Conditions: Arterial Occlusive Diseases Coronary Artery Disease Coronary Disease Arteriosclerosis Heart Diseases Myocardial Ischemia Vascular Diseases Acute Coronary Syndrome
Keywords: Platelets Platelet Aggregation Inhibitors Protease-Activated Receptor 1 Hemorrhage
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 100
Healthy volunteers: no

Brief summary:
The object of the study is to determine whether different doses of PZ-128, when added to standard medical care in persons undergoing cardiac catheterization/percutaneous coronary intervention, will increase the risk of bleeding.

A secondary objective is to determine whether patients treated with PZ-128 have fewer cardiac events such as heart attack, bypass surgery or stroke compared with those persons treated with the standard of care.

Detailed description:

Arms:
arm 1: PZ-128, 0.3 mg/kg, in 250 cc 5% dextrose, single dose, 2-hour intravenous infusion arm 2: PZ-128, 0.5 mg/kg, in 250 cc 5% dextrose, single dose, 2-hour intravenous infusion arm 3: Placebo, in 250 cc 5% dextrose, single dose, 2-hour intravenous infusion

Interventions: intervention 1: PZ-128 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
PZ-128 
CLINICAL STUDY PROTOCOL TMC-PZ128-02 
VERSION: 04 AUG 2016 
TUFTS MEDICAL CENTER, INC. 
PAGE 1 OF 144 
CONFIDENTIAL 
 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Safety of PZ-128 in Subjects Undergoing Non-Emergent 
Percutaneous Coronary Intervention 
Thrombin Receptor Inhibitory Pepducin in PCI (TRIP-PCI) 
DRUG NAME: 
PZ-128 
IND NUMBER: 
110,931  
PROTOCOL NUMBER: 
TMC-PZ128-02 
DRUG DEVELOPMENT 
PHASE: 
2 
TRIAL SPONSOR: 
Tufts Medical Center, Inc. 
800 Washington Street 
Boston, MA 02111 
SPONSOR 
REPRESENTATIVE & 
MEDICAL DIRECTOR: 
CO-PRINCIPAL  
INVESTIGATORS: 
PROTOCOL DATE: 
04 AUG 2016 
NCT02561000


PZ-128 
CLINICAL STUDY PROTOCOL TMC-PZ128-02 
VERSION: 04 AUG 2016 
TUFTS MEDICAL CENTER, INC. 
PAGE 2 OF 144 
CONFIDENTIAL 
 
 
 
 
 
THIS CONFIDENTIAL INFORMATION ABOUT AN INVESTIGATIONAL DRUG IS 
PROVIDED FOR THE EXCLUSIVE USE OF INVESTIGATORS OF THIS DRUG AND IS 
SUBJECT TO RECALL AT ANY TIME.  THE INFORMATION IN THIS DOCUMENT MAY 
NOT BE DISCLOSED UNLESS SUCH DISCLOSURE IS REQUIRED BY FEDERAL OR 
STATE 
LAW 
OR 
REGULATIONS. 
SUBJECT 
TO 
THE 
FOREGOING, 
THIS 
INFORMATION MAY BE DISCLOSED ONLY TO THOSE PERSONS INVOLVED IN THE 
STUDY WHO HAVE A NEED TO KNOW, WITH THE OBLIGATION NOT TO FURTHER 
DISSEMINATE THIS INFORMATION.  THESE RESTRICTIONS ON DISCLOSURE WILL 
APPLY EQUALLY TO ALL FUTURE ORAL OR WRITTEN INFORMATION, SUPPLIED 
TO YOU BY TUFTS MEDICAL CENTER, INC., WHICH IS DESIGNATED AS  
“PRIVILEGED” OR “CONFIDENTIAL. 


TUFTS MEDICAL CENTER, INC. 
PAGE 3 OF 144 
CONFIDENTIAL 
PZ-128 
CLINICAL STUDY PROTOCOL TMC-PZ128-02 
VERSION: 04 AUG 2016 
 
 
 
 
STUDY PROTOCOL AMENDMENT HISTORY 
 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety 
of PZ-128 in Subjects Undergoing Non-Emergent Percutaneous Coronary Intervention- 
Thrombin Receptor Inhibitory Pepducin in PCI (TRIP-PCI) (Protocol No. TMC-PZ128-02)  
 
 
 
 
 
Amendment Number 
Protocol Version Date 
 
 
 
 
Initial preparation(s) 
07 JUL 2015 
 
 
15 SEP 2015 
 
 
09 OCT 2015 
 
 
Final 
04 JAN 2016 
 
 
#1 
04 AUG 2016 
 


TUFTS MEDICAL CENTER, INC. 
PAGE 4 OF 144 
CONFIDENTIAL 
PZ-128 
CLINICAL STUDY PROTOCOL TMC-PZ128-02 
VERSION: 04 AUG 2016 
 
 
 
 
1.0 
SYNOPSIS  
Name of Sponsor/Institute:   Tufts Medical Center, Inc.  
Funding grant provided by the National Heart, Lung and Blood Institute, National Institutes of Health 
(NHLBI/NIH)  
Name of Investigational Product:  PZ-128  
Name of Active Ingredient:  PZ-128 
Title of Study: A Multi-center, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Safety of PZ-128 in Subjects Undergoing Non-Emergent Percutaneous Coronary Intervention   
Thrombin Receptor Inhibitory Pepducin in PCI (TRIP-PCI) (Protocol No. TMC-PZ128-02) 
Study Sites: 
Inova Heart and Vascular Institute, Inova Fairfax Hospital, Falls Church, VA                 
 
Tufts Medical Center, Boston, MA 
 
UMass Memorial Medical Center, Worcester, MA 
Projected Study Timelines:   
Actual date first subject enrolled:   
27 May  2016 
Estimated date last subject enrolled:   
December 2018 
Estimated date last subject completed:   March 2019 
Clinical Phase:  2 
Indication:  Non-emergent percutaneous coronary intervention (PCI) 
Primary Objective:  The primary objective is to evaluate the safety of single dose PZ-128, in 
addition to the standard of care, with respect to the incidence of major and minor bleeding events, as 
assessed by the TIMI (Thrombolysis in Myocardial Infarction) classification, in subjects undergoing 
non-emergent PCI or non-emergent cardiac catheterization with the intent to perform PCI.                      
Key Secondary Objective:  The key secondary objective is to evaluate the potential clinical benefit 
of PZ-128 with respect to the composite endpoint of major adverse cardiac events (MACE) - any of 
cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke, recurrent ischemia 
requiring hospitalization or urgent coronary revascularization.  
Other Secondary Objectives Related to Safety:  Other secondary safety objectives include 
evaluation of the incidences of the following:    
1. bleeding that does not meet the TIMI criteria for major or minor (i.e.,  minimal bleeding); 
2. “clinically significant” bleeding;  
3. TIMI bleeding related to coronary artery bypass grafting (CABG); and 
Other Secondary Objectives Related to Efficacy:  Other secondary efficacy objectives will include 
evaluation of the following:  
1. incidence of the individual components of the MACE composite as measures of potential clinical 
benefit;  
2. incidence of definite or probable stent thrombosis as a measure of potential clinical benefit; 
3. inhibition of platelet aggregation induced by SFLLRN (PAR1 agonist) and thrombin as an 
indicator of the desired pharmacodynamic effect, and ADP (adenosine diphosphate), collagen and 
AYPGKF (PAR4 agonist) to evaluate the specificity of PZ-128;   
4. effect of the investigator choice of P2Y12 inhibitor on the individual components of the MACE   
composite; and  
5. population pharmacokinetics.  
Exploratory Objectives: Exploratory objectives will include the following:    
 
1. incidence of bleeding events according to the BARC (Bleeding Academic Research Consortium) 
classification;   
2. effect on expression of systemic markers of thrombosis and platelet reactivity, inflammation, and 
metabolomics; and 
3. population pharmacogenomics.  
 


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CONFIDENTIAL 
PZ-128 
CLINICAL STUDY PROTOCOL TMC-PZ128-02 
VERSION: 04 AUG 2016 
 
 
 
 
 
Methodology: Multicenter, prospective, randomized, double-blind, placebo-controlled, balanced-
parallel-groups, non-inferiority investigation.  
Number of Subjects (planned):  Approximately 600 (400 to receive PZ-128, 200 to receive 
placebo).  There is no pre-specified minimum or maximum enrollment for each site.  
Diagnosis and Main Criteria for Inclusion:  Adult subjects (≥18years), meeting all inclusion 
criteria and none of the exclusion criteria, scheduled to undergo non-emergent coronary angiography 
+/- PCI (if indicated) for either stable coronary artery disease or non-ST-segment elevation acute 
coronary syndromes (NSTE-ACS) (i.e., candidates for elective or urgent PCI), and for whom 
elective use of a GP IIb/IIIa inhibitor (GPI) is not intended, will be enrolled. 
Investigational Product, Dose and Mode of Administration:  PZ-128 lyophilized powder for 
reconstitution in Sterile Water for Injection and dilution in 5% Dextrose.  Subjects receive 0.3 mg/kg 
or 0.5 mg/kg as a single-dose via a continuous, 2-hour, intravenous infusion.  
Reference therapy, Dose and Mode of Administration:  Matching placebo lyophilized powder for 
reconstitution in Sterile Water for Injection and dilution in 5% Dextrose.  Subjects receive placebo 
corresponding to PZ-128 0.3 mg/kg or 0.5 mg/kg as a single-dose via a continuous, 2-hour, 
intravenous infusion.  
Duration of Treatment:  Single dose infusion to start within one hour before the diagnostic 
angiography begins.  Subjects are expected to receive the entire 2-hour infusion regardless of 
whether they proceed to undergo PCI, CABG or medical management. 
Criteria for Evaluation 
Primary Safety Endpoint:  The primary safety endpoint of the study will be the incidence of TIMI 
major plus minor bleeding not related to CABG through 30 days after treatment.  TIMI Major 
bleeding is defined as (1) intracranial hemorrhage or (2) clinically significant overt signs of bleeding 
associated with a decrease in hemoglobin concentration of ≥5 g/dL (or hematocrit ≥15%) or (3) fatal 
bleeding within 7 days.  TIMI Minor bleeding is defined as clinically overt signs of bleeding 
(including imaging) associated with a decrease in hemoglobin concentration of 3 to <5 g/dL (or 
hematocrit of 9 to <15%) that does not otherwise meet criteria for major bleeding.  Hemoglobin 
concentration and hematocrit will be adjusted for any transfusion of packed red blood cells or whole 
blood given between enrollment and post-transfusion measurements.    
Key Secondary Efficacy Endpoint:  The key secondary efficacy endpoint is the incidence of any 
component of the MACE composite through 30 days and 90 days after treatment.  
Other Secondary Endpoints Related to Safety:  Other secondary safety endpoints include the 
incidences of the following: 
1. TIMI minimal bleeding not related to CABG (defined as clinically significant overt signs of 
bleeding associated with a drop in hemoglobin concentration of <3 g/dL (or hematocrit of <9%) 
that does not otherwise meet criteria for major or minor bleeding) through 30 days after 
treatment; 
2. “clinically significant” bleeding  (defined as TIMI major or minor bleeding or bleeding 
requiring medical attention) through 30 days after treatment; 
3. TIMI bleeding related to CABG through 30 days after treatment (subjects who undergo CABG 
will specifically have assessment of (a) surgical wound bleeding using quantitative total chest 
tube drainage in the first 24 hours; (b) need for transfusion of blood products in the first 48 
hours; and (c) need for surgical re-exploration). 
Other Secondary Endpoints Related to Efficacy:  Other secondary efficacy endpoints will include 
the following: 
1. incidence of the individual components of the MACE composite through 30 days and 90 days 
after treatment; 


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CONFIDENTIAL 
PZ-128 
CLINICAL STUDY PROTOCOL TMC-PZ128-02 
VERSION: 04 AUG 2016 
 
 
 
 
2. incidence of definite or probable stent thrombosis through 30 days and 90 days after treatment; 
3. inhibition of platelet aggregation induced by SFLLRN, thrombin, ADP, collagen and AYPGKF,  
relative to baseline at several time points following treatment at select sites; 
4. population pharmacokinetics at baseline and at several time points following treatment; and  
5. effect of the investigator choice of P2Y12 inhibitor (i.e., clopidogrel versus prasugrel/ticagrelor) 
on the individual components of the MACE composite.   
Exploratory Endpoints:  These endpoints are not part of the formal objectives and are included as 
additional ways to evaluate bleeding and to gather information for future research.  
1. incidence of bleeding events according to the BARC (Bleeding Academic Research  
Consortium) classification through 30 days after treatment;  
2. change from baseline in select systemic markers of thrombosis and platelet reactivity, 
inflammation, and metabolomics at select time points; 
3. population pharmacogenomics at baseline. 
 
Clinical evaluations including physical examinations, vital signs, laboratory tests, 
electrocardiograms and the assessment of adverse events will be performed for all subjects during 
hospitalization and at follow-up time points as measures of the safety profile. 
Randomization:   Randomization will be conducted prior to the diagnostic angiography.   
Stratification:   Randomized assignment of PZ-128 and placebo will be stratified for whether the 
cardiac catheterization ± PCI is being done on an elective or urgent basis at the time the operator 
decides to perform the procedure.  
Sample Size/Power:  The current design anticipates a sample size of 600 subjects who will undergo 
non-emergent cardiac catheterization ± PCI.  The sponsor anticipates that the incidence of major 
plus minor bleeding among placebo-treated subjects will range from 2% to 6% on the basis of 
historical experience.  Given the anticipated sample sizes and estimated range of incidences 
associated with placebo, the study will be able to demonstrate that the bleeding risk of PZ-128 is 
non-inferior to the risk associated with placebo with non-inferiority margins in the range of 2.6 to 
7.6%, depending on the underlying bleeding risk of placebo.  Given the anticipated benefits of PZ-
128, these non-inferiority margins are reasonable for the planned safety decisions generated from 
this trial.  
Statistical Methods:   All subjects who are randomized will be considered evaluable for the 
analyses.  The following statistical analysis will be provided for the primary endpoint.     The point 
estimate of the difference in risk of any event of non-CABG TIMI major plus minor bleeding 
through 30 days post treatment for between PZ-128 and placebo (e.g., Pr (Event in PZ-128 patient)-
Pr (Event in placebo patient)), and corresponding lower one-sided 95% confidence interval will be 
presented.  These estimates will be generated using subjects who underwent diagnostic angiography 
for all PZ-128 treatment arms pooled across both doses (~400 subjects) and all placebo (~200 
subjects) and descriptive results will also be generated for each individual dose. The proposed phase 
2 study is not of sufficient size or of sufficient follow-up duration to allow formal analysis of clinical 
efficacy.  
Sub-analyses of the endpoints will be performed across subject cohorts (i.e., PCI, CABG and 
medical management). Comparisons for primary and secondary endpoints will be done for PZ-128 
in aggregate and per dosing group. The potential influence of baseline risk factors and concomitant 
therapies such as statins, choice of P2Y12, and aspirin dosing on the incidences of the endpoints will 
also be explored using generalized linear models and survival models.   
Subgroup analyses will be conducted for baseline characteristic variables such as age, sex, and race.  
All bleeding events will be characterized as non-CABG or CABG related and the following bleeding 
rates will be reported:  total, CABG-related and non-CABG-related.   


