketones 
leukocyte esterase 
reflex microscopy (at Screening and Check-in only, if dipstick is 
positive for protein or blood value ≥1+); includes  


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 bacteria 
casts 
 crystals 
epithelial cells 
 RBCs 
WBCs 
 nitrites 
occult blood 
 pH  
protein 
 specific gravity (SpGr) 
turbidity 
 
 urobilinogen 
Serology 
hepatitis B surface antigen (HBsAg) 
hepatitis C virus (HCV) antibody 
human immunodeficiency virus (HIV)  
 types 1 and 2 antibodies (Screening only) 
Other analyses 
 urine drug screen (Screening and Check-in only): 
amphetamines 
barbiturates 
benzodiazepines 
cannabinoids 
cocaine 
cotinine 
methylenedioxymethamphetamine (MDMA) 
opiates 
phencyclidine 
propoxyphene 
tetrahydrocannabinol  
urine alcohol (Screening and Check-in only) 
female subjects: 
 
follicle-stimulating hormone (FSH; Screening only) 
 
serum pregnancy test (human chorionic gonadotropin  
 
 
[Screening, Check-in, and Day 28 (±2 days) only])  
 
 
Abnormal clinical laboratory values will be flagged as either high or low (or normal or 
abnormal) based on the reference ranges for each laboratory parameter. The investigator 
will determine whether any of the abnormally high or low results are CS or NCS. Clinical 
significance is defined as any variation in results that has medical relevance and may result in 
an alteration in medical care (e.g., active observation, diagnostic measures, therapeutic 
measures). If a CS change from the Screening value is noted, the CS value and etiology or 
reason for clinical significance will be documented on the AE page of the eCRF. The 
investigator will continue to monitor the subject with additional assessments until the values 
have reached either the reference range or the values at Screening or until the investigator 
determines that follow-up is no longer medically necessary. 
When schedule procedures overlap at the same time point (see Schedule of Events  
(Appendix 7.1).  there must be planning to collect the specific information within the 
designated time window. Accordingly, the importance of these procedures is: 
1.  Blood collection (whether for PD, PK, immunology, or safety) should always be collected 
at the designated time point (if possible). However, multiple collections (PD, PK, 
immunology, and safety) may be required at the same time point. Therefore, the 


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recommendation is for blood to be drawn in this order: PD, PK, immunology, and safety 
(see lab collection manual from CirQuest for additional information related to collection 
of PD samples).  
2.  The 12-lead ECG Holter monitoring has a ±10-minute window (unless otherwise 
 
designated in the Schedule of Events, [Appendix 7.1]) when this may be done, either 
 
before or after blood collection.  
3.  If time permits, vital sign measurements should be completed just prior to or just after 
 
blood collection; this may be still be done within the designated window in the Schedule 
 
of Events (Appendix 7.1). 
3.5.4 Vital Signs Measurements 
Vital signs will be measured at the time points indicated in the Schedule of Events  
(Appendix 7.1).   
Vital sign measurements will include SBP, DBP, oral body temperature, RR, and HR. The 
subject will have rested in a supine position for ≥10 minutes before all measurements are 
taken. Note: Vital signs collected during the initial 30 minutes of infusion of study drug 
require only the BP and HR. 
The investigator will determine whether any of the vital sign measurements are CS or NCS. 
Clinical significance is defined as any variation in results that has medical relevance and may 
result in an alteration in medical care (e.g., active observation, diagnostic measures, 
therapeutic measures). If a CS change from Screening values is noted, the CS value and 
reason for clinical significance will be documented on the AE page of the eCRF. The 
investigator will continue to monitor the subject with additional assessments until the value 
has reached either the reference range or the value at Screening or until the investigator 
determines follow-up is no longer medically necessary. 
3.5.5 Twelve-lead Electrocardiogram 
Twelve-lead ECGs will be obtained after the subject has rested in the supine position for ≥10 
minutes or as clinically indicated based on reported AEs or laboratory findings, as necessary. 
The investigator should review and sign the ECG for any immediate issues. 
Electrocardiogram assessments will include comments concerning whether the tracings are 
normal or abnormal, rhythm, presence of arrhythmia or conduction defects, morphology, 
and any evidence of MI, or ST-segment, T-Wave, and U-Wave abnormalities. In addition, 
measurements of these intervals will be reported: RR interval, PR interval, QRS width,  
and and QTcF  
The investigator will determine whether any of the 12-lead ECG results are CS or NCS. 
Clinical significance is defined as any variation in results that has medical relevance and may 
result in an alteration in medical care (e.g., active observation, diagnostic measures, 
therapeutic measures). If a CS change from Screening is noted, the CS value and reason for 


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CS will be documented on the AE page of the eCRF. The investigator will continue to 
monitor the subject with additional assessments until either the values have reached either 
reference range or the values at Screening or until the investigator determines follow-up is no 
longer medically necessary.  
3.5.6 Holter Monitoring (Continuous Twelve-lead ECG) 
Holter monitoring (continuous 12-lead ECG recording) for 24 hours will be performed at the 
time points indicated in the Schedule of Events (Appendix 7.1) to monitor HR and rhythm 
activity as standard safety measurements. The clinical research site will be responsible for 
providing trained study personnel for setting up and managing the Holter monitoring system 
to ensure that reports of Holter findings for each subject will be available for review at the 
safety review meeting for each cohort. The continuous ECG waveform data recorded by the 
Holter device will be stored for optional exposure-response QTc analysis. The Holter 
monitoring system used will be maintained in accordance with the clinical research site 
SOPs.  
The SRC will determine if any of the Holter findings are CS at the safety review meetings. 
Clinical significance is defined as any variation in results that has medical relevance and may 
result in an alteration in medical care (e.g., active observation, diagnostic measures, 
therapeutic measures).  
If a CS finding from the Holter report is noted, the CS findings and etiology or reason for 
clinical significance will be documented in the AE page of the eCRF. The SRC may 
recommend repeat Holter monitoring during the 28-day safety period if clinically indicated.  
3.5.7 Physical Examinations 
A physical examination will be performed at the time points indicated in the Schedule of 
Events (Appendix 7.1).   
A full physical examination will include assessment of skin, head, ears, eyes, nose, throat, 
neck, thyroid, lungs, heart, cardiovascular system, abdomen, lymph nodes, and 
musculoskeletal system/extremities.  
A brief physical examination will include assessment of skin (including any signs of 
cutaneous erythema), lungs, cardiovascular system, and abdomen (liver, spleen). Interim 
physical examinations will be performed at the discretion of the investigator, if necessary, to 
evaluate AEs or clinical laboratory abnormalities. Height and weight will be measured, and 
BMI will be calculated at Screening and at Day 28 (±2 days).  


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3.5.8 Infusion Site Assessments 
The infusion site will be examined by the investigator or designée concerning pain, 
tenderness, erythema/redness, and induration/swelling, as indicated in the Schedule of Events 
(Appendix 7.1). Infusion site reactions will be assessed according to the CTCAE v5 grading 
scale and will be recorded as AEs; these should be followed until resolution. 
3.5.9 Immunogenicity Assessments 
Immunogenicity (antibody) samples will be screened for the presence of binding anti-drug 
antibodies (ADA) at the time points indicated in the Schedule of Events (Appendix 7.1). 
Results of immunogenicity samples taken prior to administering study drug do not need to 
be available prior to dosing nor to confirm subject eligibility. A subject who tests positive for 
ADAs at the final scheduled visit (Day 28 ±2 days) will be asked to return for follow-up 
sampling approximately 3 months after the final visit and approximately every 6 months 
thereafter until ADAs no longer test positive or until levels return to a predose state. 
3.6 
STATISTICAL CONSIDERATIONS 
3.6.1 Sample Size Calculations 
The sample size (N) of up to 3 cohorts of up to 12 subjects for Part B of this study is based 
on clinical and practical considerations rather than on formal statistical power calculation. 
The sample size will provide preliminary safety, efficacy and PK information in a 
dose/regimen finding fashion.  
3.6.2 Analysis Populations 
The Safety Population will include all subjects who receive any amount of study drug.  
The PK Population will include subjects in the safety population who have ≥1 measurable 
PK concentration. 
The PD Population will include subjects in the safety population who receive ≥1 dose of 
ticagrelor and have ≥1 measurable post dose PRU value. 
3.6.3 Statistical Analysis 
Details concerning all statistical analyses will be described in a separate Statistical Analysis 
Plan (SAP). All data collected during the study will be presented in Data Listings.  
Data from subjects excluded from an analysis population will be presented in the Data 
Listings but will not be included in the calculation of summary statistics.  
Data from subjects who receive placebo will be pooled across cohorts for all presentations.  


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For categorical variables, frequencies and percentages will be presented. Continuous 
variables will be summarized using descriptive statistics (number of subjects, mean, median, 
standard deviation [SD], minimum, and maximum).  
Demographic and baseline characteristics will be summarized. The number of subjects who 
enroll in the study and the number and percentage of subjects who complete the study will be 
presented. Frequency and percentage of subjects who withdraw or discontinue from the 
study, and the reason for withdrawal or discontinuation, will also be summarized. 
3.6.3.1 
Pharmacokinetic Analyses 
Plasma concentrations will be listed and summarized descriptively (number of subjects, 
arithmetic mean, SD, coefficient of variation [CV], median, minimum, and maximum). 
Plasma concentration versus time profiles for each subject will be presented graphically. 
The mean plasma concentration versus scheduled time profiles will be presented graphically 
by dose. 
Pharmacokinetic parameters will be summarized by time point for each dose level using 
descriptive statistics (number of subjects, mean, standard deviation (SD), CV, median, 
minimum, and maximum). Geometric means will be reported for AUCs and Cmax.  
The PK parameters of PB2452, ticagrelor, and TAM will be determined with 
noncompartmental methods using Phoenix® WinNonlin® (Certara, L.P., Princeton, NJ) 
Version 6.4 or higher or SAS® Version 9.3 or higher (SAS Institute Inc., Cary, NC). Actual 
sampling times, rather than scheduled sampling times, will be used in all calculations of PK 
parameters. However, for ease of presentation, scheduled sampling times will be used to 
present results in tables, listings, and figures.  
3.6.3.2 
Pharmacodynamic Analyses 
Pharmacodynamic data will be summarized for each time point using descriptive statistics 
(number of subjects, mean, SD, CV, median, minimum, and maximum) for each treatment 
group or by cohort at each time point. Pharmacodynamic parameters will also be 
summarized . Inferential analysis maybe carried out to compare the % inhibition of PRU, 
LTA, PRI between PB2452 vs Placebo individually. However due to the limited sample size, 
efficacy analysis results will be considered descriptive.   
 
3.6.3.3 
Safety Analyses 
Adverse events will be coded by preferred term and system-organ-class (SOC) using the 
latest version of the Medical Dictionary for Regulatory Activities (MedDRA). All AE data 
will be presented in Data Listings. Treatment-emergent AEs (TEAEs) will be summarized by 


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treatment and overall, as well as by severity and relationship to study drug. All SAEs and 
AEs leading to discontinuation of study drug will be presented in the Data Listings. 
Actual values and changes from Baseline in clinical laboratory test results, vital sign 
measurements, and 12-lead ECG results will be summarized by treatment at each time point 
using descriptive statistics (number of subjects, mean, standard deviation [SD], median, 
minimum, and maximum). Clinical laboratory test results, vital sign measurements, 12-lead 
ECG results, Holter monitor results, immunogenicity results, and physical examination 
findings will be presented in Data Listings. 
3.6.4 Handling of Missing Data 
Missing PD data will not be imputed. Missing safety data will not be imputed except for the 
sake of determining TEAE and prior/concomitant medicine.  
For PK data, concentrations below the limit of quantification (BLQ) will be treated as zero 
for descriptive statistics. Mean BLQ concentrations will be presented as BLQ, and the SD 
and CV will be reported as not applicable. Missing concentrations will be excluded from the 
calculations. 
For the PK analysis, BLQ values will be treated as zero with the exception that a BLQ value 
between 2 quantifiable concentrations will be set as missing. Missing concentrations will be 
treated as missing from the PK parameter calculations. If consecutive BLQ concentrations 
are followed by quantifiable concentrations in the terminal phase, those concentrations after 
BLQ concentrations will be treated as missing. 
3.6.5 Interim Analyses 
There is no interim analysis planned for this study. 
3.7 DATA QUALITY ASSURANCE 
This study will be conducted using quality processes described in applicable procedural 
documents. The quality management approach to be implemented will be documented and 
will comply with current ICH guidance on quality and risk management. All aspects of the 
study will be monitored for compliance with applicable government regulatory requirements, 
current GCP, the protocol, and SOPs. The monitor will maintain current personal knowledge 
of the study through observation, review of study records and source documents, and 
discussion of the conduct of the study with the investigator and staff.  
Electronic CRFs and electronic data capture will be used. The electronic data capture system 
is validated and compliant with US Title 21 CFR Part 11. Each person involved with the 
study will have an individual identification code and password that provides record 


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traceability. There may be an internal quality review audit of the data and additional reviews 
by the clinical monitor. 


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4. 
INVESTIGATOR OBLIGATIONS 
Administrative items provided in this section are meant to guide the investigator in the 
conduct of the study and may be subject to change based on industry and government SOPs, 
working practice documents, or guidelines. Changes will be reported to the IRB but will not 
result in protocol amendments. 
4.1 CONFIDENTIALITY 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without written 
permission of the subject (or the subject’s legal guardian), except as necessary for monitoring 
and auditing by the Sponsor, designee, the US Food and Drug Administration, or the IRB.  
The investigator and all employees and coworkers involved in this study may not disclose or 
use for any purpose other than performance of the study, any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the Sponsor or designee must be obtained for the 
disclosure of any said confidential information to other parties. 
4.2 INSTITUTIONAL REVIEW 
Federal regulations and ICH guidelines require approval to be obtained from an IRB before 
human subjects participate in research studies. Before study onset, the protocol, ICF, 
advertisements to be used for recruitment of study subjects, and any other written 
information concerning this study must be provided to the subject must be approved by the 
IRB. Documentation of all IRB approvals and of the IRB compliance with the ICH E6(R2): 
GCP will be maintained by the site and will be available for review by the Sponsor or 
designee. All IRB approvals should be signed by the IRB chairman or designee and must 
identify the IRB name and address, the clinical protocol by title or protocol number or both, 
and the date approval or a favorable opinion was granted. 
4.3 SUBJECT CONSENT 
Written informed consent in compliance with US Title 21 CFR Part 50 will be obtained from 
each subject before he or she enters the study or before any unusual or non-routine procedure 
is performed that involves risk to the subject. If any institution-specific modifications to 
study-related procedures are proposed or made by the site, the consent should be reviewed by 
the Sponsor or designee or both before IRB submission. Once reviewed, the investigator will 
submit the ICF to the IRB for review and approval before the start of the study. If the ICF is 
revised during the course of the study, all active participating subjects must sign the 
revised form. 