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CONFIDENTIAL 
PZ-128 
CLINICAL STUDY PROTOCOL TMC-PZ128-02 
VERSION: 04 AUG 2016 
 
 
 
 
 
 
 
Tabulations of descriptive statistics will be provided for TIMI major plus minor bleeding.  In 
addition, tabulations of descriptive statistics will also be provided on the incidence of all other 
relevant variables.  
Although no formal stopping boundaries will be utilized, one interim safety analysis will be 
performed at approximately one year following the enrollment of the first subject, or after 
enrollment of 50% of the study population, whichever occurs first.  The Data and Safety Monitoring 
Board (DSMB) will be provided point and interval estimates of PZ-128 benefit at the time of that 
analysis based on survival estimates, and will evaluate evidence of bleeding risk in light of the 
potential efficacy benefits in making recommendations about stopping the trial.  
Among the committees formed to oversee the conduct of the study will be an independent DSMB to 
protect further the rights, safety and well-being of subjects who will be participating in this study by 
monitoring the progress and results of the trial, and an independent Clinical Events Committee 
(CEC) to review and adjudicate each suspected bleeding and efficacy endpoint event while blinded 
to treatment. 


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PAGE 8 OF 144 
CONFIDENTIAL 
PZ-128 
CLINICAL STUDY PROTOCOL TMC-PZ128-02 
VERSION: 04 AUG 2016 
 
 
 
 
1.1 
Study Design Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
                                   
           
 
 
 
 
 
 
 
 
 
 
 
Subjects Undergoing Non-Emergent PCI or Cardiac 
Catheterization With Intent to Perform PCI 
(elective use of a GP IIb/IIIa inhibitor is not intended) 
(Screening up to 14 days prior to procedure) 
Randomization (n=600; 2:2:1:1) 
                             
PZ-128 
0.3 mg/kg 
PZ-128 
0.5 mg/kg 
Placebo 
0.3 mg/kg 
Cardiac Catheterization 
Initiate PZ-128/Placebo infusion 0-60 minutes prior to start of angiography & 
administer over 2 hours 
 
Presumptive PCI 
Patients receive Antithrombotic Agent (unfractionated 
heparin or low-molecular-weight heparin) and P2Y12 
Inhibitor 
No PCI 
PCI Commences 
(wire crosses lesion) 
CABG 
Medical 
Management 
In-Hospital Stay  
(Post Treatment – Hospital Discharge) 
14 days (± 5 d) Post Study Drug Visit Follow-up  
Safety:  TIMI Major + Minor Bleeding (Primary) 
Efficacy:  MACE, Stent Thrombosis and Inhibition of Platelet Aggregation 
(Secondary) 
30 days (± 5 d) and 90 days (± 7 d) Post Study Drug Telephone Follow-up 
No 
Yes 
Placebo 
0.5 mg/kg 


PAGE 9 OF 144 
PZ-128 
CLINICAL STUDY PROTOCOL TMC-PZ128-02 
VERSION: 04 AUG 2016 
 
 
 
 
1.2 
Study Flow Chart 
 
Study Assessment/Procedure  
Screening10 
Enrollment  
Always in Hospital 
Post-Treatment Follow-up 
Immediately 
Prior to 
Study Drug 
Infusion11 
Immediately 
Post Study 
Drug 
Infusion 
Post 
Cardiac 
Cath ± 
PCI14 
24 Hours (±2)  
Post Start of 
Study Drug or  
Discharge17, 18 
14 days (± 5) 
Post Study 
Drug Infusion 
Office Visit 
30 days (± 5) 
Post Study 
Drug Infusion 
Phone Call 
90 days (± 7) 
Post Study 
Drug Infusion 
Phone Call 
Explain Study / Written 
Informed Consent(s)1 
X 
 
 
 
 
 
 
 
 
Review of Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
Medical History2 and 
Demographics 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
X19 
X 
 
 
Electrocardiogram  
(12-Lead ECG) 
X 
 
 
 
X 
 
X 
 
 
Vital Signs3 Assessment 
X 
 
X 
X 
X 
X 
X 
 
 
Previous and Concomitant  
Medications 
         X 
 
Adverse Events Assessment 
(Bleeding and Non-Bleeding) 
 
X 
 
 
Serious Adverse Events 
Assessment  
(Bleeding and Non-Bleeding) 
 
X   
Clinical Efficacy Endpoint 
Events Assessment  
(MACE, Stent Thrombosis) 
 
X  
Standard Local Laboratory Tests: 
 
 
 
 
 
 
 
 
 
 Hematology4 
X 
 
 
 
X 
X 
X 
 
 
 Serum Chemistry5 
X 
 
 
 
 
X 
 
 
 
 PT/INR, aPTT 
X 
 
 
 
 
X 
 
 
 
 Activated Clotting Time 
 
 
 
 
X 15 
 
 
 
 
 Lipid Panel6 
X 
 
 
 
 
 
 
 
 
 Hemoglobin A1c 
X 
 
 
 
 
 
 
 
 
 Pregnancy Test7 (urine) 
X 
 
X7 
 
 
 
X 
 
 
 
 


PAGE 10 OF 144 
PZ-128 
CLINICAL STUDY PROTOCOL TMC-PZ128-02 
VERSION: 04 AUG 2016 
 
 
 
 
Study Assessment/Procedure  
Screening10 
Enrollment  
Always in Hospital 
Post-Treatment Follow-up 
Immediately 
Prior to 
Study Drug 
Infusion11 
Immediately 
Post Study 
Drug 
Infusion 
Post 
Cardiac 
Cath ± 
PCI14 
24 Hours (±2)  
Post Start of 
Study Drug or  
Discharge17, 18 
14 days (± 5) 
Post Study 
Drug Infusion 
Office Visit 
30 days (± 5) 
Post Study 
Drug Infusion 
Phone Call 
90 days (± 7) 
Post Study 
Drug Infusion 
Phone Call 
Sample Collections For Research 
(required): 
 
 
 
 
 
 
 
 
 
 Cardiac Troponin I8 
 Serum 
 
 
X 
 
X16 
X16 
 
 
 
Sample Collections For Research 
(optional1):  
 
 
 
 
 
 
 
 
 
 Pharmacodynamics (PD)- 
 Platelet Aggregation9 
 Whole Blood 
 
 
X 
X12 
X12, 20 
X 
 
 
 Pharmacokinetics  (PK)9 
 Plasma 
 
 
X 
X12 
X12, 20 
X 
 
 
 Exploratory Biomarkers 
 Plasma 
 
 
X 
X13 
X13, 20 
X 
 
 
 Pharmacogenomics (DNA/RNA) 
 Whole Blood 
 
 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Written informed consent for the optional sampling:  pharmacogenomics (DNA/RNA), pharmacodynamics-platelet aggregation, pharmacokinetics, and exploratory 
biomarkers may be contained in the same instrument as written informed consent for the rest of the study, or may be a separate document, at the discretion of the 
institutional review board (IRB). Regardless, separate signatures of informed consent are required to collect each of the optional samples.   
2. Including subject’s cardiac history, the clinical evaluation leading to the cardiac catheterization procedure (i.e., CAD presentation, Canadian Cardiovascular 
Society Classification for angina, Thrombolysis in Myocardial Infarction Risk Score for UA/NSTEMI, and New York Heart Association Classification of 
Functional Status for heart failure), bleeding history and allergy history (drugs, IV contrast media, food, stings and atopic conditions and any required treatment/ 
medical intervention). 
3. Vital signs to include heart rate, blood pressure, and at Screening only, height and weight. 
4. Hematology includes a complete blood cell count, differential WBC count and platelet count. 
5. Chemistry includes sodium, potassium, chloride, carbon dioxide, glucose, BUN, creatinine, alkaline phosphatase, total bilirubin, ALT and AST.    
6. Lipid Panel includes total cholesterol, high-density lipoprotein cholesterol, calculated low-density lipoprotein cholesterol and triglycerides (does not have to be 
fasting). 
7. Urine pregnancy test (urine beta-HCG) must be performed on all women of child-bearing potential prior to randomization and must also be repeated prior to study 
drug administration if screening assessment >24 hours. 


PAGE 11 OF 144 
PZ-128 
CLINICAL STUDY PROTOCOL TMC-PZ128-02 
VERSION: 04 AUG 2016 
 
 
 
 
8. Cardiac Troponin I (cTnI) analysis to be conducted by a centralized lab at Tufts Medical Center.  Additional cardiac biomarkers (i.e., Troponin I or T, CK-MB) 
analyzed locally at the clinical site for routine management of the subject will be guided by standard of care/local hospital clinical practice and the results will be 
collected when applicable.    
9. At select sites only in the Sub-study. 
10. Screening evaluations must be performed prior to Enrollment/Randomization and must be within 14 days prior to cardiac catheterization and study drug treatment 
(may include standard of care preadmission testing for the planned procedure). 
11. Study drug infusion must be started within 0-60 min prior to the commencement of the cardiac catheterization procedure (diagnostic angiography). 
12. Samples will be collected at 30 min ± 5 min, 1 h ± 5 min, 2 h + 15 min (immediately after completion of infusion), 6 h – 2 h (4 to 6 h) and 24 h ± 2 h (or at hospital 
discharge, whichever occurs sooner) after the start of the study drug infusion (T=0). 
13. Samples will be collected at 2 h + 15 min (i.e., immediately after completion of infusion), 6 h – 2 h (4 to 6 h) and 24 h ± 2 h (or at hospital discharge, whichever 
occurs sooner) after the start of the study drug infusion (T=0).  
14. After cardiac catheterization, if PCI does not commence or after PCI commences, regardless of outcome.  Except as specifically noted, timing should be consistent 
with standard practice at the clinical site. 
15. Following administration of the initial bolus of anticoagulant (UFH/LMWH), activated clotting time will be measured locally at “peak dose” and just prior to 
sheath removal, as well as according to the standard of care and applies only to PCI subjects.    
16. Collect samples for research cTnI at 4 to 8 h and 12 to 24 h after completion of PCI. In addition, collect samples immediately after occurrence of symptoms 
suggestive of acute coronary syndrome, and again 4 to 8 h and 12 to 24 h after symptoms if the subject has not yet been discharged from the hospital.  
17. Assessments should be performed at 24 Hours (± 2 h) post start of study drug infusion or just prior to Discharge, whichever occurs sooner. 
18. If a subject remains in the hospital for >24 hours, additional testing/evaluation will be guided by standard of care and local guidelines.  
19. The clinical site’s standard of care, cardiac catheterization nursing assessment may be performed to evaluate the subject’s clinical status in lieu of a complete 
physical exam at the 24 hour/Discharge (whichever occurs sooner) time point. 
20. After the 24 hour collection, if a subject remains in the hospital for ≥48 h, collect an additional sample at discharge.  
 
 
 


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CONFIDENTIAL 
PZ-128 
CLINICAL STUDY PROTOCOL TMC-PZ128-02 
VERSION: 04 AUG 2016 
 
 
 
 
2.0 
TABLE OF CONTENTS 
 
TITLE PAGE ..................................................................................................................... 1 
STUDY PROTOCOL AMENDMENT HISTORY ........................................................ 3 
1.0 
PROTOCOL SYNOPSIS .................................................................................... 4 
1.1 
Study Design Diagram ........................................................................................... 8 
1.2 
Study Flow Chart ................................................................................................... 9 
2.0 
TABLE OF CONTENTS .................................................................................. 12 
2.1 
List of Appendices  .............................................................................................. 15 
3.0 
ABBREVIATIONS AND DEFINITIONS OF TERMS ................................. 16 
4.0 
 INTRODUCTION ............................................................................................. 21 
4.1 
 Background ......................................................................................................... 21 
4.1.1  Clinical Overview ............................................................................................... 21 
4.1.2  Investigational Agent:  PZ-128 ........................................................................... 25 
4.1.2.1  Preclinical Studies ............................................................................................... 26 
4.1.2.2  Clinical Studies ................................................................................................... 26 
4.2 
 Rationale .............................................................................................................. 28 
4.2.1  Rationale for Study Design and Subject Population ........................................... 28 
4.2.2  Rationale for PZ-128 Doses ................................................................................ 30 
5.0 
 STUDY OBJECTIVES ..................................................................................... 31 
5.1 
Primary Objective ............................................................................................... 31 
5.2 
Key Secondary Objective .................................................................................... 31 
5.3 
Other Secondary Objectives Related to Safety ................................................... 31 
5.4 
Other Secondary Objectives Related to Efficacy ................................................ 31 
5.5 
Exploratory Objectives  ....................................................................................... 32 
6.0 
INVESTIGATIONAL AND ANALYSIS PLAN ............................................ 33 
6.1 
Overall Study Design and Plan:  Description ...................................................... 33 
6.2 
Participation in and Completion of the Study ..................................................... 35 
6.3 
Study Population ................................................................................................. 36 
6.3.1 
Subject Inclusion Criteria .................................................................................... 37 
6.3.2 
Subject Exclusion Criteria ................................................................................... 38 
6.3.3 
Study Drug Discontinuation and Study Termination Criteria ............................. 41 
6.3.4 
Replacement of Subjects ..................................................................................... 43 
6.4 
Study Treatments ................................................................................................. 43 
6.4.1 
Blinded Investigational Study Drugs .................................................................. 43 
 
 


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PZ-128 
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VERSION: 04 AUG 2016 
 
 
 
 
6.4.3 
Other Required and Potential Rescue Treatment(s) (Standard of Care) ............. 44 
6.4.4 
Method of Study Drug Assignment, Randomization and/or Stratification ......... 46 
6.4.5 
Selection and Timing of Dose for Each Subject ................................................. 46 
6.4.6 
Blinding of Study Drug ....................................................................................... 47 
6.4.7 
Investigational Product(s) ................................................................................... 48 
6.4.7.1 Identity of Investigational Product(s) .................................................................. 48 
6.4.7.2 Source .................................................................................................................. 48 
6.4.7.3 Labeling ............................................................................................................... 49 
6.4.7.4 Packaging ............................................................................................................ 49 
6.4.7.5 Storage ................................................................................................................. 49 
6.4.7.6 Reconstitution, Dilution and Dispensing ............................................................ 49 
6.4.7.7 Administration ..................................................................................................... 50 
6.4.7.8 Drug Accountability ............................................................................................ 51 
6.4.8 
Non-Study Treatments ........................................................................................ 52 
6.4.8.1 Prior and Concomitant Medications .................................................................... 52 
6.4.8.1.1 Medications/Therapies Prohibited Prior to Randomized Study Treatment 
Assignment and During the Study ...................................................................... 52 
6.4.8.1.2 Medications/Therapies Allowed During the Study ............................................ 53 
6.4.8.2 Other Restrictions ................................................................................................ 53 
6.4.9 
Procedures for Monitoring Compliance .............................................................. 53 
6.5 
Study Schedule .................................................................................................... 54 
 
Figure 1.  Study and Treatment Schema ............................................................. 55 
6.5.1 
Screening ............................................................................................................. 56 
6.5.2 
Enrollment and Randomization ........................................................................... 57 
6.5.3 
Pre-Cardiac Catheterization Procedure ............................................................... 58 
6.5.4 
Cardiac Catheterization ± Percutaneous Coronary Intervention ......................... 59 
6.5.5 
Post-PZ-128/Placebo Infusion ............................................................................. 59 
6.5.6 
Post-Cardiac Catheterization/PCI ....................................................................... 60 
6.5.7 
24 hours (± 2 h) Post Start of Study Drug Infusion or At Discharge from 
Hospital (whichever occurs sooner) .................................................................... 60 
6.5.8 
Hospitalization lasting >24 Hours ....................................................................... 61 
6.5.9 
14 days (± 5 d) Post Study Drug Infusion Follow-Up Outpatient Visit .............. 61 
6.5.10 30 days (± 5 d) Post Study Drug Infusion Follow-Up Telephone Call ............... 62 
6.5.11 90 days (± 7 d) Post Study Drug Infusion Follow-Up Telephone Call ............... 63 
6.5.12 Non-PCI Subjects:  Catheterization to Study Completion .................................. 63 
6.6 
Study Procedures ................................................................................................. 64 
6.6.1 
Standard Procedures and Clinical Evaluations .................................................... 64 
6.6.2 
Standard Laboratory Tests .................................................................................. 67 
6.6.3 
Research Laboratory Tests and Collections ........................................................ 68 
6.6.3.1 Mandatory ........................................................................................................... 68 
6.6.3.2 Optional ............................................................................................................... 69 


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Table 1.  Summary of Total Blood Sampling ..................................................... 71 
6.7 
Study Assessments .............................................................................................. 72 
6.7.1 
Safety/Activity/Efficacy Endpoints ..................................................................... 72 
6.7.1.1 Primary Endpoint (Safety) .................................................................................. 72 
6.7.1.2 Key Secondary Endpoint (Efficacy).................................................................... 72 
6.7.1.3 Other Secondary Endpoints Related to Safety .................................................... 72 
6.7.1.4 Other Secondary Endpoints Related to Efficacy ................................................. 73 
6.7.1.5 Exploratory Endpoints ......................................................................................... 73 
6.7.1.6 Appropriateness of Measurements ...................................................................... 73 
6.7.2 
Additional Safety Assessment ............................................................................. 73 
6.7.2.1 Specification of Safety Variables ........................................................................ 73 
6.7.2.2 Assessment and Reporting of Adverse Events .................................................... 74 
6.7.2.2.1 Assessment of Adverse Event Severity and Relationship to Treatment ............ 75 
6.7.2.2.2 Monitoring Adverse Events ............................................................................... 77 
6.7.2.2.3 Known Adverse Events Relating to the Underlying Clinical Condition ........... 77 
6.7.2.2.4 Known Potential Toxicities of Study Drug ....................................................... 77 
6.7.2.2.5 Definition of Serious Adverse Events ............................................................... 78 
6.7.2.2.6 Reporting of Subject Death................................................................................ 81 
6.7.2.2.7 Reporting of Pregnancies ................................................................................... 81 
6.7.2.2.8 Preplanned Hospitalizations or Procedures ....................................................... 82 
6.7.2.2.9 Reports of Overdose .......................................................................................... 82 
6.7.2.2.10 Protocol-Specific Exceptions to SAE Reporting to Sponsor ........................... 83 
6.7.2.2.11 Reporting of Investigational Medicinal Product Quality Complaints .............. 84 
6.7.2.3 Guidelines and Management of Special Situations ............................................. 84 
6.7.3 
Other Assessments .............................................................................................. 87 
6.7.3.1 Optional Pharmacogenomics (DNA and RNA) Analysis ................................... 87 
6.7.3.2 Optional Sampling for Pharmacokinetics, Pharmacodynamics  
 
(Platelet Aggregation), Exploratory Biomarkers ................................................ 87 
6.7.4 
Criteria for Termination of Trial ......................................................................... 88 
7.0 
STATISTICAL AND ANALYTICAL PLAN ................................................. 89 
7.1 
Study Design ....................................................................................................... 89 
7.2 
General Aspects of Statistical Evaluation ........................................................... 89 
7.3 
Data Sets .............................................................................................................. 90 
7.4 
Demographic and Other Baseline Characteristics ............................................... 90 
7.5 
Safety Analyses ................................................................................................... 90 
7.5.1 
Primary Endpoint ................................................................................................ 90 
7.5.2 
Secondary Safety Endpoints ................................................................................ 91 
7.5.3 
Exploratory Safety Endpoints ............................................................................. 91 
7.5.4 
Methodology ....................................................................................................... 91 
7.6 
Efficacy Analyses ................................................................................................ 92 


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7.6.1 
Secondary Efficacy Endpoints ............................................................................ 92 
7.6.2 
Methodology ....................................................................................................... 93 
7.7 
Determination of Sample Size/Power ................................................................. 93 
7.8 
Interim Analysis .................................................................................................. 94 
7.9 
Other Analyses .................................................................................................... 94 
7.9.1 
Pharmacokinetics ................................................................................................ 94 
7.9.2 
Pharmacodynamics .............................................................................................. 94 
7.9.3 
Exploratory Biomarkers ...................................................................................... 95 
8.0 
ADHERENCE TO ETHICAL, REGULATORY, AND 
ADMINISTRATIVE CONSIDERATIONS .................................................... 97 
8.1 
Ethical Conduct of the Study .............................................................................. 97 
8.1.1 
Institutional Review Board .................................................................................. 97 
8.1.2 
Subject Information and Consent ........................................................................ 98 
8.1.3 
Protocol-Related Regulatory Issues .................................................................... 98 
8.2 
Reporting to Sponsor and Subject Confidentiality .............................................. 99 
8.3 
Publications and Other Rights ........................................................................... 100 
9.0 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ... 102 
9.1 
Sponsor .............................................................................................................. 102 
9.2 
  Investigators ...................................................................................................... 102 
9.3 
  Committees and Central Organizations ............................................................. 102 
9.3.1 
Data and Safety Monitoring Board (DSMB) .................................................... 103 
9.3.2 
Clinical Events Committee (CEC) .................................................................... 103 
9.3.3 
Centralized Randomization Service (Medidata Rave®) ................................... 104 
9.3.4 
Research Triangle Institute, International (RTI) ............................................... 104 
9.3.5 
Clinical Supplies Management (CSM) ............................................................. 104 
9.3.6 
Central Research Laboratory- Tufts Center for Hemostasis and Thrombosis...104 
10.0   REFERENCES ................................................................................................ 106 
 
2.1 
List of Appendices 
 
Appendix A 
SIGNATURES ................................................................................ 112 
Appendix B 
DEFINITIONS OF CLINICAL ENDPOINTS ............................... 115 
Appendix C 
ADDITIONAL SAFETY INFORMATION ................................... 131 
Appendix D 
GENERAL REQUIREMENTS FOR CLINICAL TRIALS ........... 134 
Appendix E 
CONFIDENTIALITY AND SECURITY OF  
 
  
PHARMACOGENOMICS RESEARCH ..................................... ..140 
Appendix F 
SUGGESTED MODEL INFORMED CONSENT DOCUMENT..144 
 


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3.0 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
ACC 
American College of Cardiology 
ACS 
Acute coronary syndrome(s) 
ACT 
Activated clotting time 
ADP 
Adenosine diphosphate 
AE 
Adverse event  
AHA 
American Heart Association 
ALT 
Alanine aminotransferase 
AMI 
Acute myocardial infarction 
API 
AmbioPharm, Inc. 
aPTT 
Activated partial thromboplastin time 
ARC 
Academic Research Consortium 
ASA 
Acetyl salicylic acid (aspirin) 
AST 
Aspartate aminotransferase 
AUC 
Area under plasma concentration-time curve from zero to infinity 
AYPGKF 
Ala-Tyr-Pro-Gly-Lys-Phe (PAR4 agonist peptide) 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CABG 
Coronary artery bypass graft surgery 
CAD 
Coronary artery disease 
cAMP  
Cyclic adenosine monophosphate  
CBC 
Complete blood count 
CEC 
Clinical Events Committee 
CFR 
USA Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CK 
Creatine kinase 
CKD 
Chronic kidney disease  
CK-MB 
Creatine kinase-myocardial band  
Cmax 
Maximum plasma (peak) drug concentration 
CRF 
Case report form 
CRS 
Central Randomization Service 


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CSR 
Clinical study report  
cTn 
Cardiac troponin  
CVA 
Cerebrovascular accident 
CXR 
Chest x-ray 
DAPT 
Dual anti-platelet therapy 
DSMB 
Data and Safety Monitoring Board 
ECG, EKG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
Endpoint 
A status of the subject that constitutes the ‘endpoint’ of a subject’s 
participation in a clinical study and that is used as the final outcome 
FACS 
Fluorescence activated cell sorter 
FAX 
Telefacsimile 
FDA 
Food & Drug Administration, USA 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices  
GMP 
Good Manufacturing Practices  
GPI 
Glycoprotein IIb/IIIa inhibitors 
GPCR 
G protein coupled receptor 
GPRP 
Gly-Pro-Arg-Pro (fibrinogen inhibitor) 
h 
Hour(s) 
Hct 
Hematocrit 
HDL-C 
High-density-lipoprotein cholesterol 
Hgb 
Hemoglobin 
HPR 
High platelet reactivity 
HR 
Heart rate 
IATA 
International Air Transport Association 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use  
IFU 
Instructions for Use  
IND 
Investigational New Drug Application 
INDSR 
Investigational New Drug Safety Report 
INR 
International Normalized Ratio 


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IPA 
Inhibition of platelet aggregation 
IP 
Investigational Product(s) 
IRB 
Institutional Review Board 
IPA 
Inhibition of platelet aggregation 
ITT 
Intent-to-treat- refers to a study population for statistical analysis 
IUD 
Intrauterine device 
IV 
Intravenous, intravenously 
IVRS 
Interactive voice response system 
Kg 
Kilogram 
LBBB 
Left bundle branch block 
LC/MS/MS 
Liquid chromatography/tandem mass spectrometry 
LDL-C 
Low-density-lipoprotein cholesterol 
LMWH 
Low molecular weight heparin 
LTI 
Lyophilization Technology, Inc. 
LVEF  
Left ventricular ejection fraction 
MACE 
Major adverse cardiac events 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MI 
Myocardial infarction 
min 
Minute(s) 
nM 
Nanomolar  
MMP-1 
Matrix metalloprotease-1 
NSTE-ACS 
Non-ST segment elevation acute coronary syndrome 
NSTEMI 
Non-ST segment elevation myocardial infarction 
NYHA 
New York Heart Association  
PAR 
Protease Activated Receptor 
PAR1 
Protease Activated Receptor-1 
PAR4 
Protease Activated Receptor-4  
P2Y12 
A sub-type of P2 receptor found on platelets 
PCI 
Percutaneous coronary intervention 
PD 
Pharmacodynamic 
PE 
Physical exam 


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PK 
Pharmacokinetic 
PPP 
Platelet poor plasma 
PRBCs 
Packed red blood cells 
PRN 
Pro re nata (as needed, as necessary) 
PRP 
Platelet rich plasma 
Principal Investigator 
A person responsible for the conduct of a clinical study at an 
investigational study site 
PSI 
Post start of the infusion 
PT 
Prothrombin time 
Qualified designee 
 A person designated by the investigator who is qualified by training 
and/or experience to perform the specified tests, evaluation, 
measurement, recording, procedure, or other technique,  for the 
purpose of a physical examination, a qualified designee is a medical 
professional licensed and/or approved per local requirements to 
performed the required portions of a physical examination 
RAVE 
Proprietary name for Medidata web based data capture software 
RBC 
Red blood cell  
SAE 
Serious adverse event  
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SFLLRN 
Ser-Phe-Leu-Leu-Arg-Asn (PAR1 agonist peptide) 
SGOT 
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
Serum glutamic pyruvic transaminase (ALT) 
SNP 
Single nucleotide polymorphism 
SOC 
Standard(s) of care 
SOP 
Standard operating procedure(s) 
STEMI 
ST-segment-elevation myocardial infarction 
t1/2 
Half-life 
TAT 
Thrombin-anti thrombin III complex 
TEG 
Thromboelastography 
TIA 
Transient ischemic attack 
TIMI 
Thrombolysis in Myocardial Infarction 
TNFα 
Tumor necrosis factor-α 
TRAP 
Thrombin receptor activating peptide (SFLLRN) 


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TRA-PCI 
Thrombin Receptor Antagonist-Percutaneous Coronary Intervention 
TXA2 
Thromboxane A2 
TRIP-PCI 
Thrombin Receptor Inhibitory Pepducin-Percutaneous Coronary 
Intervention 
UA 
Unstable angina 
UFH 
Unfractionated heparin 
ULN 
Upper limit of normal 
URL 
Upper reference limit 
US, USA 
United States of America 
WBC 
White blood cell count 
WHO 
World Health Organization 
WHODD 
World Health Organization drug dictionary 
µg 
Microgram 
µM 
Micromolar 
 
 


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4. 
INTRODUCTION 
 
The investigator should refer to the current version of the Investigator’s Brochure (IB) for 
more detail. 
 
4.1 
Background   
 
4.1.1 Clinical Overview 
 
Ischemic complications during and after percutaneous coronary interventions (PCIs) are 
strongly influenced by platelet function [1, 2]. Platelets play a critical role in normal 
hemostasis after injury, as well as in the formation of an arterial thrombus that causes acute 
closure of vessels in the cardiovascular system [3] and in atherogenesis [4]. Platelet activation 
is initiated and perpetuated by binding of multiple agonists to specific G-protein–coupled 
receptors (GPCRs) [5]. Protective hemostasis involves platelet adhesion to sites of vascular 
injury mediated by von Willebrand factor and collagen in the vessel wall, activation and 
recruitment of additional platelets (mediated primarily by collagen-stimulated release of 
thromboxane A2 (TXA2) and adenosine diphosphate (ADP) from adherent platelets), and 
stabilization of the fibrin-mesh clot mediated by thrombin generation [4].  
 
Currently, the only effective agent preventing thromboxane A2 generation is aspirin (ASA). 
Although ASA does not impact strong agonists like thrombin or collagen-dependent platelet 
activation under high arterial shear stress, it lowers the risk of cardiovascular events in 
subjects with established cardiovascular disease by approximately 25%. ASA is first-line 
antiplatelet therapy [6]. ADP is an agonist for the platelet P2Y1 and P2Y12 receptors and is a 
key cofactor in platelet activation induced by thrombin and collagen, which results in release 
of more ADP. Clopidogrel is a pro-drug yielding an active metabolite that binds irreversibly to 
the P2Y12 receptor. In the Clopidogrel in Unstable angina to prevent Recurrent Events 
(CURE) study, the addition of clopidogrel to ASA reduced the incidence of the composite of 
cardiovascular death, non-fatal MI, or stroke by 20% relative to ASA alone (9.3% vs 11.4%) 
in subjects mainly receiving medical treatment for non-ST-segment-elevation acute coronary 
syndrome (NSTE-ACS); however, the combination also resulted in a modest increased risk of 
major bleeding (3.7% vs 2.7%) [7]. Among the subset of subjects who received PCI, the 
incidence of minor bleeding was greater among those who received clopidogrel (3.5%) rather 
than placebo (2.1%) [8]. Pharmacodynamic studies evaluating antiplatelet responses in 
subjects undergoing stenting have revealed various limitations of P2Y12 inhibition such as a 
delayed or irreversible pharmacodynamic response; distinct subject-to-subject response 
variability with a substantial percentage of subjects exhibiting non-responsiveness; and a 
potential influence of drug-drug interactions [9].  Compared with clopidogrel, new and more 
potent oral P2Y12 inhibitors such as prasugrel and ticagrelor reduce the risk of ischemic events 
by ~20% in subjects with acute coronary syndrome (ACS) [10, 11]. However, intensified 
blockade of P2Y12 with new P2Y12 agents may be associated with elevated bleeding and 
potentially other side effects such as dyspnea [12]. In this regard, ASA and P2Y12 receptor 
antagonists inhibit platelet aggregation induced by collagen, TXA2 and ADP, properties that 
may interfere with normal hemostasis. The slow offset of P2Y12 inhibition by all currently 


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approved oral agents may be problematic in subjects requiring coronary artery bypass graft 
surgery [13]. 
 