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Before recruitment and enrollment, each prospective subject will be given a full explanation 
of the study and be allowed to read the approved ICF. Once the investigator is assured the 
subject understands the implications of participating in the study, the subject will be asked to 
give his/her consent to participate in the study by signing the ICF. A copy of the ICF will be 
provided to the subject/legal guardian. 
4.4 STUDY REPORTING REQUIREMENTS 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the time line and method outlined in this protocol. In addition, the investigator agrees to 
submit annual reports to his/her IRB, as appropriate. 
4.5 FINANCIAL DISCLOSURE AND OBLIGATIONS 
The investigator is required to provide financial disclosure information to allow the Sponsor 
to submit the complete and accurate certification or disclosure statements required under US 
Title 21 CFR Part 54. In addition, the investigator must provide the Sponsor with a 
commitment to promptly update this information if any relevant changes occur during the 
course of the investigation and for  
1 year following completion of the study. 
Neither the Sponsor nor PPD is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the Sponsor nor PPD is financially responsible for 
further treatment of the disease under study. 
4.6 INVESTIGATOR DOCUMENTATION 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R2) 
Section 8.2 and US Title 21 of the CFR by providing the following essential documents, 
including but not limited to:  
•  IRB approval 
•  The original signed investigator agreement page of the protocol 
•  Form FDA 1572, fully executed, and all updates on a new fully executed Form FDA 1572  
•  Curriculum vitae for the principal investigator and each sub-investigator listed on  
Form FDA 1572. Current licensure must be noted on the curriculum vitae. CVs will be 
signed and dated by the principal investigators and sub-investigators at study start-up, 
indicating they are accurate and current.  
•  Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under US Title 21 CFR Part 54. In 
addition, the investigators must provide to the Sponsor a commitment to promptly update 
this information if any relevant changes occur during the course of the investigation and 
for 1 year after the completion of the study.  


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•  An IRB-approved ICF, samples of site advertisements for recruitment for this study, 
and any other written information about this study to be provided to the subject or 
legal guardians  
•  Laboratory certifications and reference ranges for any local laboratories used by the site, 
in accordance with US Title 42 CFR Part 493. 
4.7 STUDY CONDUCT 
The investigator will agree to perform all aspects of this study in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, ICH E6(R2): GCP, the 
protocol, and all national, state, and local laws or regulations. 
4.8 DATA COLLECTION 
4.8.1 Case Report Forms and Source Documents 
Site personnel will maintain source documentation and enter subject data into the eCRF as 
accurately as possible and will rapidly respond to any reported discrepancies.  
Electronic CRFs and electronic data capture will be used. The electronic data capture system 
is validated and compliant with US Title 21 CFR Part 11. Each person involved in the study 
will have an individual identification code and password that provides record traceability. 
Therefore, the system, and subsequently any investigative reviews, can identify coordinators, 
investigators, and individuals who have entered or modified records, as well as the time and 
date of any modifications. There may be an internal quality review audit of the data and 
additional reviews by the clinical monitor. 
Each eCRF is presented as an electronic copy, allowing data entry by site personnel, who can 
add and edit data, add new subjects, identify and resolve discrepancies, and view records. 
This system provides immediate direct data transfer to the database, as well as immediate 
detection of discrepancies, enabling site coordinators to resolve and manage discrepancies in 
a timely manner.  
Paper copies of the eCRFs and other database reports may be printed and signed by the 
investigator. This system provides site personnel, monitors, and reviewers with access to 
hardcopy audits, discrepancy reviews, and investigator comment information. 
4.9 ADHERENCE TO PROTOCOL 
The investigator will agree to conduct the study as outlined in this protocol, in accordance 
with ICH E6(R2) and all applicable guidelines and regulations. 
4.10 REPORTING ADVERSE EVENTS 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the time line and method outlined in this protocol. In addition, the investigator agrees to 


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submit annual reports to his/her IRB, as appropriate. The investigator also agrees to provide 
the Sponsor with an adequate report, if applicable, shortly after completion of the 
investigator’s participation in the study. 
4.11 INVESTIGATOR’S FINAL REPORT 
Upon completion of the study, the investigator, when applicable, should inform the 
institution; the investigator/institution should provide the IRB with a summary of the study 
outcome and provide the Sponsor and regulatory authority(ies) with any reports required. 
4.12 RECORD RETENTION 
Essential documents should be retained until ≥2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or ≥2 years have elapsed since the formal discontinuation of 
clinical development of PB2452. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement with the 
Sponsor. It is the Sponsor’s responsibility to inform the investigator/institution when these 
documents no longer need to be retained. 
4.13 PUBLICATIONS 
After completion of the study, the study data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the Sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publications to which 
it will be submitted, and any other related issues. The Sponsor has final approval authority 
over all such issues.  
Data from this study are the property of the Sponsor and cannot be published without their 
prior authorization; however, data and any publication thereof will not be unduly withheld. 


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5. 
ETHICS 
5.1 ETHICAL CONDUCT OF THE STUDY 
PhaseBio Pharmaceuticals, Inc and designées carried out all aspects of this study in 
accordance with the US Code of Federal Regulations (CFR) governing the protection of 
human subjects (21 CFR 50), IRBs (21 CFR 56), and the obligations of clinical investigators 
(21 CFR 312). U.S. Title 21 CFR on Good Clinical Practice (GCP) is consistent with 
principles set forth by the Declaration of Helsinki and the International Conference on 
Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for 
Human Use. The study will be registered on Clinicaltrials.gov in accordance with Section 
801 of the FDA Amendments Act of 2007 (FDAAA). 
All Investigators were required to review and sign a Food and Drug Administration (FDA) 
Form 1572 and Sponsor-provided Study Operations Manual which described the 
Investigator’s responsibility according to ICH/GCP guidelines. 
5.2 INSTITUTIONAL REVIEW BOARD 
The study protocol and amendments, ICFs, advertisements, and other information given to 
study subjects and/or their guardians will be reviewed and approved by the Institutional 
Review Board (IRB) of each study center prior to use. Each investigator will be responsible 
for informing the IRB of the progress of the study and submitting annual reports. This study 
will be conducted in the US, North America.  


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6. 
STUDY MANAGEMENT 
6.1 MONITORING 
6.1.1 Monitoring the Study 
The clinical monitor, as a representative of the Sponsor, is obligated to follow the study 
closely. In doing so, the monitor will visit the investigator and study site at periodic intervals 
in addition to maintaining necessary telephone and email contact. The monitor will maintain 
current personal knowledge of the study through observation, review of study records and 
source documents, and discussion of the conduct of the study with the investigator and staff. 
All aspects of the study will be carefully monitored by the Sponsor or designee in 
compliance with applicable government regulation with respect to current ICH E6(R2) 
guidelines and SOPs. 
6.1.2 Inspection of Records 
The investigator and institution involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study records. 
In the event of an audit, the investigator agrees to allow the Sponsor, their representatives, 
the FDA, or other regulatory agency access to all study records.  
The investigator should promptly notify the Sponsor and study site(s) of any audits 
scheduled by any regulatory authorities and promptly forward to the Sponsor copies of any 
audit reports received. 
6.2 MANAGEMENT OF PROTOCOL AMENDMENTS  
AND DEVIATIONS 
6.2.1 Modification of the Protocol 
Any changes in this clinical study, except those necessary to remove an apparent immediate 
hazard to a subject, must be reviewed and approved by the Sponsor or designee. 
Amendments to the protocol must be submitted in writing to the investigator’s IRB and 
approved before subjects are enrolled into an amended protocol. 
6.2.2 Protocol Deviations  
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from or a change to the protocol without prior IRB approval to eliminate an 
immediate hazard to study subjects. As soon as possible after such an event, the implemented 
deviation or change, the reasons for it, and any proposed protocol amendments should be 


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submitted to the IRB for review and approval, to the Sponsor for agreement, and to the 
regulatory authorities, if required.  
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. An important protocol deviation (sometimes referred to as 
a protocol violation or a major protocol deviation) is a subset of protocol deviations that 
might significantly affect the reliability of study data or might significantly affect subject 
safety. An important deviation can include nonadherence to inclusion or exclusion criteria or 
nonadherence to FDA regulations or ICH E6(R2) guidelines.  
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. The investigator will be notified by the monitor of deviations in writing. 
The IRB should be notified of protocol deviations, if appropriate, in a timely manner. 
6.3 STUDY TERMINATION 
Although the Sponsor has every intention of completing the study, the Sponsor reserves the 
right to discontinue at any time for clinical or administrative reasons.  
The EOS is defined as the date on which the last subject completes the last visit; this includes 
the EOS visit and any additional long-term follow-up required for monitoring the resolution 
of an AE; the finding may be appended to the Clinical Study Report CSR. 
6.4 FINAL REPORT 
Whether the study is completed or prematurely terminated, the Sponsor will ensure CSRs are 
prepared and provided to regulatory agency(ies) according to the applicable regulatory 
requirement(s). The Sponsor will also ensure CSRs in marketing applications meet the 
standards of the ICH E3: Structure and Content of Clinical Study Reports.  
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for approval of the CSR. The investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have an opportunity to review 
complete study results. 
Upon completion of the CSR, the investigator(s) will be provided with the final approved 
CSR, as appropriate. 
 
 


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7. 
APPENDICES 
This section presents the following: 
Appendix 7.1 Schedule of Events 
Appendix 7.2 Examples of Inhibitors and Inducers of CYP3A4 
Appendix 7.3 Definition and Management of Anaphylaxis Summary Report 
Appendix 7.4 Clinical Criteria for Diagnosing Anaphylaxis 
 
 
 


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7.1 PART B SCHEDULE OF EVENTS 
Procedure 
Screeninga 
Check-in/ 
Pretreatment 
Rand 
 
Subjects 
Discharged FUP 
FUP/End 
of Study 
(EOS) 
Study Day(s) 
–45 to –4 
–3 
-2 
–1 
1 
2 
3 
7 
28 (±2) 
Sign informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Urine drug screen  
X 
X 
 
 
 
 
 
 
 
Urine alcohol screen 
X 
X 
 
 
 
 
 
 
 
Serum pregnancy testb 
X 
X 
 
 
 
 
 
 
X 
Serology testing 
X 
 
 
 
 
 
 
 
 
Stool occult blood test 
X 
 
 
 
 
 
 
 
 
Admission to study site clinic 
 
X 
 
 
 
 
 
 
 
Physical examinationc,d 
Xc 
Xc 
 
 
 
 
Xd 
Xd 
Xc 
Vital sign measurementse 
X 
X 
 
 
X 
X 
X 
X 
X 
12-lead ECGf 
X 
 
 
X 
X 
X 
X 
X 
X 
Continuous ECG recording (Holter)  
 
 
 
 
X 
Xi 
 
 
 
Clinical laboratory testing 
X 
X 
 
X 
 
X 
 
X 
X 
Randomization 
 
 
 
 
X 
 
 
 
 
Drug administration 
 
 
 
 
 
 
 
 
 
Ticagrelorg 
 
 
X 
X 
X 
 
 
 
 
PB2452/Placeboh 
 
 
 
 
X 
 
 
 
 
PK blood sampling* 
 
 
 
 
 
 
 
 
 
Plasma PB2452 
 
 
 
 
X 
X 
X 
X 
X 
Plasma ticagrelor/TAM 
 
 
 
 
X 
X 
X 
X 
X 
Free plasma ticagrelor/TAM 
 
 
 
 
X 
X 
X 
X 
X 
PK urine sampling** 
 
 
X 
 
X 
X 
X 
 
 
PD sampling (LTA/PRU/VASP)j 
 
X 
X 
 
X 
X 
X 
 
 
 Biomarkers* 
 
 
 
X 
 
X 
 
X 
X 
Infusion site assessmentk 
 
 
 
 
X 
X 
X 
X 
 
Serum immunogenicity 
 
X 
 
 
Xl 
 
 
X 
Xl 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
Discharge from clinical site 
 
 
 
 
 
 
Xm 
 
 
 
Abbreviations: ADA=anti-drug antibody; BMI=body mass index; DBP=diastolic blood pressure; 
ECG=electrocardiogram; EOS=end of study; FUP=follow-up; HR=heart rate; LTA=light transmittance 
aggregometry; PD=pharmacodynamics; PK=pharmacokinetics; PRU=P2Y12 reaction units; QD=once daily; 
Rand=Randomization; RR=respiratory rate; SBP=systolic blood pressure; TAM=ticagrelor active metabolite 
AR-C124910XX; VASP=vasodilator-stimulated phosphoprotein 
(Continued) 
Schedule of Events (Cohort 1) (continued) 


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* 
Modifications to this schedule may be made in a Dosing Memo from Sponsor to site prior to initiation of 
each cohort.  
** Modifications to this schedule may be made in a Dosing Memo from Sponsor to site prior to initiation of 
each cohort.  
a=Screening Period=Days -45 to -4  
b=Serum pregnancy test for women of childbearing potential  
c=A full physical examination is conducted  at Screening, Day -3 and Day 28. Height and BMI calculation are 
completed at Screening and Day 28 only. Weight is collected at Screening, Day -3 and Day 28.  
d=Brief physical examination (querying the subject concerning any changes from Baseline) 
e=Vital sign measurements (SBP and DBP, oral body temp, RR, and HR) will be collected at screening, check-
in, before dosing (30 to 60 minutes prior to the initiation of the study drug infusion) and at 10, 20, 30, 45, 60 
min, 24 and 48 hours following initiation of study drug. Vital Signs are also collected on Day 7 and 28.  Vital 
signs at 10, 20 and 30 minutes following infusion require only SBP and DBP, and HR. 
f=12-lead ECGs will be obtained at Screening before initiation of PB2452 (or placebo), pre-treatment Day -1, 
and on treatment Days 1, 2, 3, 7 and 28. The specific time points for 12-lead ECG on Day 1 and 2 will be pre-
dose, after bolus, end of infusion, and after 24 hours. If there is change to this schedule it will be 
communicated in a Dosing Memo. ECGs will be collected anytime on Day 3, 7, and 28.  
g=Beginning in the morning on Day –2, a dose of oral ticagrelor 180 mg will be given, followed by oral 
ticagrelor 180 mg every 12 hours for 4 additional doses through to Day 1 (2 hours before study drug is 
initiated; this will be 5 total doses of ticagrelor). 
h=PB2452 (or placebo) will be administered at Hour 0 of Day 1. 
i=Continuous 12-lead Holter monitor placed 2 hours before administration of study drug will remain in place 
for 24 hours after initiation of study drug (to Day 2). The resting schedule for Holter monitors will be aligned 
with PK draws 
j=PD samples may be tested for additional hematologic biomarkers, such as P-selectin. 
k=Infusion site assessments will be performed for all subjects within 15 minutes before initiation of PB2452 (or 
placebo) infusion at Hour 0, and at 1, 3, 24, and 48hours after initiation of PB2452 (or placebo) infusion, and 
on Day 7.   
l=Subjects may be required to return to the site for collection of additional follow-up samples, if the sample 
collected at Day 28 tests positive for treatment-emergent ADAs. These visits may occur approximately 3 
months after the final study visit and approximately every 6 months thereafter or until antibody levels return 
to Baseline level.. 
 