Moreover, despite improvements in morbidity and mortality, subjects with cardiovascular 
disease remain at a substantial risk of future ischemic events. Thus, there exists a need for new 
antiplatelet strategies that will provide additional efficacy with minimum to no added risks of 
bleeding [14].  
 
Thrombin, a plasma serine protease, plays a key role not only in coagulation and hemostasis, 
but also in the activation of a variety of cell types [15]. Three thrombin responsive, G-protein-
coupled, protease-activated receptors (PARs) are known (PAR1, PAR3, and PAR4); however, 
many of the cellular actions of thrombin in the human body appear to be mediated through the 
high-affinity PAR1 thrombin receptor on the surface of these target cells [15]. PAR1 is 
activated through proteolysis and cleavage of the N-terminal extracellular domain of the 
receptor [16]. This cleavage leads to the generation of a new amino terminus, which functions 
as a tethered ligand that binds to extracellular loops of the receptor, leading to a 
conformational change and transmembrane signaling to intracellular G proteins [17]. Many of 
the resulting cellular effects are thought to be mediated via the induction and release of a host 
of secondary intracellular mediators, including the raising of intracellular calcium [18]. The 
high affinity PAR1 thrombin receptor has been implicated in a variety of cardiovascular 
disorders including atherosclerosis, thrombosis, and restenosis following PCI [15]. The 
generation of thrombin is markedly increased at the sites of vascular injury [19]. Both 
atherosclerotic lesions and angioplasty specimens express tissue factor, PAR1 and actively 
generate thrombin. PAR1 is also expressed on smooth muscle cells and monocytes/ 
macrophages isolated from atherectomy samples of human blood vessels and on the surface of 
smooth muscle cells following angioplasty procedures. These facts suggest that both thrombin 
and its receptor are involved in the pathology of thrombotic disorders [15, 20, 21]. By 
selectively interfering with the cellular actions of thrombin, an antagonist would have an 
antiplatelet effect under conditions in which thrombin-stimulated platelet activation is critical, 
including PCI, acute coronary syndromes such as unstable angina and acute myocardial 
infarction, and stroke. Hence, a thrombin-receptor antagonist should have an improved safety 
profile over direct and indirect thrombin inhibitors.  
 
Contrary to thrombin inhibitors (bivalirudin, hirudin, argatroban, and dabigatran), PAR1 
antagonists do not directly interfere with the procoagulant activity of thrombin cleavage of 
fibrinogen. Because thrombin-dependent fibrin generation is largely unaffected by inhibition 
of PAR1, a thrombin-receptor antagonist should be more specific than a thrombin inhibitor in 
treating arterial thrombosis. Indeed, early preclinical studies demonstrated that PAR1 
antagonism did not prolong bleeding time or coagulation-related time (activated partial 
thromboplastin time (aPTT), prothrombin time (PT), or thrombin time) [22, 23]. PAR1 
antagonism also did not inhibit ADP- or collagen-induced platelet aggregation. Taken 
together, these findings suggest that PAR1 inhibition can permit the formation of initial 
platelet monolayer necessary for control of bleeding, but block pathological thrombus 
propagation that occurs at the site of plaque rupture or endothelial denudation [24]. 
 


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Approved by the U.S. Food and Drug Administration (FDA) in 2014 for secondary prevention 
of cardiac events, the PAR1 antagonist, vorapaxar (SCH 530348) is marketed by Merck & Co, 
Inc. (Whitehouse Station, NJ) and E-5555 (atopaxar) was developed by Eisai Company, Ltd. 
(Japan). Vorapaxar, an orally active, synthetic analog of himbacine with high affinity (Ki = 3-
8 nM) [25] to PAR1, has an exceptionally long elimination half-life of 6.6-13 days [26] and a 
functionally irreversible binding mode [27]. The pharmacodynamic half-life typically exceeds 
the entire lifespan of a circulating platelet with 50% recovery of platelet function by 4-8 
weeks after a single 20 or 40 mg loading dose of vorapaxar [28].  The onset of inhibition of 
vorapaxar on PAR1 activity occurs by 2 h after receiving the loading dose.  A phase 2 
randomized clinical trial, TRA-PCI, tested the safety, tolerability and preliminary efficacy of 
this compound in 1030 subjects undergoing non-emergent cardiac catheterization with intent 
to perform percutaneous revascularization [29].  The trial was designed as a sequential 
randomization scheme. First, prior to angiography all subjects were randomized 3:1 to receive 
one of three loading doses (10, 20 or 40 mg) or matching placebo. Subsequently, only those 
who actually underwent PCI (n = 573; 56% of the total cohort) – representing the primary 
cohort of interest – were further randomized to a 60-day maintenance treatment of 0.5, 1 or 
2.5 mg or matching placebo. The PCI cohort also received unfractionated heparin, low-
molecular-weight heparin, or bivalirudin, and a loading dose of clopidogrel (300-600 mg) and 
aspirin (162-325 mg oral or iv 150-500 mg). The incidence of the primary endpoint of TIMI 
major plus minor bleeding was low overall (3% in both the treatment and placebo groups) and 
no significant differences were observed in the primary cohort between the placebo and study 
drug groups. Similarly, TIMI major plus minor bleedings were not significantly different in 
both of the secondary cohorts of subjects medically managed and surgically revascularized. 
Although the study was not powered to detect these differences, the composite endpoint of 
death, major cardiac adverse event or stroke was proportionately less in subjects treated with 
any vorapaxar dose (n = 24; 6%) than with placebo (n = 13; 9%; odds ratio 0.67; 95% CI 0.33, 
1.34), a difference mainly driven by a reduction of the myocardial infarction (MI) component 
in vorapaxar-treated subjects. Also, a dose-effect relationship was observed, with the 40 mg 
loading dose achieving the strongest reduction in the rate of MI. This study suggested a 
potential benefit with trends towards lower thrombotic events, without an increased bleeding 
risk and encouraged the development of phase 3 trials to evaluate the clinical benefit of 
vorapaxar in combination with current standard-of-care dual antiplatelet therapy in high risk 
subjects with coronary artery disease.  
 
The safety and efficacy of vorapaxar was also conducted in Japanese subjects (n=117) with a 
history of non-ST-segment elevated (NSTE) ACS who were receiving standard-of-care 
therapy (aspirin, ticlopidine and heparin) [30].  Subjects were randomized to receive a loading 
dose (20 or 40 mg) or placebo and daily oral maintenance doses (1 or 2.5 mg) or placebo for 
60 days post PCI. The primary endpoint was bleeding (TIMI criteria) and the exploratory 
endpoint included all-cause death and MACE (non-fatal MI, non-fatal stroke, hospitalization 
for recurrent ischemia or urgent coronary revascularization). Periprocedural MI was defined as 
an elevated CK-MB or troponin-I (above 3 times the upper limit of normal with >50% 
increase above baseline) was measured at baseline, 8, 16 and 24 h after PCI. Vorapaxar did not 
result in excess bleeding in the Japanese subjects with NSTE ACS and significantly (p=0.013) 
reduced the incidence of periprocedural MI by 2.5-fold in subjects undergoing PCI. The 


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majority of MIs that did occur were asymptomatic elevations of CK-MB and troponin-I that 
were documented during the periprocedural period shortly after PCI. The safety of vorapaxar 
was also evaluated in Japanese subjects (n=90) with a history of ischemic cerebral infarction 
[31]. All subjects received 1.0 mg or 2.5 mg vorapaxar or placebo once daily for 60 days plus 
aspirin (75-150 mg/day). The primary endpoint was overall incidence of adverse events (AE 
excluding MACE). The AE rate was not significantly different with the dual vorapaxar/aspirin 
regimen at either dose. The secondary endpoint of bleeding (TIMI categorized) was similar 
between placebo and vorapaxar [31]. 
 
The efficacy and long-term safety of vorapaxar over 1-2.5 year treatment periods was 
evaluated in two large phase 3 randomized trials. The effects of vorapaxar in preventing MI 
and stroke in subjects (n=26,449) with atherothrombotic disease (either post-MI, a history of 
stroke, or peripheral arterial disease) was assessed in the Thrombin Receptor Antagonist TRA 
2°P-TIMI 50 study [32].  In addition, a second trial assessed the ability of vorapaxar to 
prevent MI and stroke in subjects (n=12,944) with chronic ACS (TRA-CER) [26]. Due to 
elevated bleeding rates, TRA 2°P-TIMI 50 was terminated early in subjects that had 
experienced a stroke before or during the trial (17% of the enrolled subjects) [32], and TRA-
CER was terminated in all subjects due to significantly increases in the risk of moderate and 
severe bleeding, including intracranial hemorrhage [33]. When added to standard of care in 
subjects with non-ST elevation ACS and high use of aspirin and P2Y12 inhibition, vorapaxar 
did not significantly reduce the composite of cardiovascular death, MI, stroke, hospitalization 
for ischemia, or urgent revascularization. Vorapaxar therapy was associated with a reduction 
in recurrent myocardial infarction at the expense of more bleeding, including more intracranial 
bleeding. Vorapaxar reached ≥80% inhibition of SFLLRN-induced aggregation at 2 h after a 
40 mg loading dose in 96% of subjects [29]. Unlike the relation of ADP-induced platelet 
aggregation to clinical thrombotic event occurrence, little is known about whether the 
magnitude of SFLLRN-induced aggregation affects clinical event occurrence. In the 
PREPARE POST-STENTING trial, we demonstrated that high thrombin-induced platelet – 
fibrin clot strength was a marker for recurrent ischemic event occurrence in subjects treated 
with PCI [34]. The effects of vorapaxar and PZ-128 on thrombin activation on platelets in 
subjects are unknown, as we documented in PCI subjects receiving the direct thrombin 
inhibitor bivalirudin [19]. Vorapaxar has a suboptimal onset of pharmacodynamic effects with 
very long pharmacodynamic half-lives of ≥3 weeks. Both of these properties are important 
limitations for emergent ACS subjects or subjects requiring unscheduled surgery.  
 
PZ-128 is a first-in-class ‘pepducin’ inhibitor of PAR1 intended for use in PCI and ACS 
subjects [35, 36]. Pepducins are lipidated peptides which selectively target the cytoplasmic 
surface of their cognate GPCR to inhibit G protein signaling both in vitro and in vivo [37-41]. 
The PAR1-based pepducin, PZ-128 (P1pal-7), is administered by 2 h duration intravenous 
injection as a single dose. PZ-128 consists of a seven amino acid peptide (KKSRALF) that is 
conjugated to palmitate lipid to form an N-palmitoylated peptide which is formulated in a 5% 
Dextrose USP solution. 
 
PZ-128 has been extensively tested in human blood samples and animals for the ability to 
block thrombin-PAR1-dependent platelet activation, arterial thrombosis and atherosclerosis.  


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PZ-128 (IV; t1/2~1-2 h) has proven to be highly effective in inhibiting platelet function and  
arterial thrombosis in baboons and guinea pigs and is safe and tolerated up to 30 mg/kg iv (1 h 
infusion) in non-human primates in 7-day repeat dose GLP studies. PZ-128 has had no effects 
on coagulation parameters, bleeding time and/or platelet counts in baboon and monkey. A 
PAR1-dependent blood clotting mechanism has also been identified that is driven by matrix 
metalloprotease-1 (MMP-1) after platelets are exposed to collagen within the blood vessel 
wall [42].  PZ-128 also blocked the MMP1-PAR1 pathway and prevented occlusive thrombi 
from forming [42], suggesting that drugs targeting PAR1 on the inside surface of the plasma 
membrane such as PZ-128 could offer a new method to treat subjects with ACS and other 
manifestations of atherothrombotic disease. 
 
There are three areas in which an intracellular PAR-1 antagonist may improve on small 
molecule inhibitors: 1) effective inhibition of both thrombin and MMP-1 activation of PAR1 
by blocking downstream of the receptor, 2) rapid-onset and 3) reversible inhibition of PAR1-
induced aggregation, which limits potential side effects such as bleeding when used in 
combination with standard-of-care ASA and a P2Y12 blocker.  
 
4.1.2 Investigational Agent: PZ-128 
 
Pepducins are the first agents to target the cytoplasmic surface of their cognate receptor. PZ-
128 is a first-in-class, cell-penetrating lipopeptide pepducin that selectively inhibits PAR1-G 
protein signaling on the inner leaflet of the lipid bilayer [37, 43, 44].  PZ-128 (P1pal-7) 
closely resembles the off-state of the corresponding juxtamembrane region of the PAR1 third-
intracellular loop and TM6 region. The pepducin rapidly flips across the plasma membrane to 
target the PAR1-G protein interface to block thrombin activation of the receptor in platelets 
[43, 45]. The chemical structure of PZ-128 is depicted below.   
Chemical Structure of PZ-128 
 
 
 
 
PZ-128 drug substance consists of 7 amino-acid residues (KKSRALF) conjugated to palmitate 
lipid to form an N-palmitoylated peptide. One batch of the active drug substance was 
manufactured for the phase 2 trial by Ambiopharm, Inc. (API, North August, SC) according to 
current Good Manufacturing Practices (cGMP) as a sterile white to off-white powder 
consisting of
 
 
N
H
O
NH
HN
NH2
H
N
O
NH2
N
H
O
NH2
H
N
O
OH
H
N
O
N
H
O
C
H
N
O
O
NH2


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One batch of PZ-128 active drug product for injection was manufactured for the phase 2 trial 
by Lyophilization Technology, Inc. (LTI, Ivyland, PA) according to current cGMP as a sterile 
white to off-white solid lyophilized powder cake contained in 20 cc glass vials stored at -20 ºC 
± 10 ºC. 
 
 One batch of PZ-128 matching placebo for injection (inactive components only) was 
manufactured for the phase 2 trial by LTI, Inc. according to current cGMP as a sterile white to 
off-white solid lyophilized powder cake contained in 20 cc glass vials stored at -20 ºC ± 10 ºC.  
PZ-128 and placebo reconstituted in SWFI are diluted into a final IV bag of sterile Dextrose 
5% in Water, USP (D5W).  
 
4.1.2.1 Preclinical Studies 
 
An overview of the preclinical studies is provided in the current version of the Investigator’s 
Brochure (IB).  
 
4.1.2.2 Clinical Studies 
 
A phase 1 first-in-human safety study was conducted in 32 subjects who had documented 
vascular disease or 2 or more risk factors for coronary artery disease. The goal was to test the 
safety of the PAR1 pepducin in a population which closely approximated the eventual 
clinical population, namely patients with a risk of developing life-threatening acute arterial 
thrombosis during PCI.  Thirty-one subjects received a single intravenous dose of PZ-128 (1-
2 h duration) with escalating dose levels ranging from 0.01 mg/kg to 2 mg/kg, 1 subject 
received saline only. Subjects either had documented vascular artery disease (22%) or had a 
variety of risk factors for coronary disease including prior MI (16%), prior PCI and/or 
CABG (22%), obesity (53%), smoking (41%), hypertension (69%), diabetes (34%), 
dyslipidemia (81%), and/or age >45 for males and >55 for females. Consistent with the CAD 
population in the US, the subjects were 57 ± 8 years old, 50% white, 47% black, 59% male, 
91 ± 17 kg with a BMI of 31 ± 6. In addition to CAD or multiple CAD risk factors, many of 
the subjects had a number of co-morbid conditions and were taking multiple medications. 
Safety evaluations consisted of vital signs, physical exams, ECG, pulmonary function tests, 
blood tests (clinical chemistry, hematology), bleeding time and coagulation tests, urinalysis, 
and exploratory tests for allergic markers. 
 
Maximal and final Light Transmission Aggregation (LTA) to the PAR1 agonist SFLLRN 
versus agonists for other platelet receptors (PAR4, ADP and collagen), was determined for 
all subjects at several time points. The inhibitory effects of PZ-128 on PAR1 platelet 
aggregation were dose-dependent with 20-40% inhibition at 0.3 mg/kg, 40-60% at 0.5 mg/kg 
and up to 80-100% at 1-2 mg/kg. There were no significant effects on aggregation to any 
other platelet agonists including 160 µM AYPGKF, 5 µM ADP, 20 µM ADP, 4 µg/mL 
collagen, or 20 µg/mL collagen in any dose cohort.  
 
Aspirin (ASA) appeared to enhance the ability of PZ-128 to block PAR1 platelet aggregation, 
especially at the 0.5 mg/kg dose. This was expected as ASA monotherapy has been shown to 
inhibit PAR1 responses in platelets [46] and is used as a concomitant standard-of-care anti-


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platelet agent during PCI as discussed above. The subgroup of subjects on concomitant ASA 
therapy revealed stronger apparent effects of PZ-128 on inhibition of maximal and final 
aggregation to 8 µM (P=0.084) and 12 µM (P=0.06) SFLLRN in the 0.5 mg/kg dose cohort. 
The subgroup of subjects receiving ASA in the 0.5 mg/kg dose cohort had 60-80% average 
inhibition of final aggregation to 8 µM SFLLRN at 30 min-2 h and 100% inhibition by 6 h. 
There was 40% of recovery to aggregation to 8 µM PAR1 agonist by 24 h and 60% recovery 
by 192 h (the next sampling time point). Higher concentrations of PAR1 agonist (e.g., 20 µM 
SFLLRN) showed 80% recovery of aggregation by 24 h and 95% by 192 h in the 0.5 mg/kg 
dose cohort receiving concomitant ASA. At high doses of 1-2 mg/kg, PZ-128 gave significant 
mean ~90-100% inhibition at 1-2 h time points regardless of whether the subjects received 
ASA or not.  
 
At 0.3-0.5 mg/kg doses where anti-PAR1 effects on platelet aggregation were observed at 
30 min-2 h, drug levels of PZ-128 achieved therapeutic concentrations of 1-3 µM (~920-
2800 µg/mL). Peak drug levels (Cmax) occurred at the end of the 1 h or 2 h infusion in all 
dose cohorts with a terminal t1/2 of elimination of 1.3-1.8 h. Drug was undetectable in plasma 
at 24-192 h in all subjects. There was little (≤1-2.6 ng/mL) or no PZ-128 detected in urine at 
any time point in all subjects consistent with the notion that the pepducin is not eliminated by 
the kidneys. The drug concentrations were highly linearly correlated with increasing dose at 
0.25-8 h time points with R values of 0.980-0.998. Likewise, AUC and Cmax of PZ-128 in 
plasma were linearly correlated with dose. 
 
In agreement with pre-clinical studies in non-human primates, persistent anti-platelet effects 
of 60-100% inhibition were still observed at the 6 h time point with the 0.5 mg/kg dose 
where plasma PZ-128 drug levels had fallen to <0.5 µM. This is highly consistent with the 
mechanism of action of the pepducin which flips across the cell membrane where it 
associates with its cognate receptor on the inner leaflet of the lipid bilayer to give prolonged 
and selective inhibition of PAR1 activity. Much higher, super-therapeutic drug 
concentrations were achieved at the 1 mg/kg and 2 mg/kg dose levels with mean peak PZ-
128 levels reaching 5 µM and 12 µM, respectively. Accordingly, PZ-128 blocked 85-100% 
of aggregation to 8 µM SFLLRN agonist at the 1-2 h time points in the 1-2 mg/kg dose 
cohorts.  The drug was well tolerated at 0.01, 0.03, 0.1 and 0.3 mg/kg dose cohorts using a 1 
h intravenous infusion with no significant AEs attributable to PZ-128.  
 
 
 
 
 
 
 
 
 
  


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No significant effects on coagulation, hemostasis parameters or bleeding were seen at any  
dose, despite the fact that 65% of the subjects (20/31) who received PZ-128 were also taking 
aspirin. Of all the laboratory tests, only BUN levels gave a trend towards transiently 
increasing at the high doses of PZ-128. As creatinine levels were completely unaffected by 
PZ-128, it is likely that the non-significant increase in BUN was due to transient 
hypovolemia in certain subjects at the high dose cohort secondary to the drug allergic effect 
or NPO status. All other laboratory outcomes including ECG parameters, pulmonary 
function, and urinalysis were not affected by PZ-128. 
 
 
 
 
 
 
 
 
 
 
 
In summary, PZ-128 is a fast-onset PAR1 pepducin which provides significant anti-platelet 
efficacy without affecting bleeding or coagulation parameters even in the setting of 
concomitant aspirin use.  Safety and tolerability analysis indicates that PZ-128 should be able 
to be safely administered at doses of ≤0.5 mg/kg using a 2 h intravenous infusion to subjects 
with CAD and significant comorbidities typically associated with the PCI population. The 
information gathered to address the objectives of this study will be used to determine 
whether the clinical program will proceed to Phase 3, and if so, the dosing regimen to be 
used.  
 
4.2 
Rationale 
 
4.2.1 Rationale for Study Design and Subject Population 
 
This study will be a multicenter, prospective, randomized, double-blind, placebo-controlled, 
balanced-parallel-groups, non-inferiority investigation to be conducted in conformance with 
Good Clinical Practice (GCP).  
 


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In this phase 2 trial named TRIP-PCI, two intravenous dose levels of PZ-128 (0.3 mg/kg and 
0.5 mg/kg) and matching placebo will be studied to determine the safety and efficacy of PZ-
128 when added to standard antiplatelet therapy in subjects undergoing non-emergent PCI or 
non-emergent cardiac catheterization with intent to perform PCI. Standard-of-care procedures 
outlined in the protocol are based upon practice guidelines for cardiovascular angiography and 
interventions [47]. 
 
Dosing was determined by the safety profile observed in previous GLP animal studies (non-
human primates and rodents) and the recently completed phase 1 study which examined the 
safety, tolerability, pharmacokinetics and pharmacodynamics of PZ-128 in subjects with 
multiple coronary artery disease risk factors. The phase 1 population closely approximated the  
eventual clinical population, namely subjects with a risk of developing life-threatening acute 
arterial thrombosis during PCI.  
 
The phase 2 subject population will consist of approximately 600 low-to-moderate risk 
subjects including those undergoing elective PCI and subjects with NSTE-ACS. Outcomes 
will be assessed over 30 day and 90 day time periods. Higher risk subjects with STEMI or 
those requiring GPI therapy will be excluded. Based on the phase 1 data with PZ-128 which 
documented anaphylactoid/histaminic reactions in some subjects at high doses of 1-2 mg/kg, 
subjects with baseline hypotension (systolic blood pressure <95 mm Hg) or history/high risk 
of drug allergies will be excluded, and a prophylactic anti-histamine regimen will be 
incorporated. Based on the extensive clinical data with vorapaxar, subjects with a prior 
history of stroke or transient ischemic attack, or body weight of <60 kg will also be excluded. 
Bleeding is the most common and severe side effect of anti-thrombotic and/or anti-platelet 
agents in general. In standard-of-care treatment, subjects undergoing PCI may be exposed 
to several of these medications (e.g., ASA, P2Y12 inhibitor, heparin).  When introducing 
additional potent anti-platelet agents in this setting such as PZ-128, potential efficacy must 
be balanced against a possible increase in the frequency of bleeding events.  The design of 
the primary outcome measure in this study (relative bleeding rate of PZ-128 vs placebo) is 
consistent with established practice for evaluation of bleeding events in subjects undergoing 
cardiac catheterization with intent to perform PCI in phase 2 studies such as TRA-PCI.  
Addition of an antiplatelet agent to existing standard-of-care in this setting, so-called dual 
anti-platelet therapy (DAPT), has been studied extensively and found to be beneficial [7]. 
As PZ-128 is an effective platelet aggregation inhibitor with a unique intracellular 
mechanism, consequently assessing bleeding (hemostasis) will be the primary endpoint in 
the present study from a safety and feasibility perspective. Although not sufficiently 
powered, an early efficacy signal (e.g. reduction in MACE or stent thrombosis) may be 
detected in this 600 subject study as occurred in earlier studies with oral PAR1 inhibitors 
(vorapaxar, atopaxar). Thus, this design offers the opportunity to assess the safety and 
potentially early efficacy of PZ-128 in a setting of current clinical practice.  
 
The study will incorporate extensive PK and PD assessments in a large subset of subjects at 
the various clinical sites. Inhibition of platelet aggregation will be measured by optical 
aggregometry (maximal and final LTA) in response to the PAR1 agonist SFLLRN (5-20 µM) 
and thrombin (1 nM-1 µM) versus agonists for other platelet receptors PAR4, ADP and 


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collagen (160 µM AYPGKF, 5-20 µM ADP, 4-20 µg/mL collagen) for subjects at select 
time points. The PK/PD data generated will facilitate the continuing evaluation of the 
relationship between the pharmacokinetics and IPA and will assess these parameters in this 
subject population for the first time before progressing into the large Phase 3 program. 
Other relevant biomarkers including systemic levels of the two PAR1 agonists, thrombin (in 
complex with anti-thrombin III: TAT) and MMP-1, will be assessed and correlated with 
outcomes. Pharmacogenomic analysis will be undertaken to investigate whether DNA 
polymorphisms, RNA levels and microRNAs correlate with the expression of genes 
involved in thrombosis, inflammation, and cardiometabolic diseases and whether these 
genetic components correlate with PZ-128 outcomes. 
 
4.2.2 Rationale for the PZ-128 Doses 
 
The design consists of a single dose regimen of PZ-128 0.3 mg/kg, or PZ-128 0.5 mg/kg, or 
Placebo 0.3 mg/kg, or Placebo 0.5 mg/kg in 2:2:1:1 ratio using a 2-hour continuous IV infusion 
started within 1 hour prior to commencement of the cardiac catheterization procedure (i.e., 
diagnostic angiography).  This regimen is supported by the:   
• short half-life of PZ-128 (1-2 h) with reversibility by higher concentrations 
of PAR1 agonist; 
• inhibition of up to 50-100% PAR1 platelet aggregation with quick onset (by 
30 min) and prolonged inhibition of PAR1 platelet activation for at least 6 h 
after initiation of IV infusion; and 
• synergy of anti-PAR1 effects with ASA and P2Y12 inhibitors 
 
A single-dose infusion of PZ-128 0.3 mg/kg or 0.5 mg/kg will be administered in this study 
because patients undergoing non-emergent cardiac catheterization (especially those with 
NSTE-ACS) are in an acute-care situation that requires rapid and reversible inhibition of the 
ability of platelets to become activated by thrombin, which can be accomplished by these 
doses. The dose levels of PZ-128 to be evaluated in this study have been selected based on 
pharmacodynamic, pharmacokinetic, safety and tolerability data from the recently completed 
phase 1 study in 32 subjects with known cardiovascular disease or multiple coronary artery 
disease risk factors.  The two dose levels will be studied concurrently.  
 
 
 
 


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5.0 
STUDY OBJECTIVES 
 
5.1 
Primary Objective 
 
The primary objective is to evaluate the safety of a single dose of PZ-128, in addition to the 
standard of care, with respect to the incidence of major and minor bleeding events, as assessed 
by the TIMI (Thrombolysis In Myocardial Infarction) system of classification, in subjects 
undergoing non-emergent PCI or non-emergent cardiac catheterization with the intent to 
perform PCI. 
 
5.2 
Key Secondary Objective 
 
The key secondary objective is to evaluate the potential clinical benefit of PZ-128 with respect 
to the composite endpoint of major adverse cardiac events (MACE) - any of cardiovascular 
death, non-fatal myocardial infarction (MI), non-fatal stroke, recurrent ischemia requiring 
hospitalization or urgent coronary revascularization. 
 
5.3  
Other Secondary Objectives Related to Safety  
 
Other secondary safety objectives will include evaluation of PZ-128 in terms of the incidences 
of the following:  
 
1. 
bleeding that does not meet the TIMI criteria for major or minor (i.e.,  minimal 
bleeding); 
2. 
“clinically significant” bleeding;  
3. 
TIMI bleeding related to coronary artery bypass grafting (CABG); and 
 
5.4 
Other Secondary Objectives Related to Efficacy  
 
Other secondary efficacy objectives will include evaluation of PZ-128 in terms of the 
following: 
  
1. 
incidence of the individual components of the MACE composite as measures of 
potential clinical benefit;  
2. 
incidence of definite or probable stent thrombosis as a measure of potential clinical 
benefit; 
3. 
inhibition of platelet aggregation induced by SFLLRN (PAR1 agonist) and thrombin 
as an indicator of the desired pharmacodynamic effect, and ADP (adenosine 
diphosphate), collagen and AYPGKF (PAR4 agonist) to evaluate the specificity of PZ-
128;  
4. 
effect of the investigator choice of P2Y12 inhibitor on the individual components of the 
MACE composite; and  


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5. 
population pharmacokinetics.  
 
5.5 
Exploratory Objectives 
 
Exploratory objectives will include evaluation of PZ-128 in terms of the following: 
 
1. 
incidence of bleeding events according to the BARC (Bleeding Academic Research 
Consortium) classification;  
2. 
effect on expression of systemic markers of thrombosis and platelet reactivity (e.g., 
thrombin and MMP-1), inflammation, and metabolomics; and  
3. 
population pharmacogenomics.  
 
 
 
 
 
 
 
 
 
 
 


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6.0 
INVESTIGATIONAL AND ANALYSIS PLAN 
 
6.1 
Overall Study Design and Plan:  Description 
 
The study will be a multicenter, prospective, randomized, double-blind, placebo-controlled, 
balanced-parallel-groups investigation to assess the safety of two dose levels of PZ-128 given 
as a single intravenous (IV) infusion over  2 hours in addition to standard of care dual-
antiplatelet therapy (DAPT) in subjects undergoing non-emergent PCI or non-emergent 
cardiac catheterization with the intention to perform PCI.  The study will be conducted at 
approximately 3 US clinical sites in conformance with GCP.  During this trial of PZ-128, 
investigators are encouraged to follow current applicable standard of care guidelines that 
outline appropriate medical therapy for subjects with established atherosclerosis, including 
antiplatelet therapy (e.g., aspirin, P2Y12), lipid-modification therapy, antianginal therapy and 
invasive cardiac procedures/interventions (e.g., cardiac catheterization, cardiac 
revascularization). Refer to the Study Design Diagram (Section 1.1) for an illustration of the 
overall design, the Study and Treatment Schema (Figure 1, Section 6.5) for an illustration of 
the treatment and follow-up plan, and the Study Flow Chart (Section 1.2) for information on 
tests and measurements to be performed in the main study, and in a sub-study at selected 
site(s) among those anticipated above.  
 
Eligible subjects will include men and women at least18 years of age who are scheduled to 
undergo non-emergent PCI, or non-emergent cardiac catheterization with the intent to undergo 
PCI, and for whom elective use of a GP IIb/IIIa inhibitor is not intended. Subjects will receive 
aspirin; if PCI proceeds, subjects will receive an anticoagulant and loading dose of a P2Y12 
inhibitor. The study design specifies randomized assignment of PZ-128 or matching placebo 
in a 2:1 ratio and the initiation of the study drug infusion prior to the start of the coronary 
angiography portion of the cardiac catheterization.  The sponsor estimates that 600 subjects, 
400 to receive PZ-128 and 200 to receive placebo, will be adequate for clinical evaluation.   
 