 
 


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Schedule of Events (Cohort 1) (continued) 
m=Subjects are discharged from the clinic on Day 3. Subjects are permitted, if necessary/convenient to the 
subject to remain housed at PPD following discharge through Day 7 visit. There are no study assessments to 
be completed on Days 4, 5, and 6.   
 
 


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7.2 EXAMPLES OF INHIBITORS AND INDUCERS OF CYP3A4 
Strong Inhibitors (≥5-fold increase in AUC or >80% decrease in oral clearance):  
Boceprevir  
Clarithromycin  
Conivaptan  
Grapefruit juice  
Indinavir  
Itraconazole  
Ketoconazole  
Lopinavir/ritonavir  
Mibefradil  
Nefazodone  
Nelfinavir  
Posaconazole  
Ritonavir  
Saquinavir  
Telaprevir  
Telithromycin  
Voriconazole  
 
Moderate Inhibitors (>2-fold and <5-fold increase in AUC) 
aprepitant 
cimetidine 
ciprofloxacin,  
clotrimazole 
crizotinib 
cyclosporine 
dronedarone 
erythromycin 
fluconazole 
fluvoxamine 
imatinib 
tofisopam 
verapamil 
diltiazem 
 


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Strong Inducers (≥80% decrease in AUC):  
Avasimibe  
Carbamazepine  
Phenytoin  
Rifampin  
St John’s wort  
 
Note: This list is not all-inclusive. Please refer to the following website for further guidance: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers 
 
 
 
 


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7.3 COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS (CTCAE) 
 
Summary Report – Second National Institute of Allergy and Infectious 
 
Disease/Food Allergy, and Anaphylaxis Network Symposium 
The common terminology criteria for adverse events, V5, can be found at the following link:  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
 
Clinical criteria for diagnosing anaphylaxis are presented in Appendix  7.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.4 CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS 
Anaphylaxis is highly likely when any ONE of the following 3 criteria is fulfilled: 
1.  Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) AND 
AT LEAST ONE OF THE FOLLOWING:  
 
a.  Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced  
 
 
peak expiratory flow [PEF], hypoxemia)  
 
b.  Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (e.g.,  
 
 
hypotonia [collapse], syncope, incontinence)  
2.  Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours):  
 
 
a.  Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen  
 
 
lips-tongue-uvula)  
 
b.  Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced  
 
 
PEF, hypoxemia)  
 
c.  Reduced BP or associated symptoms (e.g., hypotonia [collapse],  
 
 
syncope, incontinence)  
 
d.  Persistent gastrointestinal (GI) symptoms (e.g., crampy abdominal pain, vomiting)  
3.  Reduced BP after exposure to known allergen for that patient (minutes to several hours):  
 
 
a.  Infants and children: low systolic blood pressure (SBP; age specific) or >30% decrease 
 
 
 
in SBP*  
 
 
b.  Adults: SBP <90 mm Hg or >30% decrease from that person’s Baseline 
*   Low SBP for children from 1 month to 1 year is defined as <70 mm Hg (<70  mmHg + [2 x age]); 
 
<70  mmHg + [2 x age] from 1 to 10 years; and <90 mm Hg from 11 to 17 years.  
 
 


PhaseBio Pharmaceuticals, Inc 
 
 
 
 
 
 
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Protocol No. PB2452-PT-CL-0002                                                        Clinical Study Protocol 
 
   Page 74 
8. 
REFERENCES 
Armstrong D, Summers C, Ewart L, Nylander S, et al. Characterization of the adenosine 
pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside 
transporter 1. Journal of Cardiovascular Pharmacology and Therapeutics 2014;19(2):209-19. 
Baharoglu MI, Cordonnier C, Al-Shahi SR, de Gans K, et al. Platelet transfusion versus standard care 
after acute stroke due to spontaneous cerebral haemorrage associated with antiplatelet therapy 
(PATCH): a randomized, open-label, phase 3 trial. Lancet 2016 Jun 25;387(10038):2605-13. 
Bell AD, Roussin A, Cartier R, Chan WS, et al. The use of antiplatelet therapy in the outpatient 
setting: Canadian Cardiovascular Society guidelines. Can J Cardiol 2011;27(2):208-21. 
Beshay JE, Morgan H, Madden C, Yu W, et al. Emergency reversal of anticoagulation and 
antiplatelet therapies in neurosurgical patients. J Neurosurg 2010 Feb;112(2):307-18. 
Catteneo M, Schulz R, Nylander S. Adenosine-mediated effects of ticagrelor: evidence and potential 
clinical relevance. JACC 2014 Jun;63(23):2503-9. 
Dalén M, Ivert T, Lindvall G, van der Linden J. Ticagrelor-associated bleeding in a patient 
undergoing surgery for acute type A aortic dissection. J Cardiothorac Vasc Anesth 2013 
Oct;27(5):e55-7. 
Doessegger L, Banholzer ML. Clinical development methodology for infusion-related reactions with 
monoclonal antibodies. Clin Transl Immunology 2015 Jul 17;4(7):e39. 
Dornbos III D, Katz JS, Youssef P, Powers CJ, et al. Glycoprotein IIb/IIIa Inhibitors in Prevention 
and Rescue Treatment of Thromboembolic Complications during Endovascular Embolization of 
Intracranial Aneurysms. Neurosurgery 2018 Mar;82(3):268-77. 
FDA Website for complete lists of strong inhibitors and strong inducers of CYP3A4: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeli
ng/ucm093664.htm 
Fitchett DH, Theroux P, Brophy JM, Cantor WJ, et al. Assessment and management of acute 
coronary syndromes (ACS): a Canadian perspective on current guideline-recommended treatment--
part 1: non-ST-segment elevation ACS. Can J Cardiol 2011 Nov-Dec;27 Suppl A:S387-S401. 
Godier A, Taylor G, Gaussem P. Inefficacy of platelet transfusion to reverse ticagrelor. NEJM 2015 
Jan 8;372(2):196-7. 
ICH E3: Structure and Content of Clinical Study Reports 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_Guideline
.pdfMaillard J, Cartier Faessler V, Fontana P, Bonhomme F. Lack of effect of platelet transfusions 
and desmopressin on intracranial bleeding in a patient receiving ticagrelor. A Case Rep 2015 Jun 
15;4(12):169–71. 
National Cancer Institute. Common Terminology Criteria for Adverse Events v5.0 (CTCAE). 
Bethesda, MD: National Cancer Institute, November 27, 2017. Available at 


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Protocol No. PB2452-PT-CL-0002                                                        Clinical Study Protocol 
 
   Page 75 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50. Accessed 
March 16, 2018. 
Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G, et al. Inhibition of platelet 
aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in 
patients with acute coronary syndromes. JACC 2007 Nov 6;50(19):1852-6. 
Storey RF. New P2Y12 inhibitors. Heart 2011;97:1262-7. 
Taylor G, Osinski D, Thevenin A, Devys JM. Is platelet transfusion efficient to restore platelet 
reactivity in patients who are responders to aspirin and/or clopidogrel before emergency surgery? J 
Trauma Acute Care Surg 2013 May;74(5):1367-9. 
Teng R, Carlson GF, Nylander S, Andersson TL. Effects of autologous platelet transfusion on platelet 
inhibition in ticagrelor-treated and clopidogrel-treated subjects. J Thromb Haemost. 2016 Dec 14; 
14(12):2342-52. 
 

SAP_001.pdf: 
 
Confidential 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
AUTHOR(S): 
Sulagna Sarkar 
SAP VERSION: 
Draft 2.0 
DATE OF SAP VERSION 
13 March 2020 
 
 
SPONSOR: 
PhaseBio Pharmaceuticals Inc. 
1 Great Valley parkway, Suite 30, Malvern, PA, USA 
19355 
Tel: 1-610-981-6500 
 
STUDY TITLE: 
A Phase 2A, Randomized, Double-blind, Placebo-
controlled, Single Dose, Sequential Group Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, 
and Pharmacodynamics of PB2452 with Ticagrelor 
Pretreatment in Older (age 50 to 64 years) and 
elderly (age 65 to 80 years) subjects (Part A), and a 
High Dose Ticagrelor Pretreatment in Healthy Subjects 
aged 15-50 (Part B)  
PHASE OF STUDY: 
Phase 2A 
PROTOCOL NUMBER: 
PB2452-PT-CL-0002:  Part A and Part B 
PROTOCOL VERSION/DATE: 
Protocol version 2.0 / 25 July 2019 (Part A)  
Protocol version 1.0 / 25 July 2019 (Part B) 
 
 
 
 
 


3/20/2020


PhaseBio Pharmaceuticals, Inc. 
 
Draft Statistical Analysis Plan, Draft Version 2.0 
PB2452-PT-CL-0002 
 
Date Issued: 13MAR2020 
 
  
 
  III 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... V 
1. 
INTRODUCTION ............................................................................................................ 1 
2. 
OBJECTIVES ................................................................................................................... 1 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 2 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 2 
3.2. STUDY ENDPOINTS ............................................................................................................. 4 
3.2.2. 
Pharmacokinetic Endpoints ........................................................................................ 5 
3.2.3. 
Pharmacodynamic Endpoints ..................................................................................... 5 
3.3. TREATMENTS ...................................................................................................................... 6 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 7 
4.1. SAMPLE SIZE ...................................................................................................................... 8 
4.2. RANDOMIZATION, STRATIFICATION, AND BLINDING .......................................................... 8 
4.3. REPLACEMENTS .................................................................................................................. 9 
4.4. HANDLING OF MISSING DATA ............................................................................................. 9 
4.5. ANALYSIS POPULATIONS .................................................................................................. 10 
4.5.1. 
Safety Population ...................................................................................................... 10 
4.5.2. 
Pharmacokinetic (PK) Population ............................................................................ 10 
4.5.3. 
Modified Intention-to-Treat (mITT) Population ....................................................... 10 
5. 
SUBJECT DISPOSITION ............................................................................................. 10 
5.1. DISPOSITION ..................................................................................................................... 10 
5.2. PROTOCOL DEVIATIONS AND ELIGIBILITY CRITERIA DEVIATIONS ................................... 11 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 11 
6.1. DEMOGRAPHICS ................................................................................................................ 11 
6.2. MEDICAL HISTORY ........................................................................................................... 11 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 11 
7.1. PRIOR AND CONCOMITANT MEDICATIONS ........................................................................ 12 
7.2. MEDICAL AND SURGICAL PROCEDURES ........................................................................... 12 
7.3. STUDY TREATMENTS ........................................................................................................ 12 
8. 
SAFETY ANALYSIS ..................................................................................................... 12 
8.1. ADVERSE EVENTS ............................................................................................................. 12 
8.1.1. 
Incidence of Adverse Events ..................................................................................... 13 
8.1.2. 
Relationship of Adverse Events ................................................................................. 13 
8.1.3. 
Severity of Adverse Event.......................................................................................... 14 
8.1.4. 
Dose Limiting Toxicities ........................................................................................... 14 
8.1.5. 
Infusion Site Assessments .......................................................................................... 14 
8.1.6. 
Serious Adverse Events ............................................................................................. 14 
8.1.7. 
Adverse Events Leading to Early Discontinuation ................................................... 15 


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  IV 
8.2. CLINICAL LABORATORY EVALUATIONS ........................................................................... 15 
8.3. VITAL SIGN MEASUREMENTS ........................................................................................... 17 
8.4. TWELVE-LEAD ELECTROCARDIOGRAM ............................................................................ 18 
8.5. HOLTER MONITORING (CONTINUOUS TWELVE-LEAD ELECTROCARDIOGRAM) ................ 19 
8.6. PHYSICAL EXAMINATION AND PHYSICAL MEASUREMENT ............................................... 19 
9. 
IMMUNOGENICITY ASSESSMENTS....................................................................... 19 
10. 
PHARMACOKINETICS ............................................................................................... 20 
10.1. 
PLASMA PHARMACOKINETICS ....................................................................................... 20 
10.1.1. 
Plasma Pharmacokinetics Concentration ............................................................. 20 
10.1.2. 
Plasma Pharmacokinetic Parameters ................................................................... 21 
10.2. 
URINE PHARMACOKINETICS .......................................................................................... 23 
10.2.1. 
Urine pharmacokinetic Concentrations ................................................................ 23 
10.2.2. 
Urine Parameters .................................................................................................. 23 
11. 
PHARMACODYNAMICS ............................................................................................ 23 
11.1. 
PHARMACODYNAMIC DATA .......................................................................................... 23 
11.2. 
10.2 PHARMACODYNAMIC PARAMETERS ...................................................................... 25 
12. 
INTERIM ANALYSIS ................................................................................................... 26 
13. 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 26 
14. 
REFERENCES ................................................................................................................ 27 
15. 
APPENDICES ................................................................................................................. 28 
15.1. 
SCHEDULE OF STUDY PROCEDURES .............................................................................. 28 


PhaseBio Pharmaceuticals, Inc. 
 