Two central committees will participate in the trial: 
• An independent Clinical Events Committee (CEC) will be established to review and 
adjudicate in blinded fashion all bleeding events and MACE and stent thrombosis 
events identified by investigators or triggered from specific criteria on a rolling basis 
as they occur.  The adjudicated findings will be used to address study objectives. 
• An independent Data and Safety Monitoring Committee (DSMB) will be established 
to further the rights, safety and well-being of subjects who will be participating in this 
study by monitoring the progress and results.  The DSMB will review in blinded 
fashion: 
o unadjudicated bleeding and associated data (aggregated) through 30 days, 
primarily to determine whether the type and occurrence of bleeding is in accord 
with anticipated results (i.e., no potential meaningful additional risk), and 
o unadjudicated MACE and stent thrombosis results. 
 
 


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Data may be unblinded if the DSMB believes that this is warranted.  The DSMB may 
elect to review data on platelet aggregation, if deemed necessary and will review other 
SAE/AE data as indicated. The DSMB will perform one interim safety analysis to 
evaluate evidence of bleeding risk in light of any potential efficacy benefit(s) and to 
allow the DSMB to make recommendations to the sponsor (i.e., continuing the study 
under the current protocol, amending the current protocol, or stopping the study). 
Otherwise, the DSMB will meet quarterly or as required to perform its function.    
 
Separate charters will be prepared to describe the composition and operating procedures of the 
two committees.  
 
After written informed consent is obtained, eligibility tests/evaluations will be performed.  All 
screening assessments must be completed prior to randomization and be within 14 days of the 
study drug treatment (this may include standard of care preadmission testing for the planned 
procedure).  For the purposes of this study, a subject is considered enrolled into the trial upon 
successful randomization and an assignment of study drug and a unique subject randomization 
number.   On the day of the procedure, subjects will receive a dose of aspirin (81-325 mg) 
orally.  Subjects will receive the randomized assignment of PZ-128 or matching placebo as a 
single, 2-hour continuous IV infusion, to be initiated within 1 hour prior to the start of the 
cardiac catheterization procedure (defined as the time of the arterial sheath placement prior to 
the diagnostic angiography) in a 2:2:1:1 parallel, double-blind fashion of either: 1) PZ-128 0.3 
mg/kg, 2) PZ-128 0.5 mg/kg, or 3) Placebo 0.3 mg/kg, or 4) Placebo 0.5 mg/kg. 
 
If PCI is deemed necessary and appropriate during catheterization, an anticoagulant 
(unfractionated heparin or low-molecular-weight heparin) will be added and a loading dose of 
an oral P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) will be administered per 
investigator choice and standard of care guidelines before PCI. All other subsequent therapy 
or care provided and not specified by the protocol will be in accordance with the local 
standard.  
 
PCI successfully begins when the guide wire crosses the lesion, regardless of any subsequent 
event or process, including completion of the intended procedure. The planned treatment with 
any GP IIb/IIIa Inhibitor (GPI) during the PCI will not be allowed, but investigators may use 
these agents as a thrombotic bailout if indicated.  Following the procedure, subjects will be 
advised regarding continuing/maintenance treatment with aspirin and a P2Y12 inhibitor 
according to local standard of care.  
 
If a PCI is not indicated during catheterization, or is indicated but does not commence (guide 
wire does not cross the lesion) for any reason, the subject will undergo medical management 
or surgical revascularization (i.e., CABG) according to the local standard of care.  
 
All subjects will complete the protocol-specified in-hospital tests, collections, and evaluations 
up to the time they are discharged from the hospital.  The duration of hospitalization will vary 
depending upon the clinical circumstances (e.g., subject comorbidities, type of procedure(s), 
complications from procedure(s), and need for further testing /procedures) and local standards 


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of care and may include same day discharge, overnight stay for observation or inpatient 
admission.  
 
Prior to discharge from the hospital, the return visit will be scheduled for 14 days (± 5 d) after 
the administration of the study drug, and follow-up telephone contacts should be scheduled 
for 30 days (± 5 d) and 90 days (± 7 d) after the administration of the study drug.   
 
Appropriate assessments will be used to characterize the overall effects of PZ-128.  In 
particular, selected center(s) will participate in a sub-study that will include specific testing to 
assess inhibition of platelet aggregation and the pharmacokinetic/pharmacodynamics (PK/PD) 
relationship of PZ-128.   
 
6.2 
Participation in and Completion of the Study 
 
The subject is considered to be enrolled in the study when the subject is successfully 
randomized and is assigned a study drug treatment regimen and a unique subject 
randomization number. A subject who receives a randomization assignment without ever 
receiving any amount of study drug treatment (“randomized but not treated”) is still part of the 
intent-to-treat (ITT) data set for efficacy endpoints and must be followed thereafter per 
protocol (a telephone contact may be used in lieu of the 14-day follow-up visit for those not 
having taken any amount of study drug). A subject who signs the informed consent to 
participate in the study but does not undergo a successful randomization (i.e., screen failure, 
withdrew consent) will not be followed beyond the point it is determined that the subject will 
not be randomized- no further data will be collected and the subject will not be included in 
safety or efficacy analyses.  Information on subjects who are screened and consented for the 
study but fail to undergo randomization will be submitted to the sponsor as per Section 8.2 for 
regulatory purposes and to establish that the study population was selected without bias.  
 
The subject is considered to have completed the study drug treatment following cessation of 
the study drug infusion.  Given the single-dose design of the study, once the subject has 
received the study drug infusion (or once a subject permanently discontinues the study drug 
infusion), the study drug will no longer be available to the subject.  
 
The subject is considered to have completed the entire study when he/she has undergone the 
final protocol-specified contact (i.e., study telephone call at 90-days following the study drug 
administration).  Subject participation may be terminated prior to completion for reasons 
described in Section 6.3.3. For those subjects who do not complete the entire study protocol, 
subject participation will be considered terminated upon the completion of the last visit or 
phone contact.   
 
The overall study ends when the last remaining subject has completed or has been 
discontinued/ terminated from the study as defined above.  The sponsor, Tufts Medical 
Center, the sponsor’s Institutional Review Board (IRB), the FDA, or the National Heart, Lung 
and Blood Institute/National Institutes of Health (NHLBI/NIH) may terminate the study at 
any time.  If the study is terminated prior to the completion of expected enrollment for any 


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reason, all participating centers will be notified within 5 business days.  All subjects already 
enrolled will continue to be followed for the planned course of study described in the 
protocol, unless otherwise indicated by the sponsor.  
 
6.3 
Study Population 
 
This study will be conducted at approximately 3 clinical sites in the United States (US) 
without any pre-specified minimum/maximum enrollment target per site or per the study 
stratum:  
• Inova Heart and Vascular Institute, Inova Fairfax Hospital (Falls Church, VA) 
• Tufts Medical Center (Boston, MA) 
• UMass Memorial Medical Center (Worcester, MA) 
 
This study will enroll a total of approximately 600 subjects. Subjects who are randomized, but 
who discontinue from the study prior to receiving any amount of study drug may be replaced. 
 
The sponsor estimates a maximum screen failure rate of 20% (i.e., those who sign consent but 
fail to be randomized for any reason).  Therefore, the study will require a maximum of 720 
prospective participants to sign consent in order to successfully randomize 600 subjects. 
 
Subjects must meet all inclusion criteria and none of the exclusion criteria to be 
enrolled/randomized and receive study drug assignment.  
 
 
 


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6.3.1 Subject Inclusion Criteria 
 
The subject must meet all of the following criteria listed below for entry: 
 
1. 
The subject is at least 18 years of age and may be of either sex/gender and of any race 
and ethnicity. 
 
2. 
The subject is scheduled to undergo non-emergent PCI or non-emergent cardiac 
catheterization with the intention of performing PCI.   The following classifications of 
the urgency of the procedure at the time the operator decides to perform it will be used 
for randomization stratification [54]:  
 
a. Elective:  The cardiac catheterization procedure ± PCI can be performed on an 
outpatient basis or during a subsequent hospitalization without significant risk of MI or 
death.  For stable inpatients, this is a procedure that is performed during the 
hospitalization for convenience and ease of scheduling only, and not because the 
subject’s clinical situation demands that the procedure be performed prior to discharge.    
 
OR 
 
b. Urgent:   The cardiac catheterization ± PCI procedure should be performed on an 
inpatient basis and before discharge because of significant concerns about the risk of 
myocardial ischemia, MI and/or death.  For subjects who are outpatients or in the 
emergency department at the time that the cardiac catheterization is requested, this is a 
procedure that would warrant hospital admission based on clinical presentation. 
 
3. 
There is no anticipation that the subject would require treatment with a GP IIb/IIIa 
inhibitor prior to the initiation of the cardiac catheterization ± PCI procedure if the 
subject were not a participant in the current research study, and no anticipation of use 
during the procedure. 
 
4. 
The subject is willing and able to give appropriate informed consent and complete all 
study-related procedures, and able to adhere to dosing and visit schedules (i.e., subject 
signs an approved informed consent document(s) and provides HIPAA authorization).  
 
5. 
The subject will undergo all of the pre-enrollment parameters according to Section 1.2 
prior to randomization and have them completed within 14 days prior to the scheduled 
cardiac catheterization ± PCI procedure and study drug administration.  
 
6. 
Women of childbearing potential (all postmenarchal women who are <1 year 
menopausal or who have not had surgical sterilization or a hysterectomy are considered 
to be women of child-bearing potential) must agree to use a medically accepted method 
of contraception from the time written informed consent is given up until 90 days 
following the study drug administration. 
 


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(Injectable, implantable, patch or oral (“the pill”) hormonal contraceptives, medically 
prescribed intrauterine device (IUD) or partner vasectomy are medically accepted 
methods of contraception.  Double barrier methods are acceptable although the risk of 
pregnancy is higher.  Examples of double barrier methods are diaphragm with 
spermicidal gel or condoms with contraceptive foam.)  
  
6.3.2 Subject Exclusion Criteria  
 
The subject will be excluded from entry if any of the criteria listed below are met: 
 
(General Exclusions) 
 
1. 
Subject is pregnant, intends to become pregnant or is breast-feeding (all women of child-
bearing potential must have a negative pregnancy test result confirmed prior to 
randomization and it must be repeated to be within 24 hours prior to the study drug 
administration if necessary).  
 
2. 
Any of the following allergy history(s): 
• History of an allergic reaction* or contraindication to any of the following protocol-
directed drugs:  aspirin, heparin, P2Y12 inhibitor (clopidogrel, prasugrel, ticagrelor), 
antihistamines (benadryl, famotidine); or 
• History of an allergic reaction* to contrast media; or 
• History of an allergic reaction* to a drug which required emergency medical 
treatment; 
• History of an allergic reaction* to a Hymenoptera sting which currently necessitates 
the subject to carry an EpiPen/injector or the subject has been prescribed one to treat 
an allergic reaction to a sting. 
 
*An allergic (anaphylactic) reaction is characterized by an adverse local or general 
response from exposure to an allergen involving skin/mucosal tissue manifestations 
(hives, pruritus, flushing, angioedema), and/or respiratory compromise (dyspnea, 
wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia), and/or 
hemodynamic effects (hypo/hypertension, hypotonia, syncope). 
. 
3. 
Participation in another research study of investigational therapy (drug or device) within 
the past 30 days prior to randomization or planned use of other investigational therapy(s) 
during this research study (until 90 days following the study drug administration).  
 
4. 
Subject is part of the study staff personnel directly involved with this trial, or is a family 
member of the study staff (clinical site or sponsor).  
 
5. 
Prior enrollment (randomization) in this research study. 
 
6. 
Any condition which could interfere with, or the treatment for which might interfere 
with, the conduct of the research study or which would, in the opinion of the 


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investigator, unacceptably increase the subject’s risk by participating in the research 
study.  This would include, but is not limited to alcoholism, drug dependency or abuse, 
psychiatric disease, epilepsy or any unexplained blackouts. 
 
(Exclusionary Prior/Concomitant Conditions) 
 
7. 
Evidence of an ST-segment elevation myocardial infarction (STEMI) on presentation or 
during current hospitalization or a history of STEMI within the past 30 days prior to 
randomization.    
 
8. 
Subject is scheduled to undergo PCI for known unprotected left main coronary artery 
(LMCA) disease (i.e., left main stenosis ≥50% not protected by at least 1 patent bypass 
graft).  
 
9. 
Any history of a prior stroke (hemorrhagic or ischemic) or transient ischemic attack 
(TIA) of any etiology.  
 
10. Cardiogenic or any type of shock on presentation or during current hospitalization (i.e., 
systolic blood pressure <90 mm Hg requiring vasopressor or hemodynamic support). 
 
11. History of heparin-induced thrombocytopenia (HIT). 
 
12. Any active bleeding within the past 30 days prior to randomization.  
 
13. Any condition or personal belief (e.g., Jehovah’s Witness) which would interfere with 
the subject’s ability or willingness to undergo a blood transfusion. 
 
14. Any of the following conditions associated with increased risk of bleeding: 
 
a. 
history of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra- 
articular bleeding; 
 
b. 
gastrointestinal bleeding within the past 30 days prior to randomization; 
 
c. 
gastric or duodenal ulcer disease verified by endoscopy or barium meal contrast 
technique within the past 6 months prior to randomization; 
 
d. 
history of bleeding disorder or diathesis;  
 
e. 
major surgical procedure or trauma within the past 60 days prior to randomization 
or a planned surgical procedure to take place within 30 days following the study 
drug administration; 
 
f. 
history or suspicion of intracranial neoplasm, arteriovenous malformation, or 
aneurysm; or  


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g. 
clinical finding(s) in the judgment of the investigator that poses an increased risk 
of bleeding. 
 
15. Sustained severe hypertension: systolic blood pressure >185 mm Hg or diastolic blood 
pressure >105 mm Hg with or without anti-hypertensive treatment (as demonstrated by 
repeated BP measurements >185/105 mm Hg including the final BP measurement before 
randomization). 
 
16. Hypotension:  systolic blood pressure <95 mm Hg (as demonstrated by repeated systolic 
BP measurements <95 mm Hg including the final systolic BP measurement prior to 
randomization). 
 
17. Known active hepatobiliary disease, or known unexplained persistent increase in serum 
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) activity to ≥2.5 
times the upper limit of the reference range within the past 30 days prior to 
randomization. 
 
18. Hemoglobin <10 g/dL or hematocrit <30%. 
 
19. Platelet count <75,000/mm3.  
 
20. Stage 4-5 Chronic Kidney Disease (National Kidney Foundation) or on dialysis. 
 
21. Active sepsis or suspected sepsis. 
 
22. Body weight <60 kg or >175 kg. 
 
23. Current evidence of invasive cancer (persistent disease excluding basal cell carcinoma of 
the skin) or treatment for invasive cancer within the past 6 months prior to 
randomization.  
 
24. Left ventricular ejection fraction <25% if known (any imaging technique) or New York 
Heart Association (NYHA) Class IV congestive heart failure. 
 
(Exclusionary Prior/Concomitant/Anticipated Medication/Therapy) 
 
25. Coronary interventional procedure of any kind within the past 30 days prior to 
randomization.  
 
26. Anticipated subsequent staged multi-vessel PCI within 30 days following the study drug 
administration.  
 
27. 
History of treatment with any parenteral GP IIb/IIIa inhibitor (GPI) within the past 30 
days prior to randomization.  (As stated in the Inclusion section, the planned treatment 
with a GPI prior to initiation of the cardiac catheterization ± PCI is not allowed; 


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however, GPI for thrombotic bailout may be used during the PCI at the investigator’s 
discretion).  
 