Draft Statistical Analysis Plan, Draft Version 2.0 
PB2452-PT-CL-0002 
 
Date Issued: 13MAR2020 
 
  
 
 
 V
List of Abbreviations 
AA 
arachidonic acid 
ACS 
acute coronary syndrome 
ADA 
anti-drug antibodies 
ADP 
adenosine diphosphate 
AE 
adverse event 
ASA 
acetylsalicylic acid, aspirin 
AUC 
area under the plasma concentration versus time curve 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CLr 
renal clearance 
Cmax 
observed maximum plasma concentration 
CrCl 
creatinine clearance 
CS 
clinically significant 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DAPT 
dual antiplatelet therapy 
DBP 
diastolic blood pressure 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
FA 
final-extent aggregation 
HR 
heart rate 
IV 
intravenous 
LTA 
light transmittance aggregometry 
MA 
maximal-extent aggregation 
MedDRA 
MI 
Medical Dictionary FOR Regulatory Activities 
myocardial infarction 
NCS 
not clinically significant 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PRI 
platelet reactivity index 
PRU 
P2Y12 reaction units 
PT 
prothrombin time 
QD 
once daily 
QTcB 
Bazett’s-corrected QT interval 
QTcF 
Fridericia-corrected QT interval 
RBC 
red blood cell(erythrocyte) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SRC 
Safety Review Committee 
t1/2 
terminal elimination half-life 


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Date Issued: 13MAR2020 
 
  
 
  VI 
TAM 
ticagrelor active metabolite AR-C124910XX 
TEAE 
treatment-emergent adverse event 
Tmax 
time to reach the observed maximum (peak) concentration 
TRAP 
thrombin receptor activating peptide 
VASP 
vasodilator-stimulated phosphoprotein 
WBC 
white blood cell 
 
 
 


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Date Issued: 13MAR2020 
 
  
 
 
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1. Introduction 
 
PB2452 is a specific and selective recombinant human neutralizing antibody IgG1λ monoclonal 
fragment antigen-binding antibody that binds with high affinity to ticagrelor and to 
AR-C124910XX (TAM), the major active circulating ticagrelor metabolite. PB2452 is intended 
to reverse the antiplatelet effects of ticagrelor in patients who experience major bleeding or who 
require urgent surgery or intervention. Platelet transfusion has appeared to be inferior to standard 
care for those taking antiplatelet therapy.(Baharoglu, 2016)  
 
This is a two-part Phase 2A, randomized, double-blind, placebo-controlled, single dose, 
sequential group study to evaluate the safety, tolerability, PK, and PD of PB2452 vs matching 
placebo. Part A investigates various dose regimens of PB2452 administered intravenously to 
older (ages 50 to 64 years) and elderly (ages 65 to 80 years) male and female subjects pretreated 
with ticagrelor + aspirin (ASA) as part of dual antiplatelet therapy. Part B investigates various 
dose levels and regimens of PB2452 administered to healthy male and female subjects (ages 18-
50) pretreated with a high dose of ticagrelor alone (180 mg) twice daily (BID).  
This statistical analysis plan (SAP) is written according to protocol PB2452-PT-CL-0002, 
version Final 2.0 (Part A) and Final 1.0 (Part B), both dated 29 July, 2019. This SAP will cover 
the final analysis for both parts, Part A and B, of the study. 
 
2. Objectives 
 
2.1 Primary Objectives: 
 
• 
To evaluate the safety and tolerability of intravenous (IV) doses of PB2452 vs matching 
placebo with oral ticagrelor plus ASA pretreatment in older (age 50 to 64 years) and elderly 
(age 65 to 80 years) male and female subjects in Part A, and, to evaluate the safety and 
tolerability of intravenous (IV) doses of PB2452 vs matching placebo with a High Dose of 
oral ticagrelor plus ASA pretreatment in healthy patients (age 15 to 50) in Part B 
• 
To assess the efficacy/PD of IV doses of PB2452 vs matching placebo in reversing ticagrelor 
antiplatelet activity by measuring P2Y12 reaction units (PRU) with VerifyNow® P2Y12 assay 
in older (age 50 to 64 years) and elderly (age 65 to 80 years) subjects, and in healthy patients 
(age 15 to 50) with a High Dose of oral ticagrelor plus ASA pretreatment in Part B 
 
2.2 Secondary Objectives: 
 
• 
To determine the PK of PB2452 in the presence of ticagrelor, for each of Part A and B 
• 
To determine the PK of ticagrelor and TAM in the presence of PB2452, for each of Part A 
and B 
• 
To evaluate the effect of PB2452 on ticagrelor antiplatelet activity by measuring platelet 
aggregation with light transmittance aggregometry (LTA) and platelet reactivity index (PRI) 
with vasodilator-stimulated phosphoprotein (VASP) assay by enzyme-linked immunosorbent 
assay (ELISA), for each of Part A and B 
• 
To evaluate the immunogenicity potential of PB2452, for each of Part A and B 
 


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Date Issued: 13MAR2020 
 
  
 
 
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2.3 Exploratory Objectives: 
 
• 
To evaluate the effect of PB2452 on the PK profile of unbound ticagrelor and unbound TAM 
plasma concentrations, for each of Part A and B 
• 
To investigate the effect of PB2452 vs matching placebo on circulating biomarkers of platelet 
activation, such as P-selectin, in subjects pretreated with ticagrelor + ASA, for each of Part A 
and B 
• 
To examine the correlation between estimated creatinine clearance (CrCl) and the PK of 
ticagrelor and TAM, for each of Part A and B 
 
3. Investigational Plan 
 
3.1. Overall Study Design and Plan 
 
This is a Phase 2A, randomized, double-blind, placebo-controlled, single dose, sequential group 
study. Part A evaluates the safety, tolerability, PK and PD of PB2452 vs matching placebo with 
ticagrelor + ASA pretreatment when various dose levels and administration regimens are 
administered to 1) healthy older (age 50 to 64 years) and elderly (age 65 to 80 years) male and 
female subjects in Part A. Part B investigates various dose levels and regimens of PB2452 
administered to healthy male and female subjects (ages 18-50) pretreated with a high dose of 
ticagrelor alone (180 mg) twice daily (BID).. All references to study drug within this SAP apply 
to PB2452 or matching placebo. Part B evaluates the safety, tolerability, PK and PD of PB2452 
vs matching placebo with High Dose of ticagrelor + ASA pretreatment to healthy male and 
female subjects. All references to study drug within this SAP apply to PB2452 or matching 
placebo. 
 
Each cohort was planned to include approximately 8 to 12 subjects randomized in a 3:1 ratio, 
PB2452:placebo.  
 
 
PART A:  
 
The initial cohort (Cohort 1) included approximately 8 subjects ages 50 to 80 years pretreated 
with ASA + ticagrelor randomized to 18 grams (g) of PB2452 or matching placebo administered 
as an initial 6 g bolus infused over 10 minutes, followed by 12 g infused over the next 15 hours 
and 50 minutes to complete a 16 hour administration regimen.  
 
Following completion of Cohort 1, a subsequent cohort was tested, also at an 18 g dose level of 
PB2452 or matching placebo in the same population as in Cohort 1.  A written Dosing Memo 
was provided by the Sponsor to the clinical site describing details of the dosing regimen, cohort 
population, cohort size, sampling schedules, and other cohort-specific study activities prior to 
initiation of each cohort. The maximum total dose of PB2452 administered to any subject as not 
to exceed 30g. Duration of study drug infusions was not to exceed 48 hours. The maximum 
administration rate of PB2452 was not to exceed 18g over 30 minutes. 
 


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Date Issued: 13MAR2020 
 
  
 
 
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The study consisted of a Screening period (Days –45 to –4), a Check-in day (Day -3) and 
Pretreatment Period, an on-site Randomization/Treatment day (Day 1), 3 days on-site for 
treatment and safety monitoring, a Follow-up Visit (Day 7), and a Final Follow-up visit (Day 28 
[±2 days]). Seven days prior to Randomization (Day -7), subjects were administered ASA 81 mg 
orally once daily (QD) until the final dose on the morning of Day 1 before receiving study drug. 
A ticagrelor 180 mg oral loading dose was administered on the morning of Day -2 followed by 
90 mg every 12 hours until the 5th dose was administered on the morning of Day 1. After 
completion of Cohort 1, the Sponsor had the choice to have a 6th dose of ticagrelor administered 
24 hours after the initiation of study drug in a subsequent cohort.  
 
Subjects checked into the clinical site (PPD) on Day -3. In the morning on Day -2, subjects 
began pretreatment with ticagrelor as described in the preceding paragraph. On Day 1, subjects 
who met all the inclusion criteria and none of the exclusion criteria were randomized in a ratio 
3:1 (PB2452:placebo), to receive an IV dose of PB2452 or placebo 2 hours following the 5th 
ticagrelor dose. Subjects may have been discharged from the clinical site between Days 3 and 7 
inclusive to return for a Follow-up visit on Day 7, if already discharged, and on Day 28 (±2 
days).  
 
Safety and tolerability were carefully monitored throughout the study. Immunogenicity samples 
were collected from all subjects at Day -3, Day 1, Day 7, and Day 28 (±2 days). 
 
PART B: 
 
In Part B one dose level (36 g) and administration regimens of PB2452 was evaluated in one 
cohort. Each cohort will include up to 12 subjects randomized in a 3:1 ratio (PB2452:placebo).  
 
This initial cohort of Part B (Cohort 3) pretreated subjects with 180 mg of oral ticagrelor twice 
daily for 48 hours prior to randomization to a dose and regimen of PB2452 or matching placebo 
described in a cohort-specific Dosing Memo. The written Dosing Memo provided by the Sponsor 
to the clinical site described details of the dosing regimen, cohort size, sampling schedules, and 
other cohort-specific study activities prior to initiation of each cohort. The dose level of the 
initial regimen in Part B were not exceed twice the total dose level (36 g) shown to be safe and 
well tolerated in older and elderly subjects (50-80 years) in Part A of this Phase 2A study and in 
the Phase 1 study of PB2452 in healthy subjects (PB2452-PT-CL-0001). 
 
Following completion of Cohort 3, subsequent cohort(s) may have been enrolled to test the same, 
higher or lower dose levels, and/or different infusion regimens of PB2452 or matching placebo in 
the same population as in Cohort 3, or in different populations such as elderly subjects (65 to 80 
years old), as determined by the Sponsor after examination of available PD and safety data from 
the prior cohort(s) and described in a subsequent Dosing Memo. Duration of study drug 
infusions will not exceed 48 hours. No cohort was enrolled following Cohort 3. 
 
A Safety Review Committee (SRC) reviewed all available safety data from ongoing or 
completed cohorts and documented their review and assessment in written SRC minutes prior to 
initiation of a subsequent cohort. Dose escalation would occur only if the SRC affirms the dose 


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Date Issued: 13MAR2020 
 
  
 
 
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and regimen from the previously completed cohorts were safe and well tolerated and no dose-
limiting toxicities (DLTs) were observed.  
 
The study consisted of a Screening period (Days –45 to –4), a Check-in day (Day -3), a 48 hour 
Pretreatment Period starting on Day -2, an on-site Randomization/Treatment day (Day 1), 3 days 
on-site for treatment and safety monitoring, a Follow-up Visit (Day 7), and a Final Follow-up 
visit (Day 28 [±2 days]). Two days prior to Randomization (Day -2), subjects were administered 
ticagrelor 180 mg orally twice daily (BID) until the final dose on the morning of Day 1 before 
receiving study drug. The first ticagrelor 180 mg oral dose was administered on the morning of 
Day -2 followed by 180 mg every 12 hours until the 5th dose was administered on the morning of 
Day 1.   
 
Subjects checked in to the clinical site (PPD) on Day -3. In the morning on Day -2, subjects  
began pretreatment with ticagrelor as described in the preceding paragraph. On Day 1, subjects 
who meet all the inclusion criteria and none of the exclusion criteria were randomized in a ratio 
3:1 (PB2452:placebo), to receive an IV dose of PB2452 or placebo 2 hours following the 5th 
ticagrelor dose. Subjects may have been discharged from the clinical site between Days 3 and 7 
inclusive to return for a Follow-up visit on Day 7, if already discharged, and on Day 28 (±2 
days).  
 
Serum and plasma sampling times for PB2452, ticagrelor, and TAM PK and PD assessments 
were described in the detailed Dosing Memo for each cohort. Hour 0 is the time for initiation of 
study drug infusion (2 hours following administration of the 5th ticagrelor dose). PK and PD time 
points for subsequent cohorts may have been adjusted as needed based on available PK, PD, and 
safety data from prior cohorts. In any cohort subsequent to Cohort 3, there were to be no more 
than 6 additional sampling time points.  The written Dosing Memo provided by the Sponsor prior 
to initiation of each cohort included the following instructions: 
• 
Number of subjects to be randomized  
• 
Total PB2452 dose and administration regimen  
• 
The PK and PD sampling schedule  
• 
Safety ECG schedule  
• 
Biomarkers schedule 
 
Safety and tolerability was carefully monitored throughout the study. Immunogenicity samples 
were collected from all subjects at Day -3, Randomization , Days 7 and 28 (±2 days) following 
administration of study drug. 
 
The overall schedule of required evaluations is provided in Appendix 15.1. 
 
3.2. Study Endpoints 
 
3.2.1. Safety Endpoints 
 
Safety and tolerability will be assessed by monitoring and recording of adverse events (AEs), 
clinical laboratory test results (hematology, coagulation, serum chemistry, and urinalysis), vital 
sign measurements (systolic blood pressure [SBP] and diastolic blood pressure [DBP], oral body 


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Date Issued: 13MAR2020 
 
  
 
 
 5
temperature, respiratory rate, and resting heart rate [HR]), 12-lead electrocardiogram (ECG), 
continuous 12-lead ECG (Holter monitoring), immunogenicity, and physical 
examination findings.  
 
 
3.2.2. Pharmacokinetic Endpoints 
 
Plasma PK concentration for PB2452 at each sampling timepoint as specified on the Dosing 
Memo will be assessed. The following PK parameters will be calculated: 
 
• 
Area under the curve (AUC) from time zero to the time of the last quantifiable 
concentration (AUC0-τ) 
• 
Observed maximum plasma concentration (Cmax) 
• 
Time to reach the observed maximum plasma concentration (Tmax) 
• 
AUC from time zero to 24 hours post-dose (AUC0-24) 
• 
AUC from time zero to 48 hours post-dose (AUC0-48)  
• 
AUC from time zero extrapolated to infinity (AUC0-∞); if data permit 
• 
Terminal elimination half-life (t1/2; if data permit) 
• 
Clearance (CL; if data permit) 
• 
Volume of distribution (Vd)  
 
 
Plasma PK concentration for ticagrelor and the metabolite TAM at each sampling timepoint as 
specified on the Dosing Memo will be assessed. The following PK parameters will be calculated: 
 
• 
Cmax 
• 
Tmax 
• 
AUC0-t  
• 
AUC0-τ  
• 
AUC0-24 
• 
AUC0-48 
• 
AUC0-∞; if data permit 
• 
t1/2; if data permit 
 
Pharmacokinetics parameters for PB2452, ticagrelor, and TAM concentrations in urine for all 
subjects in the PK population to be calculated are: 
 
• 
Total amount of drug excreted in urine at 24 hours after dosing (Ae24)  
• 
Ae from time t1 to t2 hours when the values of t1 to t2 are 0 to 6, 6 to 12, and 12 to 24 
(Aet1-t2) 
• 
Fraction excreted in urine from 1 to 24 hours after dosing (Fe24)  
• 
Renal clearance (CLr) for 24 hours after dosing 
 
3.2.3. Pharmacodynamic Endpoints 
 
Pharmacodynamic data and parameters will be generated from PRU, LTA and PRI assays: 


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Date Issued: 13MAR2020 
 
  
 
 
 6
 
VerifyNow®P2Y12: 
 
• 
PRU at each assessment point 
• 
Percent of reversal (%baseline) in ticagrelor antiplatelet activity by PRU at each 
assessment point 
• 
Maximum PRU 
• 
Maximal percent of baseline PRU 
• 
Time to maximum PRU 
• 
Maximum PRU within 4 hours 
• 
Time to ≥180 PRU 
• 
Time to ≥200 PRU 
• 
Time to ≥220 PRU 
• 
Time to 60%, 80%, and 90% of reversal in PRU  
 
LTA: 
 
• 
The maximum and final extent of aggregation for up to 4 platelet agonists (20µM 
adenosine diphosphate [ADP], 5µM ADP, 1.6 mM arachidonic acid [AA], and 15µM 
thrombin receptor activating peptide [TRAP]), will be recorded at each assessment point. 
• 
Percent of reversal (%baseline) in ticagrelor antiplatelet aggregation  
• 
Maximum platelet aggregation  
• 
Maximum percent of baseline platelet aggregation 
• 
Time to maximum platelet aggregation 
• 
Maximum platelet aggregation within 4 hours 
• 
Time to 60%, 80%, and 90% of reversal in platelet aggregation 
 
VASP by ELISA: 
 
• 
PRI at each assessment point 
• 
Percent of reversal (%baseline) in PRI at each assessment point 
• 
Maximum PRI  
• 
Maximum percent of baseline PRI 
• 
Time to maximum PRI 
• 
Maximum PRI within 4 hours 
• 
Time to 60%, 80%, and 90% of reversal in PRI 
• 
Time to minimum PRI 
 
3.3. Treatments 
 
Study Drug will refer to PB2452 or matching placebo. 
 
PART A: 
 
PB2452: PB2452 IV infusion, prepared according to the Pharmacy Manual, was administered on 
Day 1 for up to 48 hours. The total dose for each subject was 18g. The infusion rate was not to 


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exceed 18g over 30 minutes and the concentration was not to exceed 24g in 250mL. Subjects 
were not to receive more than 250 mL of study drug infusion within any 1-hour period.  Two 
cohorts were enrolled in Part A, both at a total dose of 18g. 
 
For each cohort, the dose, infusion rate, and duration was communicated from the Sponsor to the 
study site, PPD, in a Dosing Memo issued prior to initiation of each treatment cohort.  
 
Matching Placebo: 0.9% sodium chloride single IV infusion, administered on Day 1, was 
delivered at a rate and volume matching the active infusion.  
 
Ticagrelor: Ticagrelor 90 mg oral tablet (immediate release) administered as 180 mg (2 × 90 mg 
tablets) loading dose plus 90 mg every 12 hours for 4 additional doses.  
 
ASA: During Screening, starting on Study Day -7, subjects received ASA (enteric coated) 81 mg 
QD to be taken through to the morning of Day 1, prior to receiving study medication. Subjects 
who were already taking ASA daily before entering the study must have been willing to 
document self-administered daily 81 mg dose of ASA between Day -7 and -3, accept ASA 81 mg 
administered at the clinical site between Day -2 and Day 1, and suspend further ASA doses until 
discharge from the clinical facility.  
 
PART B: 
 
PB2452: PB2452 IV infusion, prepared according to the Pharmacy Manual, was administered on 
Day 1 for up to 48 hours. For each cohort, the dose, infusion rate, and duration 
was communicated from the Sponsor to the study site, PPD, in a Dosing Memo issued prior to 
initiation of each treatment cohort. One cohort in Part B was enrolled, at a total dose of 36 g.  
 
Matching Placebo: 0.9% sodium chloride single IV infusion, was delivered at a rate and volume 
matching the active infusion.  
 
Ticagrelor: Ticagrelor 90 mg oral tablets (immediate release) was administered as a 180 mg (2 × 
90 mg tablets) oral dose every 12 hours for 5 total doses.  
 
 
4. General Statistical Considerations 
 
All statistical analyses will be conducted using statistical analysis system SAS® Version 9.4 or 
higher (SAS Institute, Cary, NC). For tables and data listings with no data, titles and footnotes 
will be presented, and “No data to display” will be presented. 
 
Descriptive statistics for continuous variables will include number of subjects, mean, standard 
deviation (SD), median, minimum, and maximum, unless otherwise noted. Minimum and 
maximum will be presented to the same number of decimal places as the raw data, mean and 
median will be presented to one more decimal place than the raw data, and SD will be presented 
to two more decimal places than the raw data, unless otherwise specified. 


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Frequency and percentage will be calculated for categorical variables. Percentages will be 
presented with 1 decimal place, and if the value is less than 0.1, then “<0.1” will be displayed. 
 
All data will be provided in by-subject listings. 
 
For summary of safety assessments, if there are repeated measurements at a time point, the 
original measurement at that time point will be used in the summary tables. If the original 
measurement is missing, the next available measurement at that time point will be used in the 
summary tables. 
 
Baseline will be defined as the last nonmissing assessment before study drug (PB2452 or 
matching placebo) administration. 
 
Unscheduled results will not be included in the summary tables except for determining Baseline 
but will be presented in data listings. 
 
Unless otherwise stated, the following treatment groups will be used in the summaries, there C 
denotes Cohort: 
 
• 
18 g PB2452 (C1) 
• 
18 g PB2452 (C2) 
• 
36 mg PB2452 (C3) 
• 
Placebo 
• 
All PB2452 (for safety analyses only) 
• 
All Subjects (for safety analyses only) 
 
Outputs will be provided for Part A and Part B, separately. 
 
4.1. Sample Size 
 
The sample size (N) of up to 5 cohorts (Part A) up to 3 cohorts (Part B) of up to 12 subjects per 
cohort for this study is based on clinical and practical considerations rather than on formal 
statistical power calculation. The sample size is considered sufficient to adequately assess the 
safety, PK, and PD profiles of PB2452 and the PK and PD profiles of ticagrelor and its active 
metabolite TAM. 
 
4.2. Randomization, Stratification, and Blinding 
 
This is a double-blind study. Neither the subjects nor the investigator will be aware of the 
treatment assignment. Blinding will be maintained throughout the study by use of active and 
placebo dose forms prepared to be similar in appearance. Subjects will be randomized in a 3:1 
(PB2452:placebo) ratio. No stratification will be utilized. 
 
In order to prepare preliminary summaries of safety, PK, and/or PD data, as needed, to make 
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early termination of the study, certain designated staff at PhaseBio (e.g., study director, a single 
biostatistician, and bioanalytical scientist[s], study drug accountability monitor) will receive 
unblinded data after each cohort completes Day 3 assessments. 
 
The scheduled unblinding event to all study members will occur after the database is locked 
(hard-locked). 
 
4.3. Replacements 
 
At the discretion of the investigator after consultation with the Sponsor, any subject who 
withdraws before completing the study, for reasons other than a dose-limiting toxicity (DLT), 
may be replaced. Any replacement subject will be assigned to receive the same treatment as the 
subject he or she is replacing. 
 
4.4. Handling of Missing data 
 
For the purpose of determining inclusion of AEs in the treatment-emergent AE (TEAE) 
summary tables, incomplete or missing AE onset and end dates will be imputed as follows: 
 
Incomplete or missing onset dates (where UK and UNK indicate unknown or missing day and 
month, respectively): 
 
• 
UK-MMM-YYYY: If the month and year are different from the month and year of 
the dose of study drug, assume 01-MMM-YYYY. If the month and year are the same as 
the dose of study drug month and year, and the end date (after any imputation) is on or 
after the dose of study drug, then assume the date of the dose of study drug. If the month 
and year are the same as the dose of study drug month and year and the end date (after 
any imputation) is prior to the dose of study drug, then assume the end date for the onset 
date. 
• 
DD-UNK-YYYY or UK-UNK-YYYY: If the year is different from the year of dose of 
study drug, assume DD-JAN-YYYY or 01-JAN-YYYY of the onset year, respectively. If 
the year is the same as the dose of study drug year, and the end date (after any 
imputation) is on or after the dose of study drug, then assume the date of the dose of 
study drug. If the year is the same as the dose of study drug, and the end date (after any 
imputation) is prior to the dose of study drug, then assume the end date for the onset date. 
• 
Missing onset date: If the onset date is completely missing and the end date (after any 
imputation) is on or after the dose of study drug, then assume the date of the first dose of 
study drug. If the end date (after any imputation) is prior to the dose of study drug, then 
assume the end date for the onset date. 
 
Incomplete or missing end dates (where UK and UNK indicate unknown or missing day and 
month respectively): 
 
• 
UK-MMM-YYYY: Assume the last day of the month; 
• 
DD-UNK-YYYY or UK-UNK-YYYY: Assume DD-DEC-YYYY or 31-DEC-YYYY, 
respectively; 


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• 
Missing end date: Assume 31-DEC-YYYY, where YYYY is the year of the dose of study 
drug. 
 
An AE with missing onset time but with an onset date the same as the dosing date of study drug 
will be classified as treatment-emergent, unless the AE was reported pre-dose with the same or 
worse intensity or frequency. 
 
Medications with missing start time but with a start date the same as the dosing date of study 
drug will be considered as being taken on or after the initiation of study drug, unless the 
electronic case report form (eCRF) question “Was the medication/therapy taken prior to the 
study” is answered as “Yes” which is considered as being taken prior to the initiation of study 
drug. 
 
Handling of missing PK data is specified in Section 10 and handling of PD data is specified in 
Section 11. 
 
4.5. Analysis Populations 
 
4.5.1. Safety Population 
 
The Safety Population includes all subjects who receive any amount of study drug (PB2452 or 
matching placebo). The Safety Population will be analyzed for all safety assessments. Subjects in 
the Safety Population will be analyzed as treated. 
 
4.5.2. Pharmacokinetic (PK) Population 
 
The PK population includes subjects in the safety population who have ≥1 measurable PK 
concentration. The PK population will be used to summarize all PB2452 blood concentrations. 
Subjects in the PK population will be analyzed as treated. 
 
4.5.3. Modified Intention-to-Treat (mITT) Population  
 
Modified Intention-to-Treat (mITT) population includes all subjects randomly assigned to study 
treatment, who take any amount of study drug (PB2452 or placebo). Subjects will be analyzed 
according to the treatment they are randomized to. 
 
5. Subject Disposition 
 
5.1. Disposition 
 
Subject disposition will be presented by Part for all screened subjects, including number of screen-
failed subjects, number of subjects enrolled (i.e. receiving ticagrelor) and number of subjects 
randomized. 
Number and percentage of subjects in the following categories will be summarized as appropriate: 
• Screen failed 


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• Enrolled 
• Enrolled, but Not Randomized 
• Randomized 
• mITT Population 
• Safety Population 
• Per-Protocol Population 
• PK Population 
Additionally, a summary of study completion and treatment completion status will be presented 
along with reasons for discontinuation if any.  
All tables and listings will be done for both Part A and Part B of the study, separately. 
 
5.2. Protocol Deviations and Eligibility Criteria Deviations 
 
Protocol deviations will be presented by Part in a data listing. Eligibility with regards to 
inclusion and exclusion criteria will be listed in a separate listing. 
 
6. Demographics and Baseline Characteristics 
 
6.1. Demographics 
 
Demographic information collected at screening will be presented by Part in a data listing for 
both Part A and Part B. Descriptive statistics will be calculated for the following continuous 
demographic characteristics: age (years, calculated as the integer part of [date of informed 
consent - date of birth]/365.25), weight (kg), height (cm), and body mass index (BMI, kg/m2). 
Frequency counts will be tabulated for the categorical variables of sex, race, ethnicity and renal 
function (Normal [GFR ≥90], Mild [GFR 60-89], Moderate [GFR 30-59], Severe [GFR ≤29]). The 
summaries will be presented by treatment groups and overall for the safety population.  
All tables and listings for Demographics and Baseline Characteristics will be done for both Part A 
and Part B of the study, separately. 
 
6.2. Medical History 
 
All tables and listings for Medical History will be done by Part for both Part A and Part B of the 
study. 
The medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA; version 21.0 or higher) and presented in a data listing. 
 