28. 
Concurrent or anticipated treatment with a parenteral direct thrombin inhibitor (e.g., 
bivalirudin) for the cardiac catheterization ± PCI procedure.  
   
29. 
History of treatment with another PAR1 inhibitor within the past 60 days prior to 
randomization or the concurrent/anticipated use after randomization up until 30 days 
following the study drug administration.  
 
30. 
History of treatment with another IV anti-platelet drug within 30 days prior to 
randomization or the concurrent/anticipated use after randomization up until 30 days 
following the study drug administration.  
 
31. 
Any of the following anticoagulant or thrombolytic/fibrinolytic treatment(s): 
• History of treatment with warfarin within 5 days prior to randomization or the 
concurrent/anticipated use after randomization up until 2 days following the 
study drug administration; or 
• History of treatment with oral Factor Xa or direct thrombin inhibitors within 2 
days prior to randomization or the concurrent/anticipated use after randomization 
up until 2 days following the study drug administration; or 
• History of treatment with thrombolytic/fibrinolytic agents within 7 days prior to 
randomization or the concurrent/anticipated use of any of those agents after 
randomization up until 30 days following the study drug administration.  
 
Subjects excluded for any of the above reasons may be re-screened for participation at any 
time if the exclusion characteristic has changed. 
 
6.3.3 Study Drug Discontinuation and Study Termination Criteria  
 
Treatment with the study drug may be terminated/ discontinued for any of the following 
reasons: 
• Serious adverse event (SAE);  
• Failure to comply with the dosing, evaluations, or other requirements of the study; 
• Unusual or excessive bleeding/signs or symptoms of abnormal bleeding from any 
source that cannot be controlled without discontinuation of the study drug 
administration (hematoma at the site of vascular sheath insertion may normally occur 
and should not serve as a reason to discontinue study drug unless bleeding cannot be 
controlled with normal measures). 
 
Treatment with the study drug must be terminated/ discontinued for any of the following 
reasons: 
• Request of the subject (subjects have the right to discontinue study drug administration 
at any time for any reason); 


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• There is a need for concomitant medication(s), which makes the subject ineligible to 
receive the study drug; 
• Pregnancy; or 
• Anaphylaxis. 
 
In addition, if a subject who does not meet enrollment criteria is inadvertently randomized in 
the study, the sponsor must be notified.  Although the subject should be discontinued from 
receiving study drug treatment, an exception may be granted by the sponsor if there is a 
compelling reason to continue with the administration of the study drug, but the investigator 
must obtain documented approval from the sponsor.  
 
It is the right and duty of the investigator or sub-investigator to interrupt/stop study drug 
treatment of any subject if he/she feels that it is necessary to protect the subject, or that there 
are unmanageable factors, that may interfere significantly with the study procedures and/or the 
interpretation of results. If the study drug is discontinued prior to the completion of the 
infusion, the reason for the discontinuation will be obtained.  This information will be 
documented in source records and in the appropriate section of the electronic case report form 
(eCRF) and the Sponsor should be notified promptly.   Every effort should be made to ensure 
all activities outlined in the Section 1.2, Study Flow Chart and Section 6.5, Study Schedule 
are performed as usual.   
 
Normal study termination/discontinuation is defined as the completion of all visits and 
procedures listed under Section 1.2. Early study termination/discontinuation occurs if the 
subject fails to complete the entire study, through to the 90-day telephone follow-up.  Early 
termination from the study may occur for the following reasons: 
• Subjects are free to withdraw from the study at any time for any reason- formal 
withdrawal of the subject’s consent to participate further in any of the remaining study 
procedures must be documented by the investigator/qualified designee;  
• In the opinion of the investigator, the subject cannot safely perform the procedures 
required by the protocol (e.g., adverse event, concomitant treatment); 
• Subject does not comply with the protocol instructions given by the investigator/ 
qualified designee; 
• The subject becomes pregnant (pregnancy will be followed as per Section 6.7.2.2.7); 
• The sponsor, Tufts Medical Center may terminate the study for any reason; 
• The study may be terminated at any time by the national or local regulatory authorities 
overseeing and/or funding the trial (e.g., FDA, NHLBI/NIH, or IRB). 
 
A subject has the right to discontinue participation in the study at any time for any reason 
without prejudice to his/her future medical care by the investigator or at the institution.  
Withdrawal of partial consent means that the subject does not wish to receive the study drug 
any longer but is still willing to collaborate in providing further data by continuing on study 
(e.g., participate in subsequent study visits/contacts or procedures, allow release of follow-up 


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information). Withdrawal of full consent means that the subject does not wish to receive 
further study drug and does not wish to or is unable to continue further study participation; 
subject data up to withdrawal of consent will be included in the subjects’ study data.  
Withdrawal of partial or full consent by the subject must be documented in writing by the 
investigator/qualified designee.  The investigator will discuss with the subject appropriate 
procedures for withdrawal from the study drug and/or study. Should a subject request or 
decide to withdraw from the study, all efforts will be made to complete and report the 
observations as thoroughly as possible up to the date of withdrawal.  All information should 
be reported on the applicable eCRFs and the Sponsor should be notified promptly. 
 
6.3.4 Replacement of Subjects 
 
Subjects who are randomized, but who discontinue from the study prior to receiving any 
amount of study drug may be replaced.  
 
6.4 Study Treatments 
 
The investigator or qualified designee is responsible for delivering the investigational therapy 
and any required co-administered therapy and the standard of care treatment(s) outlined 
according to the protocol and verifying compliance in source documentation and on the eCRF, 
and ensuring that any other therapy not specified in the protocol is delivered according to the 
local standard of care.  
 
6.4.1 Blinded Investigational Study Drugs 
 
Approximately 600 subjects will be randomized in a 2:1 (PZ-128: PZ-128 placebo) ratio to 
receive 1 of the following 4 treatment assignments:   
• Single, 2-h IV infusion of PZ-128 0.3 mg/kg 
• Single, 2-h IV infusion of PZ-128 0.5 mg/kg  
• Single, 2-h IV infusion of Placebo 0.3 mg/kg 
• Single, 2-h IV infusion of Placebo 0.5 mg/kg 
 
The PZ-128 active drug and matching placebo are provided as vials of solid lyophilized 
powder cake for reconstitution and will be indistinguishable.  The individualized dose will be 
based upon the baseline (i.e., Screening) weight of the subject and the dose level assignment 
by the centralized randomization system used as part of the method of treatment assignment 
(Section 6.4.4).  The type and number of vials of study drug will be selected by an unblinded 
investigational pharmacist (Section 6.4.6) at the clinical site who is able to obtain the 
subject’s unmasked randomized treatment assignment via a restricted access login within the 
randomization system.  Each vial of study drug will be reconstituted with 10 mL of Sterile 
Water for Injection, USP (SWFI) and the calculated amount of reconstituted volume of study 
drug will be mixed and diluted with 250 mL (plus the manufacturer’s overfill volume) of 
Dextrose 5% in Water, USP (D5W) to yield a final IV bag (blinded) for administration.  
 


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PZ-128 or matching placebo, as determined by the randomization scheme, will be 
administered by a qualified member of the study staff or institution’s clinical staff over a 2-
hour continuous IV infusion and the infusion must begin 0-60 min prior to the start of the 
cardiac catheterization (i.e., diagnostic coronary angiography).  The infusion will run through 
completion regardless of whether the subject progresses to PCI, CABG or medical 
management.  
 
 The peripheral IV line for the 
drug infusion should not be smaller than 20-gauge. Flushing of the IV access site (not the line) 
will be done using 0.9% Sodium Chloride for Injection (Normal Saline).  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
6.4.3 
Other Required and Potential Rescue Treatment(s) (Standard of Care)  
 
Investigators will use current applicable standard of care guidelines, the individual’s clinical 
circumstances, and the local practices for the procedures surrounding the cardiac 
catheterization ± PCI and follow-up care post cardiac catheterization ± PCI [47].   
 
Standard of care treatments/parameters in the context of this study will include oral anti-
platelet therapy- aspirin and P2Y12 inhibitor (i.e., clopidogrel, prasugrel, or ticagrelor), an anti-
coagulant (i.e., unfractionated heparin or low-molecular-weight heparin) and potential rescue 
therapy (thrombotic bailout) with a GP IIb/IIIa inhibitor (e.g., eptifibatide). These treatments 
administered/taken within 30 days prior to randomization and at any time during the study 
must be documented in the subject’s source documents/medical records and recorded in the 
“Previous and Concomitant Medication” module of the eCRF.  
 
• Aspirin:  Subjects not on aspirin therapy should be given nonenteric aspirin 325 mg 
before the study drug administration (subjects already taking daily aspirin therapy 
should take 81-325 mg before the study drug administration). After the cardiac 


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catheterization/PCI aspirin 81-325 mg daily may be continued indefinitely.  ASA for 
pain relief should where possible be discouraged and acetaminophen given. 
 
• P2Y12 Inhibitor(s):  A loading dose of an FDA-approved oral P2Y12 inhibitor should be 
given to subjects before PCI with stenting (dosing may be adjusted depending upon 
prior chronic use of oral P2Y12).  Investigator discretion will be used and options include 
the following: 
o 
Clopidogrel (Plavix®) 600 mg 
o 
Prasugrel (Effient®) 60 mg 
o 
Ticagrelor (Brilinta®) 180 mg  
 
The choice and duration of oral P2Y12 inhibitor therapy after stent implantation will be 
as per investigator discretion.  Options include the following FDA-approved drugs: 
o 
Clopidogrel (Plavix®) 75 mg daily 
o 
Prasugrel (Effient®) 5-10 mg daily 
o 
Ticagrelor (Brilinta®) 90 mg twice daily 
  
• Anticoagulant:  An anticoagulant should be administered to subjects undergoing PCI. 
Following administration of the initial bolus of anticoagulant, activated clotting time 
(ACT) will be measured locally at “peak dose” and just prior to sheath removal, as 
well as according to the standard of care. 
o 
Administration of IV Unfractionated Heparin (UFH) is preferred in this 
study and should be dosed per standard of care and routine hospital practice 
(i.e., weight-based and adjusted to attain target ACT).   
o 
Low-molecular-weight heparin (LMWH) is an acceptable alternative to 
UFH within the context of this trial (weight adjusted in accordance with 
approved dosage and administration).  
o 
 It is strongly recommended to use only one anti-coagulant drug 
consistently and not switch between agents before or during the PCI 
procedures.  
o 
A parenteral direct thrombin inhibitor (e.g, bivalirudin) is not to be 
administered. 
o 
Anticoagulant should not be restarted after access sheath removal unless 
specifically indicated for another condition such as anticoagulation for a 
deep venous thrombosis, atrial fibrillation, or a mechanical prosthetic heart 
valve (Section 6.3.2).  
 
• Rescue Therapy (thrombotic bailout):  The planned administration of GP IIb/IIIa 
inhibitors (GPI) for a subject excludes that subject from participation in this study and 
therefore should not be an anticipated part of the regimen. During PCI, bail-out with an 
FDA-approved GPI such as eptifibatide (Integrilin®) may be used, at the investigator’s 


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discretion, in subjects with new ischemia on telemetry or ECG, worsening of 
angiographic coronary flow during procedure or thrombotic complication(s) related to 
stenting during or after PCI. 
 
• Coronary Stents:  During PCI, the number and type of coronary stenting will be 
determined by the investigator and will include only FDA-approved devices (bare 
metal and drug-eluting) which are indicated for PCI. The stent implant procedure will 
be performed in accordance with the device Instructions for Use (IFU).   
 
• Vascular Access and Closure Devices:  The use of radial, femoral or brachial artery 
access will be allowed.  Timing of the arterial sheath removal will be performed as per 
standard of care and local routine practice (e.g., target ACT). FDA-approved vascular 
closure devices (e.g., Angioseal™, Vasoseal™, Perclose™) may be used as an 
alternative to manual compression to attain vascular hemostasis.  Pressure on the 
access site (either manual or by a mechanical device) should be applied for a minimum 
of 30 minutes. 
 
6.4.4 Method of Study Drug Assignment, Randomization and/or Stratification 
 
A centralized randomization computerized program will provide randomized study drug 
assignment at enrollment through an interactive, web-based electronic data capture (EDC) 
system (i.e., integrated randomization within the Medidata® platform), using randomization 
schemes (permuted block method) provided by the sponsor’s designee.  After a subject 
qualifies for enrollment in the study, the designated staff at the clinical site will enter 
confirmation that the subject meets all of the inclusion criteria and none of the exclusion 
criteria into the system (available 24 hours a day, 7 days a week). Upon successful 
randomization, the subject will be assigned a unique subject randomization number. 
 
Subjects will be randomized via the interactive web-based system in the order that they 
qualify, with stratification based on clinical site as well as by the urgency of the cardiac 
catheterization/PCI procedure at the time the operator decides to perform it- Elective versus 
Urgent- to obtain balance across treatment groups.  Subject randomization numbers that are 
assigned to subjects who do not receive study drug will not be re-utilized.  No enrollment caps 
will be set for the individual clinical sites or stratum.  
 
6.4.5 Selection and Timing of Dose for Each Subject 
 
All subjects who fulfill study entry criteria as specified in Sections 6.3.1-6.3.2 and undergo 
successful randomized treatment assignment will receive PZ-128 or matching placebo, as 
determined by the randomization scheme:  a single, weight-adjusted IV dose of 0.3 mg/kg or 
0.5 mg/kg. The infusion must be started within 1 hour before the commencement of the 
cardiac catheterization procedure (i.e., coronary angiography).  
 
  
 


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There is no provision for delaying the start of the study drug administration outside of the pre-
diagnostic angiography window.  
 
There is no provision for dose modification (increase or decrease), and this is not allowed.  
See Sections 6.4.7.7 and 6.7.2.3, however for information concerning temporary study drug 
infusion interruption or permanent discontinuation.  The single dose of PZ-128 will be one of 
two possible dose levels being studied in a parallel manner- 0.3 mg/kg and 0.5 mg/kg- and the 
dose groups will enroll in parallel until the appropriate number of subjects have been treated.  
 
6.4.6 Blinding of Study Drug 
 
This will be a double-blind study.  Study drug treatment assignment (activity of IP) will be 
blinded for subjects, investigators and staff who evaluate subjects and their responses or make 
decisions about subject care, and sponsor personnel who are involved in the data analysis. 
Statisticians and programmers at the sponsor’s designated partner (Research Triangle Institute, 
International- RTI) will prepare all randomization schemes which will then be loaded into the 
randomization system by Medidata Solutions, Inc. In addition, copies of the randomization 
schemes will be made available to the following within the sponsor and/or its designee: 
• Independent statistician(s) at RTI to support requests by the DSMB 
• Study lead(s) for the analysis of the pharmacokinetic and pharmacodynamics samples, 
exploratory biomarker samples and pharmacogenomics samples.  
 
Appropriate personnel within Clinical Supplies Management, Inc® (CSM) will have access to 
vial sequencing assignment for proper labeling, packaging and shipment of study drug.   
 