7. Treatments and Medications 
 


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All tables and listings for Treatments and Medications will be done for both Part A and Part B of 
the study. 
 
7.1. Prior and Concomitant Medications 
 
Prior medications are defined as medications taken prior to the initiation of study drug. 
Concomitant medications are defined as medications that were taken on or after the initiation of 
study drug. A medication can be considered as both prior and concomitant if the medication is 
taken prior to the initiation of study drug and continued into the treatment period.  Ticagrelor and 
aspirin, which will be received by all study subjects, are considered pre-treatments. Medications 
taken prior to ticagrelor, concomitant with ticagrelor and concomitant with the study treatments 
PB2452 and placebo will be presented separately. 
Prior and concomitant medications will be coded using the latest version of the World Health 
Organization Drug Dictionary (version March 2019 or later) and presented in a listing. 
 
All tables and listings for prior and concomitant medications will be done for both Part A and Part 
B of the study. 
7.2. Medical and Surgical Procedures 
 
Medical and surgical procedures will be presented in a listing, by Part. 
 
7.3. Study Treatments 
 
Study drug (PB2452 or matching placebo), aspirin, and ticagrelor administration will be 
presented in data listings, by Part. 
 
8. Safety Analysis 
All tables and listings for Safety Analysis will be done for both Part A and Part B of the study, 
separately. 
Safety will be assessed by examination of adverse events, physical examination findings, vital 
signs, clinical laboratory measurements, antibodies to study drug and 12 lead ECGs. These results 
will be presented for the Safety Population by Part. 
 
8.1. Adverse Events 
 
An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, 
whether or not it is considered drug-related.  
 
A TEAE is defined as any AE not present before exposure to study drug or any AE already present 
that worsens in intensity or frequency after exposure to study drug.  
 
All AEs will be coded using MedDRA (version 21.0 or higher) by system organ class (SOC) and 
preferred term (PT). 


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All summary tables, except from the overall summary table and summary by relationship to 
ticagrelor, will be based on TEAEs. Frequency and percentage at subject level as well as number 
of events will be presented in the summaries. The SOCs will be displayed in descending order of 
overall frequency and then alphabetically. The PTs will be displayed in descending order of overall 
frequency and then alphabetically within SOC. A subject with 2 or more AEs within the same level 
of summarization will be counted only once in that level using the most severe (for the severity 
table) or most related (for the relationship to study drug table) incident. 
 
Summary tables will be presented by Part and by treatment group. Percentages will be based upon 
the number of subjects in the safety population overall (for the corresponding Part) and within 
each treatment group. 
 
8.1.1. Incidence of Adverse Events 
 
All AE tables and listings will be provided by Study Part. 
 
All AEs will be presented in a data listing, and all TEAEs will be presented in a summary table by 
SOC, PT, treatment group and overall. Additional table of TEAEs will be presented in a summary 
by PT only. 
 
An overall summary table, will be created with following categories: 
 
• 
Any TEAE 
• 
Any study-drug-related TEAE 
• 
Any severe TEAE  
• 
Any severe study-drug-related TEAE  
• 
Any serious adverse event (SAE) 
• 
Any treatment-emergent, study-drug-related SAE 
• 
Any AE leading to early study discontinuation 
• 
Any DLT 
• 
Any Infusion Site Reactions (ISR) 
• 
Any death 
 
The definition of DLT is defined in Section 8.1.4. For the purpose of above summary, a study-
drug-related AE is an AE with definite, probable, possible, or missing relationship to the study 
drug on eCRF.  Study drug refers to PB2452 or matching placebo.  
 
8.1.2. Relationship of Adverse Events 
 
The relationship of AE to study drug and ticagrelor will be classified by the Investigator as 
unrelated, possible, probable, and definite. Treatment-emergent AEs will be summarized by SOC, 
PT, and relationship to study drug; AEs will be summarized by SOC, PT, and relationship to 
ticagrelor. A subject with 2 or more TEAEs within the same level of summarization will be counted 
only once in that level using the most related incident. 
 


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8.1.3. Severity of Adverse Event 
 
The severity (or intensity) of an AE refers to the extent to which it affects the subject’s daily 
activities and will be classified as mild, moderate, or severe. The TEAEs will be summarized by 
SOC, PT, severity (including category ‘Missing’ for events with missing severity assessment on 
eCRF) and treatment group. A subject with 2 or more TEAEs within the same level of 
summarization will be counted only once using the most severe event.  
 
8.1.4. Dose Limiting Toxicities 
 
The SRC will review all AEs and all laboratory and ECG Holter monitoring abnormalities 
according to Common Terminology Criteria for Adverse Events (CTCAE) v5 to determine 
whether DLT has been identified in a subject who is confirmed to have received PB2452. If the 
SRC determines an AE is related to administration of ticagrelor or another confirmed cause, the 
AE will not be considered a DLT. Definitions of DLT are: 
 
• 
Any AE assessed as ≥Grade 2 based on the CTCAE v5 grading scale and occurred in a 
subject confirmed to have received PB2452 
• 
Any ≥Grade 2 laboratory abnormality (outside the clinical laboratory normal reference 
range) that occurs in a subject confirmed to have received PB2452 
o Note: For a Grade 2 electrolyte abnormality that spontaneously resolves to 
≤Grade 1 without intervention within 24 hours, the SRC may decide to exempt 
the laboratory abnormality from being considered a DLT 
• 
Any TEAE that leads to study withdrawal of a subject confirmed to have received 
PB2452 
 
The SRC will provide an external spreadsheet which contains all DLT events and this external 
spreadsheet will be used in the summaries and listings. 
 
8.1.5. Infusion Site Assessments 
 
The infusion site will be examined by the investigator or designée concerning pain, tenderness, 
erythema/redness, and induration/swelling within 15 minutes before the initiation of the study drug 
infusion at Hour 0, and at 1, 3, 24, and 48 hours after initiation of the study drug infusion and on 
Day 7. Infusion site reactions will be assessed according to the CTCAE v5 grading scale and will 
be recorded as AEs and included in the AE listings. 
 
8.1.6. Serious Adverse Events 
 
An AE or suspected adverse reaction is considered as a serious AE (SAE)/suspected unexpected 
serious adverse reaction if, in the view of either the investigator or Sponsor, it results in any of the 
following outcomes 
 
• 
Death 
• 
Life-threatening AE 
• 
Inpatient hospitalization or prolongation of existing hospitalization 


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• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
Congenital anomaly or birth defect 
 
All SAEs including deaths will be presented in a data listing, by Part. 
 
8.1.7. Adverse Events Leading to Early Discontinuation 
 
All AEs that lead to early discontinuation will be presented in a listing, by Part. 
 
8.2. Clinical Laboratory Evaluations 
 
Clinical laboratory tests will be performed by PPD Central Laboratory. Repeat clinical laboratory 
tests may be performed at the discretion of the investigator, if necessary, to evaluate inclusion 
and exclusion criteria or clinical laboratory abnormalities. The clinical laboratory performing the 
tests will provide the reference ranges for all clinical laboratory parameters. 
 
The following clinical laboratory assessments will be performed:  
 
Hematology 
Complete blood count with differential hematocrit  
hemoglobin 
mean corpuscular hemoglobin  
mean corpuscular hemoglobin concentration  
mean corpuscular volume  
mean platelet volume  
platelet count 
erythrocyte (red blood cell [RBC]) count 
total and differential leukocyte (white blood cell [WBC]) count 


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Serum Chemistry 
alanine aminotransferase  
albumin 
alkaline phosphatase  
aspartate aminotransferase  
bicarbonate 
bilirubin (total and direct) 
blood urea nitrogen  
calcium 
chloride 
cholesterol 
 
total  
 
high-density lipoprotein  
 
calculated low-density lipoprotein  
creatine phosphokinase 
creatinine 
gamma-glutamyl transferase  
glucose 
Hgb A1C 
lactate dehydrogenase  
magnesium 
phosphorus 
potassium 
sodium 
thyroid stimulating hormone (Screening only)  
total protein 
triglycerides (repeat fasting triglyceride if TG >500) 
uric acid 
Coagulation 
activated partial thromboplastin time  
international normalized ratio  
partial thromboplastin time  
prothrombin time  
Urinalysis (should be aligned to  
PPD urinalysis) 
 
 
 
 
 
 
appearance 
bilirubin 
color 
glucose 
ketones 
leukocyte esterase 
reflex microscopy (at Screening and Check-in only, if dipstick is 
positive for protein or blood value ≥1+); includes  
 bacteria 
casts 
 crystals 
epithelial cells 
 RBCs 
WBCs 
 nitrites 
occult blood 
 pH  
protein 
 specific gravity  
turbidity 
 
 urobilinogen 
Serology 
hepatitis B surface antigen 
hepatitis C virus antibody 
human immunodeficiency virus  
 types 1 and 2 antibodies (Screening only) 


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Other analyses 
 urine drug screen (Screening and Check-in only): 
amphetamines 
barbiturates 
benzodiazepines 
cannabinoids 
cocaine 
cotinine 
methylenedioxymethamphetamine  
opiates 
phencyclidine 
propoxyphene 
tetrahydrocannabinol  
urine alcohol (Screening and Check-in only) 
female subjects: 
 
follicle-stimulating hormone (Screening only) 
 
serum pregnancy test (human chorionic gonadotropin  
 
 
[Screening, Check-in, and Day 28 (±2 days) only])  
 
 
Hematology, clinical chemistry, coagulation, and urinalysis laboratory tests will be performed on 
Screening, at Check-in Days -3, on Days -1, 2, 7, and 28 (±2). 
 
Urine drug screen and urine alcohol screen tests will be performed on screening and at Check-in 
Day -3.  
 
Serum pregnancy test will be performed on Screening, at Check-in Day -3, and on Day 28 (±2). 
 
Serology tests and stool occult blood will be only performed on Screening. 
 
Abnormal clinical laboratory values will be flagged as either high or low (or normal or 
abnormal) based on the reference ranges for each laboratory parameter. The investigator 
will determine whether any of the abnormally high or low results are clinically significant (CS) 
or not CS (NCS).  
 
The hematology and coagulation, clinical chemistry, and urinalysis test results will be presented 
in the data listings sorted by treatment group, subject, laboratory test, and sample collection 
date/time. Values that are outside of the normal range as well as the clinically significance 
information will be flagged in the listings. Actual results and change from baseline will be 
summarized for the safety population. Shift tables will be generated for the safety population.  
 
All other laboratory tests will be presented in a data listing sorted treatment group, subject, 
laboratory test category, laboratory test, and sample collection date/time. 
 
All laboratory tables and listings will be provided by Part. 
 
8.3. Vital Sign Measurements 
 
Vital signs (SBP and DBP, oral body temperature, respiratory rate, and HR) will be collected at 
Screening, Check-in Day -3, before dosing (30 to 60 minutes prior to the initiation of the study 


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drug infusion), and at 10, 20, 30, 45, 60 minutes, 24 and 48 hours following initiation of the 
study drug, and on Days 7 and 28 (±2).  
 
Vital signs results will be presented in a data listing sorted by treatment group, subject, and 
collection date/time. Actual results and change from baseline will be summarized for the safety 
population. 
 
All vital sign tables and listings will be provided by Part. 
 
8.4. Twelve-Lead Electrocardiogram 
 
Twelve-lead ECGs will be obtained after the subject has rested in the supine position for ≥10 
minutes or as clinically indicated based on reported AEs or laboratory findings, as necessary. 
Scheduled visit and timepoints for 12-lead ECG will be specified on the Dosing Memo. 
 
Electrocardiogram assessments will include comments concerning whether the tracings are 
normal or abnormal, rhythm, presence of arrhythmia or conduction defects, morphology, and any 
evidence of MI, or ST-segment, T-Wave, and U-Wave abnormalities. In addition, measurements 
of these intervals will be reported: HR, PR interval, QRS duration, QT interval, Fridericia-
corrected QT interval (QTcF), and RR interval. The investigator will determine whether any of 
the 12-lead ECG results are CS or NCS. 
 
If both QT and RR intervals are not missing, the Bazett’s-corrected QT interval (QTcB) 
measured in msec will be calculated using below formula, where RR interval is measured in 
msec: 
 
• 
𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄=
𝑄𝑄𝑄𝑄
ඥ𝑅𝑅𝑅𝑅/1000 
 
If both QT and RR intervals are not missing but QTcF interval is missing in the database, QTcF 
measured in msec will be calculated using below formula, where RR interval is measured in 
msec: 
 
• 
𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄=
𝑄𝑄𝑄𝑄
ඥ𝑅𝑅𝑅𝑅/1000
3
 
 
Electrocardiogram results will be presented in data listing sorted by treatment group, subject, and 
date/time of assessment. In addition, subjects with outlying QTcF, and QTcB intervals (absolute 
value > 500 msec, absolute value > 480 msec, absolute value > 450 msec, or increase from 
baseline value >30 or >60 msec) will be listed in a separate data listing. A summary table will be 
presented for maximum QTcF and QTcB intervals (including scheduled and unscheduled 
assessments) meet the outlying criteria using count and percentage. 
 
Actual results and change from baseline will be summarized for the safety population at each 
timepoint.  
 
All ECG results will be presented in a data listing. 


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All ECG tables and listings will be provided by Part. 
 
8.5. Holter Monitoring (Continuous Twelve-lead Electrocardiogram) 
 
Continuous 12-lead Holter monitor will be placed 2 hours before administration of study drug 
and will remain in place for 24 hours after the initiation of study drug. The continuous ECG 
waveform data recorded by the Holter device will be stored for optional exposure-response QTc 
analysis. 
 
The eCRF collected interpretation from the Holter device will be presented in a data listing, by 
Part. 
 
8.6. Physical Examination and Physical Measurement 
 
A full physical examination will include assessment of skin, head, ears, eyes, nose, throat, neck, 
thyroid, lungs, heart, cardiovascular system, abdomen, lymph nodes, and musculoskeletal 
system/extremities, and will be performed on Screening, at Check-in Day -3, and at Day 28 (±2). 
 
A brief physical examination will include assessment of skin (including any signs of cutaneous 
erythema), lungs, cardiovascular system, and abdomen (liver, spleen) and will be performed at 
Day 3 and Day 7.  
 
Interim physical examinations will be performed at the discretion of the investigator, if 
necessary, to evaluate AEs or clinical laboratory abnormalities.  
 
Physical exam results will be presenting in a data listing, by Part. Physical measurements will be 
presented in a separate listing, by Part.   
 
9. Immunogenicity Assessments 
 
Immunogenicity (antibody) samples will be screened for the presence of binding anti-drug 
antibodies (ADA) at Check-in Day -3, on Days 1, 7, and 28 (±2). A subject who tests positive for 
ADAs at the final scheduled visit (Day 28 ±2 days) will be asked to return for follow-up 
sampling approximately 3 months after the final visit and approximately every 6 months 
thereafter until ADAs no longer test positive or until levels return to a predose state. 
 
The ADA result (positive or negative) will be summarized by treatment group and visit using 
counts and percentages. All ADA results with corresponding titer values will be presented in a 
data listing. The neutralizing antibody results may be listed and summarized in the clinical study 
report if the assay is available. 
 
An ADA-positive subject is defined as a subject with at least one ADA-positive sample at any 
time during the treatment or follow-up observation period. In case of a positive pre-treatment 
sample, if the titer of at least one post-treatment ADA is elevated at least 2 folds of the titer in 
pre-treatment sample, this subject is also ADA positive otherwise ADA negative. 
 


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All immunogenicity tables and listings will be provided by Part.  
 
10. Pharmacokinetics 
 
All tables and listings for pharmacokinetics will be provided by Part. 
 
10.1. 
Plasma Pharmacokinetics 
 
The ticagrelor and TAM pharmacokinetic results will be analyzed for all randomized subjects, and 
the PB2452 results will be analyzed for the PK Population.  All summary tables, graphs are listings 
will be provided by Part. 
 
10.1.1. Plasma Pharmacokinetics Concentration 
 
Throughout this document, the total MEDI2452 (PB2452) includes free MEDI2452 (PB2452), 
protein-bound MEDI2452 (PB2452), ticagrelor-complexed MEDI2452 (PB2452), and TAM-
complexed MEDI2452 (PB2452). The unbound MEDI2452 (PB2452) includes free MEDI2452 
(PB2452) and protein-bound MEDI2452 (PB2452). Similarly, total ticagrelor (or TAM) includes 
free ticagrelor (or TAM), protein bound ticagrelor (or TAM), and MEDI2452 (PB2452)-
complexed ticagrelor (or TAM). The unbound ticagrelor (or TAM) includes free ticagrelor (or 
TAM). 
 
Blood samples for PK analysis of total and unbound PB2452 concentration in plasma will be 
collected from all subjects at the following time points: before dosing (0 hour) and up to 28 days 
after initiation of the study drug (PB2452 or placebo) infusion. Collection time points for cohorts 
were be specified in a Dosing Memo from Sponsor prior to initiation of each cohort, and are 
provided below.  
 
Collection times relative to the initiation of the study drug (PB2452 or placebo) infusion on Day 
1 were: Hour 0 (up to 10 minutes prior to PB2452 infusion), 5 minutes, 0.25, 0.5, 1, 2, 4, 8, 12, 
20, 24, 36, 48 hours, and 7 and 28 days post-dose. 
 
Plasma samples for determining total and unbound concentrations of ticagrelor and its active 
metabolite TAM, will be collected at the following timepoints: before dosing (within 10 minutes 
prior to the initiation of the study drug infusion [Hour 0]), and up to 28 days following the 
initiation of PB2452 or placebo infusion on Day 1. Subjects will be administered the 5th 
ticagrelor dose two hours before the study drug infusion initiation on Day 1. 
 
Specific collection times relative to the initiation of the study drug (PB2452 or placebo) infusion 
were:  Hour 0 (up to 10 minutes prior to PB2452 infusion), 5 minutes, 0.25, 0.5, 1, 2, 4, 8, 12, 
20, 24, 36, 48 hours, and 7 and 28 days post-dose. 
 
Concentrations that are below the limit of quantification (BLQ) will be treated as zero for 
descriptive statistics. Mean BLQ concentrations will be presented as BLQ, and the SD and 


PhaseBio Pharmaceuticals, Inc. 
 
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  21 
coefficient of variation (CV) will be reported as not applicable. Missing concentrations will be 
excluded from the calculations. 
 
For each analyte, plasma concentration data will be listed by subject and summarized by time 
point for each dose level using descriptive statistics (number of subjects, arithmetic mean, SD, 
CV, median, minimum, and maximum). Plasma concentration versus time profiles for each 
subject will be presented graphically. The mean plasma concentrations versus scheduled time 
profiles will be presented graphically by dose. 
 
Scatter plots of total and unbound plasma ticagrelor and TAM versus total and unbound PB2452 
plasma concentration will be prepared for all cohorts, as appropriate. 
 
10.1.2. Plasma Pharmacokinetic Parameters 
 
The PK parameters of PB2452, ticagrelor, and TAM will be determined using noncompartmental 
methods using Phoenix WinNonlin Version 8.0 or higher or SAS® Version 9.4 or higher. For PK 
analysis, BLQ values will be treated as zero with the exception that a BLQ value between 2 
quantifiable concentrations will be set as missing. If consecutive BLQ concentrations are 
followed by quantifiable concentrations in the terminal phase, those concentrations after BLQ 
concentrations will be treated as missing. Missing concentrations will be treated as missing from 
the PK parameter calculation 
 
The following PK parameters, if data permit, will be calculated for total and unbound plasma 
PB2452 using actual sampling times. 
 
PB2452 PK parameters: 
Parameter 
Description 
Cmax 
Observed maximum plasma concentration 
Tmax 
Time to reach the observed maximum plasma concentration 
AUC0-t 
Area under the plasma concentration versus time curve (AUC) from time 0 to 
the time of last quantifiable concentration (Clast); calculated using the linear-
up/ log-down trapezoidal rule 
AUC0-inf 
AUC from time 0 extrapolated to infinity, calculated as AUC0-t + Clast/ λz, 
where Clast is the last quantifiable plasma drug concentration and λz is the 
terminal phase rate constant. 
AUC0-24 
AUC from time 0 to 24 hours post-dose; calculated using the 
linear-up/log-down trapezoidal rule 
AUC0-48 
AUC from time 0 to 48 hours post-dose; calculated using the linear-up/ 
log-down trapezoidal rule 
%AUCextrap 
Percentage of AUC0-inf due to extrapolation from the time for the last 
quantifiable concentration to infinity, calculated as (AUC0-inf - 
AUC0-t)/AUC0-inf*100 


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λz 
Terminal phase rate constant, determined by linear regression of the terminal 
points of the log-linear plasma concentration-time curve. The λz will not be 
estimated if the terminal phase of the log-concentration-time profile does not 
exhibit a linear decline phase, or if the regression coefficient (Rsq) is less than 
0.8. 
Rsq 
Regression coefficient for calculation of λz 
t1/2 
Terminal elimination half-life, calculated as t1/2= ln(2)/ λz. 
CL 
Total body clearance, calculated as Dose/AUC0-inf 
Vd 
Volume of distribution, calculated as CL/λz. 
 
The following PK parameters, as appropriate and when data permit, will be calculated for total 
and unbound ticagrelor and TAM using actual sampling times: 
 
Ticagrelor/ TAM PK parameters: 
Parameter 
Description 
Cmax 
Observed maximum plasma concentration 
Tmax 
Time to reach the observed maximum plasma concentration 
AUC0-t 
AUC from time 0 to the time of last quantifiable concentration (Clast); 
calculated using the linear-up/log-down trapezoidal rule 
AUC0-inf 
AUC from time 0 extrapolated to infinity, calculated as AUC0-t + Clast/ λz, 
where Clast is the last quantifiable plasma drug concentration and λz is the 
terminal phase rate constant. 
AUC0-24 
AUC from time 0 to 24 hours post-dose; calculated using the 
linear-up/log-down trapezoidal rule 
AUC0-48 
AUC from time 0 to 48 hours post-dose; calculated using the linear-up/ 
log-down trapezoidal rule 
%AUCextrap 
Percentage of AUC0-inf due to extrapolation from the time for the last 
quantifiable concentration to infinity, calculated as (AUC0-inf - 
AUC0-t)/AUC0-inf*100 
λz 
Terminal phase rate constant, determined by linear regression of the terminal 
points of the log-linear plasma concentration-time curve. The λz will not be 
estimated if the terminal phase of the log-concentration-time profile does not 
exhibit a linear decline phase, or if the regression coefficient (Rsq) is less than 
0.8. 
Rsq 
Regression coefficient for calculation of λz 
t1/2 
Terminal elimination half-life, calculated as t1/2= ln(2)/ λz. 
 
 
Additional PK parameters may be calculated, as necessary. Pharmacokinetic parameters will be 
listed by subject and summarized for each dose level using descriptive statistics (number of 
subjects, mean, SD, CV, median, minimum, and maximum), with the exception of %AUCextrap, 
λz and Rsq, which will be listed only. Geometric means will be reported for AUCs and Cmax. 
 


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Date Issued: 13MAR2020 
 
  
 
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10.2. 
Urine Pharmacokinetics 
 
10.2.1. Urine pharmacokinetic Concentrations 
 
Pooled urine samples to assess urine PB2452, ticagrelor and TAM concentrations will be 
collected over the following intervals: before dosing (within 60 minutes prior to the first 
ticagrelor dose on Day -2) and 0 to 6, 6 to 12, and 12 to 24 hours post dose. In patients receiving 
a 6th dose of ticagrelor, pooled urine samples to assess urine ticagrelor and TAM concentrations 
will be collected over the following intervals after the 6th ticagrelor dose: 0 to 6, 6 to 12, 12 to 
24 hours post dose. 
 
For each analyte, urine concentration and volume data will be listed by collection interval for 
each subject. 
 
10.2.2. Urine Parameters 
 
The following PK parameters for PB2452, ticagrelor and TAM concentrations in urine will be 
calculated for Day 1 whenever data permit: 
 
Parameter 
Description 
Ae24 
Total amount of drug excreted in urine from time 0 to 24 hours post-dose. 
Aet1-t2 
Ae from time t1 to t2 hours where the values of t1 to t2 are 0 to 6, 6 to 12, and  
12 to 24 post-dose. 
Fe24 
Fraction excreted in urine from 0 to 24 hours after dosing (ticagrelor only).  
CLr24 
Renal clearance, calculated as Ae24/AUC0-24 
 
Additional urine PK parameters may be calculated, as necessary. Urine parameters will be listed 
by subject and summarized for each dose level using descriptive statistics (number of subjects, 
mean, SD, CV, median, minimum, and maximum). 
 
11. Pharmacodynamics 
 
The PD population will be used for all PD analysis tables and figures, except otherwise noted. All 
tables and listings for PD will be done for both Part A and Part B of the study, separately. 
 
11.1. 
Pharmacodynamic Data 
 
Blood samples for PD analysis will be collected from subjects at the following time points: 
Day -3, before dosing (within 60 minutes prior to 1st ticagrelor dose on Day -2) and again before 
dosing (within 10 minutes prior to the initiation of the study drug infusion [Hour 0]), and up to 
48 hours after the initiation of study drug infusion. Collection time points for each cohort will be 
specified in a Dosing Memo from Sponsor to PPD prior to initiation of each cohort. The 


PhaseBio Pharmaceuticals, Inc. 
 
Draft Statistical Analysis Plan, Draft Version 2.0 
PB2452-PT-CL-0002 
 
Date Issued: 13MAR2020 
 
  
 
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sampling schedule for a given cohort may differ from that of other cohorts to accommodate 
various infusion durations that may be examined in the protocol in order to fully characterize the 
PK/PD profile.  
 
Specific collection times were identical for all 3 cohorts:  Day -3, Day -2 (up to 60 minutes prior 
to 1st ticagrelor dose) and Hour 0 (up to 10 minutes prior to PB2452 infusion), 5 minutes, 0.25, 
0.5, 1, 2, 4, 8, 12, 20, 24, 36 and 48 hours after initiation of PB2452 or placebo infusion 
 
Platelet aggregation will be assessed using the VerifyNow, LTA and VASP assays. The results for 
the VerifyNow assay will be expressed as PRU and %baseline PRU, which will be calculated 
from the platelet aggregation-time profile for each sampling time point. The results of platelet 
aggregation from the LTA assay using 5µM ADP and 20µM ADP will be expressed as 
maximal-extent aggregation (MA), %baseline MA, final-extent aggregation (FA) and %baseline 
FA, which will be calculated from the platelet aggregation-time profile for each sampling time 
point. The results of platelet aggregation from the LTA assay using agonists 1.6 mM AA and 15 
uM TRAP will be included in SDTM PD dataset only and not included in tables, listings or 
figures. Similarly, PD results from the VASP assay will be expressed as PRI and %baseline PRI, 
which will be calculated from the platelet aggregation-time profile for each sampling time point. 
 
Blood drawn for LTA PD assessments will be further processed for testing soluble and surface 
P-selectin/CD62p after completion of LTA, as per instructions. All LTA timepoints will have 
samples processed for testing however only the time points as defined below are planned for 
testing P-selectin. The remaining samples will be stored, as per their stability profiles, for future 
testing if needed to help elucidate the results. The sampling schedule for P-selectin for 
subsequent cohorts will be specified in a Dosing Memo provided by Sponsor to PPD prior to 
initiation of each cohort.  
 
Specific P-selectin collection times were: Day -2 (up to 60 minutes prior to first ticagrelor dose), 
Hour 0 (up to 10 minutes prior to PB2452 infusion), 12 and 24 hours. 
  
Pharmacodynamic data will be listed by subject and ADA status and summarized for each 
treatment group for each time point using descriptive statistics (number of subjects, mean, SD, 
median, minimum, and maximum). Mean PD data versus scheduled time profiles will be 
presented graphically. Biomarker data (P-selectin) will be listed and summarized by each cohort 
for each time point using descriptive statistics (number of subjects, mean, SD, median, 
minimum, and maximum). 
 
Scatter plots of PD data versus total and unbound PB2452 plasma concentrations will be 
prepared for all cohorts, as appropriate. A box plot of PD data versus sampling time point will be 
prepared for each dose level. 
 
Scatter plots of CrCl versus total and unbound ticagrelor and TAM plasma concentrations will be 
prepared for all cohorts, as appropriate. 
 
Correlation between VerifyNow assay, LTA assay, and VASP assay will be investigated 
graphically. Scatter plots of individual subject PRU versus MA (5µM ADP and 20µM ADP), 


PhaseBio Pharmaceuticals, Inc. 
 
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Date Issued: 13MAR2020 
 
  
 
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PRU versus PRI, and MA (5µM ADP and 20µM ADP) versus PRI will be plotted, and the 
correlation coefficient r (Spearman's rank correlation coefficient) and p-value will be displayed. 
 
11.2. 
10.2 Pharmacodynamic Parameters 
 
Pharmacodynamic parameters will be calculated using actual timepoints using SAS® Version 9.4 
or higher. Missing PD values will be treated as missing for PD parameter calculation. 
 
The following PD parameters will be calculated using %baseline/actual PRU data from the 
VerifyNow assay. 
 
Day 1 parameters following 5th ticagrelor dose 
APRUmax 
Maximal actual PRU 
APRUmax4h 
Maximal actual PRU within 4 h 
PRUmax 
Maximal percent of baseline PRU 
TPRUmax 
Time to maximal actual PRU 
TPRU180 
Time to 180 or higher actual PRU, calculated as the first observed time 
point (no extrapolation) when the actual PRU reaches 180 or above 
TPRU200 
Time to 200 or higher actual PRU, calculated as the first observed time 
point (no extrapolation) when the actual PRU reaches 200 or above 
TPRU220 
Time to 220 or higher actual PRU, calculated as the first observed time 
point (no extrapolation) when the actual PRU reaches 220 or above 
TPRU60% 
Time to 60% of baseline PRU, calculated as the first observed time point 
(no extrapolation) when %baseline PRU reaches 60% or above 
TPRU80% 
Time to 80% of baseline PRU, calculated as the first observed time point 
(no extrapolation) when %baseline PRU reaches 80% or above 
TPRU90% 
Time to 90% of baseline PRU, calculated as the first observed time point 
(no extrapolation) when %baseline PRU reaches 90% or above 
 
The following PD parameters will be calculated using %baseline/actual MA and FA data, as 
appropriate, from the LTA assay for both the 5µM and 20µM ADP conditions. 
 
Day 1 parameters following 5th ticagrelor dose 
APAmax 
Maximal actual platelet aggregation 
APAmax4h 
Maximal actual platelet aggregation within 4 h 
PAmax 
Maximal percent of baseline platelet aggregation 
TPAmax 
Time to maximal actual platelet aggregation 
TPA60% 
Time to 60% of baseline platelet aggregation, calculated as the first observed 
time point (no extrapolation) when %baseline platelet aggregation reaches 
60% or above 
TPA80% 
Time to 80% of baseline platelet aggregation, calculated as the first observed 
time point (no extrapolation) when %baseline platelet aggregation reaches 
80% or above 


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TPA90% 
Time to 90% of baseline platelet aggregation, calculated as the first observed 
time point (no extrapolation) when %baseline platelet aggregation reaches 
90% or above 
 
The following PD parameters will be calculated using %baseline/actual PRI data from the VASP 
assay. 
 
Day 1 parameters following 5th ticagrelor dose 
APRImax 
Maximal actual PRI 
APRImax4h 
Maximal actual PRU within 4 h 
PRImax 
Maximal percent of baseline PRI 
TPRImax 
Time to maximal actual PRI 
TPRI60% 
Time to 60% of baseline PRI, calculated as the first observed time point (no 
extrapolation) when %baseline PRI reaches 60% or above 
TPRI80% 
Time to 80% of baseline PRI, calculated as the first observed time point (no 
extrapolation) when %baseline PRI reaches 80% or above 
TPRI90% 
Time to 90% of baseline PRI, calculated as the first observed time point (no 
extrapolation) when %baseline PRI reaches 90% or above 
 
Additional PD parameters may be calculated, as necessary. Pharmacodynamic parameters will be 
listed by subject and summarized for each cohort using descriptive statistics (number of subjects, 
mean, SD, median, minimum, and maximum). Number and percent of subjects achieving 60%, 
80%, and 90% of reversal in PRU, LTA, and PRI within 30 minutes or 4 h will be summarized.   
 
12. Interim Analysis 
 
There is no interim analysis planned for this study. 
 
13. Changes in the Planned Analysis 
 
There is no change in the SAP compared to the protocol 
 


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14. References 
 
Baharoglu MI, Cordonnier C, Al-Shahi SR, de Gans K, et al. Platelet transfusion versus standard 
care after acute stroke due to spontaneous cerebral haemorrage associated with antiplatelet 
therapy (PATCH): a randomized, open-label, phase 3 trial. Lancet 2016 Jun 25;387(10038):2605-
13. 
Bell AD, Roussin A, Cartier R, Chan WS, et al. The use of antiplatelet therapy in the outpatient 
setting: Canadian Cardiovascular Society guidelines. Can J Cardiol 2011;27(2):208-21. 
Beshay JE, Morgan H, Madden C, Yu W, et al. Emergency reversal of anticoagulation and 
antiplatelet therapies in neurosurgical patients. J Neurosurg 2010 Feb;112(2):307-18. 
Dalén M, Ivert T, Lindvall G, van der Linden J. Ticagrelor-associated bleeding in a patient 
undergoing surgery for acute type A aortic dissection. J Cardiothorac Vasc Anesth 2013 
Oct;27(5):e55-7. 
Dornbos III D, Katz JS, Youssef P, Powers CJ, et al. Glycoprotein IIb/IIIa Inhibitors in 
Prevention and Rescue Treatment of Thromboembolic Complications during Endovascular 
Embolization of Intracranial Aneurysms. Neurosurgery 2018 Mar;82(3):268-77. 
Fitchett DH, Theroux P, Brophy JM, Cantor WJ, et al. Assessment and management of acute 
coronary syndromes (ACS): a Canadian perspective on current guideline-recommended 
treatment--part 1: non-ST-segment elevation ACS. Can J Cardiol 2011 Nov-Dec;27 Suppl 
A:S387-S401. 
Godier A, Taylor G, Gaussem P. Inefficacy of platelet transfusion to reverse ticagrelor. NEJM 
2015 Jan 8;372(2):196-7. 
Maillard J, Cartier Faessler V, Fontana P, Bonhomme F. Lack of effect of platelet transfusions 
and desmopressin on intracranial bleeding in a patient receiving ticagrelor. A Case Rep 2015 Jun 
15;4(12):169–71. 
Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G, et al. Inhibition of 
platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with 
clopidogrel in patients with acute coronary syndromes. JACC 2007 Nov 6;50(19):1852-6. 
Taylor G, Osinski D, Thevenin A, Devys JM. Is platelet transfusion efficient to restore platelet 
reactivity in patients who are responders to aspirin and/or clopidogrel before emergency surgery? 
J Trauma Acute Care Surg 2013 May;74(5):1367-9. 
Teng R, Carlson GF, Nylander S, Andersson TL. Effects of autologous platelet transfusion on 
platelet inhibition in ticagrelor-treated and clopidogrel-treated subjects. J Thromb Haemost. 2016 
Dec 14; 14(12):2342-52. 
 
 
 
 
 
 
 
 


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15. Appendices 
15.1. 
Schedule of Study Procedures 
 
Procedure 
Screeninga 
Check-in/ 
Pretreatment 
Rand 
 
Subjects 
Discharged 
FUP 
FUP/End of 
Study (EOS) 
Study Day(s) 
–45 to –4 
-7 
–3 
-2 
–1 
1 
2 
3 
7 
28 (±2) 
Sign informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
X 
 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Urine drug screen  
X 
 
X 
 
 
 
 
 
 
 
Urine alcohol screen 
X 
 
X 
 
 
 
 
 
 
 
Serum pregnancy testb 
X 
 
X 
 
 
 
 
 
 
X 
Serology testing 
X 
 
 
 
 
 
 
 
 
 
Stool occult blood test 
X 
 
 
 
 
 
 
 
 
 
Admission to study site clinic 
 
 
X 
 
 
 
 
 
 
 
Physical examinationc,d 
Xc 
 
Xc 
 
 
 
 
Xd 
Xd 
Xc 
Vital sign measurementse 
X 
 
X 
 
 
X 
X 
X 
X 
X 
12-lead ECGf 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Continuous ECG recording (Holter)  
 
 
 
 
 
X 
Xj 
 
 
 
Clinical laboratory testing 
X 
 
X 
 
X 
 
X 
 
X 
X 
Randomization 
 
 
 
 
 
X 
 
 
 
 
Drug administration 
 
 
 
 
 
 
 
 
 
 
Ticagrelorg 
 
 
 
X 
X 
X 
(X)*  
 
 
 
PB2452/Placeboh 
 
 
 
 
 
X 
 
 
 
 
ASA 81 mg QDi 
X 
X 
X 
X 
X 
X 
 
 
 
 
PK blood sampling** 
 
 
 
 
 
 
 
 
 
 
Plasma PB2452 
 
 
 
 
 
X 
X 
X 
X 
X 


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Plasma ticagrelor/TAM 
 
 
 
 
 
X 
X 
X 
X 
X 
Free plasma ticagrelor/TAM 
 
 
 
 
 
X 
X 
X 
X 
X 
PK urine sampling*** 
 
 
 
X 
 
X 
X 
X 
 
 
PD sampling (LTA/PRU/VASP)k 
 
 
X 
X 
 
X 
X 
X 
 
 
Biomarkers** 
 
 
 
 
X 
 
X 
 
X 
X 
Infusion site assessmentl 
 
 
 
 
 
X 
X 
X 
X 
 
Serum immunogenicity 
 
 
X 
 
 
Xk 
 
 
X 
Xm 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Discharge from clinical site 
 
 
 
 
 
 
 
Xn 
 
 
Abbreviations: ADA=anti-drug antibody; ASA=acetaminophen, aspirin; BMI=body mass index; DBP=diastolic blood pressure; 
ECG=electrocardiogram; EOS=end of study; FUP=follow-up; HR=heart rate; LTA=light transmittance aggregometry; PD=pharmacodynamics; 
PK=pharmacokinetics; PRU=P2Y12 reaction units; QD=once daily; Rand=Randomization; RR=respiratory rate; SBP=systolic blood pressure; 
TAM=ticagrelor active metabolite AR-C124910XX; VASP=vasodilator-stimulated phosphoprotein 
* 
In successive cohorts in Part A following Cohort 1, if indicated in a Dosing Memo from Sponsor to site, one or more cohorts may also receive a 
6th dose of ticagrelor 90 mg, 24 hours after initiation of PB2452 (or placebo) infusion on Day 1. And in successive cohorts in Part B following Cohort 
3, if indicated in a Dosing Memo from Sponsor to site, one or more cohorts may also receive a 6th dose of ticagrelor 90 mg, 24 hours after initiation of 
PB2452 (or placebo) infusion on Day 1. 
** Modifications to this schedule may be made in a Dosing Memo from Sponsor to site prior to initiation of each cohort. For cohorts receiving a 6th 
ticagrelor dose only: Sampling times will be specified in a Dosing Memo from Sponsor to site. 
*** Modifications to this schedule may be made in a Dosing Memo from Sponsor to site prior to initiation of each cohort. For cohorts receiving a 6th 
ticagrelor dose only: Pooled urine samples to assess urine ticagrelor and TAM concentrations will be collected over the following intervals beginning 
with the 6th ticagrelor dose: 0 to 6, 6 to 12, and 12 to 24 hours. 
a=Screening Period=Days -45 to -4 (including Day -7, when ASA is started).  
b=Serum pregnancy test for women of childbearing potential  
c=A full physical examination is conducted at Screening, Day -3, and Day 28. Height and BMI calculation are completed at Screening and Day 29 
only. Weight is collected at Screening, Day -3, and Day 28. 
d=Brief physical examination (querying the subject concerning any changes from Baseline) 
e=Vital sign measurements (SBP and DBP, oral body temp, RR, and HR) will be collected at screening, check-in, before dosing (30 to 60 minutes 
prior to the initiation of the study drug infusion) and at 45, 60 min, 24 and 48 hours following initiation of study drug. Vital Signs are also collected 
on Day 7 and 28. Vital signs at 10, 20, and 30 minutes following infusion require only SBP, DBP, and HR.  
f=12-lead ECGs collection time will be communicated in Dosing Memos.  


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g=Beginning in the morning on Day –2, a single dose of oral ticagrelor 180 mg will be given, followed by oral ticagrelor 90 mg every 12 hours for 4 
additional doses through to Day 1 (2 hours before study drug is initiated; this will be 5 total doses of ticagrelor). 
h=PB2452 (or placebo) will be administered at Hour 0 of Day 1. 
i=ASA will be taken on Days -7, -6, -5, -4, -3, -2, -1, and on Day 1 (2 hours before study drug is started). Subjects who enter the study already taking 
ASA daily must document a daily ASA 81 mg dose between Day -7 and Day -3. Patients will receive daily ASA 81 mg between Day -3 (or Day -2 
if the patient took ASA 81mg on Day -3 prior to Check-in) and Day 1 at the clinical facility and will suspend further ASA dosing until discharge 
from the clinical facility. 
j=Continuous 12-lead Holter monitor placed 2 hours before administration of study drug will remain in place for 24 hours after the initiation of study 
drug. The resting schedule for Holter monitors will be aligned with PK draws.  
k=PD samples may be tested for additional hematologic biomarkers, such as P-selectin. 
l=Infusion site assessments will be performed for all subjects within 15 minutes before initiation of PB2452 (or placebo) infusion at Hour 0, and at 1, 
3, 24 and 48 hours after initiation of PB2452 (or placebo) infusion, and on Day 7.   
m=Subjects may be required to return to the site for collection of additional follow-up samples, if the sample collected at Day 28 tests positive for 
treatment-emergent ADAs. These visits may occur approximately 3 months after the final study visit and approximately every 6 months thereafter or 
until antibody levels return to Baseline level. 
n=Subjects are discharged from the clinic on Day 3. Subjects are permitted, if necessary/convenient to the subject to remain housed at PPD following 
discharge through Day 7 visit. There are no study assessments to be completed on Days 4, 5, and 6.