Unblinding of the study drug assignment for a subject at a clinical site should occur only in 
the event of a medical emergency or serious adverse event for which it is necessary to know 
the study treatment to determine the appropriate medical management for the subject.  This 
circumstance is extraordinary and will likely impact a minor fraction of the enrolled subjects. 
Unblinding at the study site for any other reason, including selection of subsequent anti-
platelet therapies, will be considered a protocol violation. The investigator is strongly 
encouraged to contact the Medical Director at Tufts Medical Center before unblinding any 
subject’s study drug assignment, but must do so within 1 working day after the event and must 
document the unblinding and its rationale in the subject’s electronic case report form (eCRF).  
For emergency unblinding, the investigator should be the individual who authorizes the 
designated investigational pharmacy staff to proceed with unblinding.  When the ability to 
manage the health or welfare of the study subject is dependent upon the requested 
information, the information may be revealed by the unblinded designated investigational 
pharmacy staff immediately and independent of the investigator’s authorization.  However, 
this delegation of authority must be documented in advance (i.e., pharmacy policy and 
procedure manual, study-specific delegation of authority log).   In case of any accidental 
unblinding, the procedures noted above should be followed.   
 
The sponsor, Tufts Medical Center, retains the right to unblind the study drug assignment for 


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SAEs that potentially require expedited reporting to regulatory authorities.   
 
The external, independent DSMB (Section 9.3.1) will be allowed to inspect unblinded results 
for bleeding, platelet aggregation, MACE and stent thrombosis and other SAEs if it is felt 
necessary to make decisions about enrolling subjects into any dose group.  The operating 
procedures of the DSMB will be defined in a separate charter.  
 
The sponsor and DSMB will monitor all episodes of unblinding. 
 
6.4.7 Investigational Product(s)  
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, handling, storage, distribution, and usage of these 
materials in accordance with the protocol and any applicable laws and regulations.  The 
investigator will designate a qualified (i.e., licensed/registered) member of the institution’s 
research/investigational pharmacy staff to perform the day-to-day pharmacy activities and 
investigational product management including, but not limited to, the procurement, storage, 
preparation, dispensing, and final disposition of investigational products, keeping in mind that 
all aspects of the investigational trial, including conduct, management, and record 
maintenance, are ultimately the responsibility of the investigator. Neither the investigator nor 
any member of the clinical research team should have access to the investigational product 
supply or accountability records in a manner that would jeopardize the maintenance of the 
blind. See the Investigational Product Instruction Manual (IPIM) for complete details and 
requirements for study drug packaging, labeling, storage, preparation, administration and 
accountability  
 
6.4.7.1 Identity of Investigational Product(s) 
 
Investigational Products (IP) are active PZ-128 and its matching placebo.  The PZ-128 is 
available as a sterile, preservative-free, white to off-white, solid lyophilized powder cake for 
reconstitution.  
 
 
 
 
 
  
 
Each PZ-128 or placebo vial is intended for single-dose/single-use only and is not to be used 
to treat more than 1 subject.  
 
6.4.7.2 Source 
 
PZ-128 and matching placebo will be provided free of charge by the sponsor, Tufts Medical 
Center, and will be distributed by the sponsor’s designee, Clinical Supplies Management, Inc® 


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(CSM, Fargo, ND).  
 
6.4.7.3 Labeling 
 
Information provided on the labels for the IP will comply with ICH, GCP and local regulatory 
requirements. All vial labels will contain a unique vial sequence number, lot number, study 
number, product identity (i.e., PZ-128 48 mg/vial or Placebo), vial size ( 20 cc), 
reconstitution/ dilution instructions, storage conditions, sponsor identification, IP form 
(powder for solution for infusion), method of administration (for intravenous use) and 
investigational statement.  All box/carton labels will contain the study number, product 
identity, number of vials/box, storage conditions and sponsor identification. In lieu of an 
expiration date, stability information will be provided by the sponsor to the clinical site when 
the investigational product (IP) is shipped from CSM and will be updated during the clinical 
investigation.  
 
6.4.7.4 Packaging 
 
Multi-vial boxes/cartons will contain either 20 vials of active PZ-128 or 20 vials of placebo.    
The sponsor will request the initial IP supply shipment from CSM after the clinical site has 
completed the appropriate regulatory requirements and prior to the screening of the first 
subject for study participation.  Subsequent IP supply will be requested by each site’s 
designated pharmacy staff according to its ongoing inventory management.  
 
6.4.7.5 Storage 
 
Vials of the investigational products must be stored at a controlled freezing temperature of   
-20 °C ± 10 °C (i.e., -30 °C to -10 °C [-22 °F to 14 °F]) and protected from direct sunlight, 
unless otherwise authorized by the sponsor. The IP supply will be stored in a securely locked 
location in the site’s pharmacy and access should be strictly limited to the designated 
pharmacy staff.    
 
6.4.7.6 Reconstitution, Dilution and Dispensing 
 
The investigator agrees neither to dispense the study drug from, nor store it at any site(s) other 
than those listed on the Form FDA 1572.  The investigator agrees that study drug(s) will be 
dispensed by the investigator or subinvestigator(s) named on the Form 1572, or their qualified 
designee (i.e., prepared for administration and dispensed by registered pharmacy staff).  The 
investigator, subinvestigator(s), or qualified designee(s) also agree that the study drug(s) will 
be dispensed with a signed medical order from an authorized prescriber only to study subjects 
who have provided written informed consent, have met all entry criteria and have completed 
successful randomization (allocation of unique randomization number and assigned study 
treatment). Investigational product(s) may not be used for any purpose other than that stated in 
the research protocol.   
 
The designated, unblinded investigational pharmacist at the clinical site will access the 


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subject’s randomized study drug assignment through a password-protected and restricted role 
login within the Medidata Rave® EDC system prior to the preparation of the blinded IV bag 
for infusion. The pharmacy staff will select 1 to 2 vials from either the PZ-128 or placebo 
supply depending upon the  subject’s assigned IP and dose level (0.3 mg/kg or 0.5 mg/kg) and 
the subject’s actual body weight at the time of Screening (rounded to the nearest kg) in order 
to provide individual dosing.   
 
 
 
 
 
 
 
 
 
 
 
 
The final IV bag for administration will be labeled as per the institution’s investigational drug 
policy(s) for blinded products and should include the following: subject name/medical record 
number/study ID number, blinded IP name (PZ-128/Placebo), IP dosage form (for intravenous 
infusion), final weight-adjusted dose (mg) and total volume (mL), single-use only, method of 
administration/infusion rate (IV infusion over 120 min; infuse entire contents for full dose), 
preparation and expiration dates, storage conditions, study identifier, prescribing investigator 
name, pharmacist name, and investigational use statement.  
 
 
 
6.4.7.7 Administration  
 
The study drug will be delivered once as a continuous IV infusion using an intravenous 
infusion pump given over a 2-hour period 
 
 
  This will be a dedicated 
line for the study drug administration compatible with the institution’s IV pump module and 
will be supplied by the clinical site.  PZ-128/placebo will be administered by a qualified 
member of the study staff or institution’s clinical staff following successful enrollment/ 
randomization prior to cardiac catheterization. 
 
 
Intravenous PZ-128/placebo will be administered peripherally through an intravenous catheter 
which should not be smaller than 20-gauge. It is recommended that PK/PD/exploratory 


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biomarkers/pharmacogenomics research samples are obtained from a distal venous site, 
ideally from the opposite arm or alternatively from a site distal to the site of drug infusion.  If 
a subject has a central line in place, PZ-128/placebo may be administered via that route. If PZ-
128/placebo is administered via central venous catheter, it is strongly recommended that 
PK/PD/exploratory biomarkers/ pharmacogenomics research samples are obtained by 
peripheral venipuncture if at all possible.  Due to the potential overfill volume in the 
commercial D5W IV bag, the entire contents of the IV bag should be infused for complete 
dosing. 
 
 
 
The investigator or designated medical staff must be present during the administration of the 
investigational product to assess and treat adverse events that may arise during dosing.  
Anaphylaxis precautions must be observed during the PZ-128/placebo administration and for 
at least 1 hour following the completion of the infusion. Subjects will be monitored in the 
cardiac catheterization lab until discharge or transfer to another hospital unit per the protocol 
and local standards of care. 
 
There will be no dose modifications or alterations to the rate of infusion.  Subjects should 
receive the entire study drug infusion regardless of whether a PCI is performed. Potential drug 
allergic reactions that occur during the administration of PZ-128/placebo may necessitate 
stopping and restarting the infusion (interruption/temporary cessation of the infusion is 
allowed for up to 1 hour only) or discontinuing (permanent cessation) the study drug infusion, 
regardless of whether the reaction is deemed related or not-related to PZ-128/placebo (See 
Management of Drug Allergic Reactions Section 6.7.2.3). 
 
Based on the judgment of the investigator or qualified designee (i.e., enrolling/treating sub-
investigator), dosing with the study drug may be withheld, interrupted and/or discontinued for 
any clinical situation in order to preserve the protection, safety and well-being of the subject.   
 
 
 
 
6.4.7.8 Drug Accountability  
 
An accurate and current accounting of the supplies of investigational products that were 
received from the sponsor/designee, dispensed and administered to subjects and 
returned/destroyed/disposed of as dictated by the sponsor, will be maintained on an ongoing 
basis by the designated research/investigational pharmacist on the Investigational Product 
Accountability Record at each clinical site and will be verified by the sponsor’s study monitor 
throughout the conduct of the study.  The PZ-128/placebo Dose Preparation Worksheet will be 
completed for each subject and the subject’s receipt of study drug administration will be 
recorded in their medical records and on the eCRF.  
 


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The sponsor’s designated study monitor will perform routine site monitoring activities for 
pharmacy, drug accountability and reconciliation of the investigational products. At the 
completion of the trial, after the study monitor has conducted a final inventory and drug 
accountability, all unused drug will be returned to the sponsor, Tufts Medical Center (or 
designee) or destroyed at the clinical site as authorized by the sponsor and in accordance with 
the institution’s SOP.  In the event that study drug needs to be returned for any other reason, 
the site will receive a written request from the sponsor/designee with the identity of the drug 
product listing the vial number(s)/box number(s) to be returned and the reason for the return 
request. 
 
Inventory records must be readily available for inspection by the study monitor and/or auditor, 
and open to government inspection at any time.  
 
6.4.8 Non-Study Treatments 
 
 
6.4.8.1 Prior and Concomitant Medications 
 
All prior medications (prescription and over-the-counter, including dietary supplements) 
within 30 days prior to randomization, and all concomitant therapy taken by the subject for the 
duration of the study are to be recorded in source documentation and on the eCRF.  The 
identity of the therapy, the dose, route, and regimen, the dates started and stopped (or notation 
of “continuing” if that is the case), and the reason for use must be recorded.  The use of any 
concomitant medication must relate to an adverse event or the subject’s medical history.   
 
6.4.8.1.1 Medications/Therapies Prohibited Prior to Randomized Study Treatment 
Assignment and During the Study 
 
The medications/therapies prohibited prior to randomization treatment assignment and during 
the study after randomized treatment assignment are listed under Exclusionary Prior/ 
Concomitant/Anticipated Medication/Therapy (exclusion criteria 25 through 31) in Section 
6.3.2. A categorical summary is provided below:  
 
IV Antiplatelets 
A subject is not eligible for the study if any other IV antiplatelet drug has been administered 
within 30 days prior to randomization and they should not be used after randomization up until 
30 days following the study drug administration.  
 
Other Oral Antiplatelets 
Aside from aspirin and fish oil supplements, clinical experience of other drugs with any 
antiplatelet effect in combination with PZ-128 is not available at this time.  Treatment with 
these types of drugs (including NSAIDs) are allowed pre-study and/or during the study, at the 
investigator’s discretion. Treatment with cycloxygenase-2 inhibitors is permitted. However, as 
per the exclusion criteria (Section 6.3.2), treatment with another PAR1 inhibitor within 60 
days prior to randomization or the concurrent/anticipated use of one after randomization up 
until 30 days following the study drug administration is not allowed.  


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Oral Anticoagulants 
A subject is not eligible for the study if warfarin treatment has been administered within 5 
days prior to randomization and it should not be used after randomization up until 2 days 
following the study drug administration.  A subject is not eligible for the study if oral Factor 
Xa or direct thrombin inhibitor treatment has been administered within 2 days prior to 
randomization and they should not be used after randomization up until 2 days following the 
study drug administration.    
 
If treatment with oral anticoagulant drugs is considered essential during this study period, the 
sponsor should be contacted.  
 
Thrombolytic/Fibrinolytic Therapy 
A subject is not eligible for the study if thrombolytic/fibrinolytic therapy has been 
administered within 7 days prior to randomization and they should not be used after 
randomization up until 30 days following the study drug administration.  Clinical experience 
of thrombolytics/ fibrinolytics in combination with PZ-128 is not available at this time and 
caution should be used.   
 
Other Medications 
All previous prescription and non-prescription concomitant medications administered up to 30 
days prior to randomization, on an ongoing basis, as well as changes in such concomitant 
medication and any new concomitant medication taken while the subject is on study, should 
be recorded in the subject’s source documents and on the appropriate eCRF through 90 days 
after the completion of the study drug administration. The administration of all medication 
(including investigational products) must be recorded in the subject’s source documents/ 
medical records and in the appropriate sections of the eCRF. 
 
6.4.8.1.2 Medications/Therapies Allowed During the Study  
 
Medications or supplements that are prohibited prior to randomization and during the study 
period are identified in Section 6.3.2 and Section 6.4.8.1.1.  Other medication(s), which are 
considered necessary for the subject’s safety and well-being, may be given at the discretion of 
the investigator(s).   
 
6.4.8.2 Other Restrictions 
 
Due to the potentially acute nature of randomization of the subject prior to the administration 
of the study IP and cardiac catheterization/PCI procedure, there are no protocol restrictions on 
the food and drink intake prior to the randomization or procedure, although fatty meals should 
be avoided if possible. 
 
Subjects should not donate blood at any time during the study period. 
 
6.4.9 Procedures for Monitoring Compliance  
 
This study will be conducted as described in this protocol, except for any emergency situation 


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in which the protection, safety and well-being of the subject requires immediate intervention, 
based on the judgment of the investigator or qualified designee.  In the event of a significant 
deviation from the protocol due to an emergency, accident, or mistake, the investigator or 
designee should contact the sponsor at the earliest possible time by telephone.  This will allow 
an early joint decision regarding the subject’s continuation in the study.  The investigator will 
be responsible for complying with the local IRB established procedures for executing and 
reporting all protocol deviations. All protocol deviations will be tracked by the sponsor and 
used in the evaluation of the data sets for the protocol analysis. 
 
The investigator or qualified designee is to note in source documentation and in the 
appropriate section of the eCRF whether study drug infusion had been administered per 
protocol.  If not, the reason for deviation must be recorded.  In addition, the designated 
pharmacy staff will maintain drug accountability logs, and investigational product (IP) dose 
preparation worksheets on an ongoing basis and the supply of the IP will be cross-referenced 
with the infusion records at routine interim monitoring visits (IMV) conducted by the 
sponsor’s monitor. 
 
6.5 
Study Schedule 
 
An overview of the study is provided in the Study Design Diagram in Section 1.1 and the 
schedule of assessments/events is shown in the Study Flow Chart in Section 1.2.  See Section 
6.6 for specific information on processes. Figure 1 provides a treatment and follow-up 
schema.   
 
The sponsor has specified a schedule of intervals relative to the day of randomized treatment 
for the return visit to the clinic and the telephone contacts, with a “window” of days around 
each visit/contact.  The sponsor strongly requests that the subjects return for clinical visits or 
undergo telephone contacts as close to the specified interval as possible, and preferable within 
the defined window.  If it is not possible for the subject to return within the visit “window”, 
then the visit should be scheduled as close to the interval as is convenient for the subject and 
clinical site.    Note that these are regularly scheduled visits/time points; if an unscheduled 
visit is required by the investigator or sponsor because of clinical circumstances or other 
unforeseen event, this will be allowed.  All other aspects of care beyond those specified in the 
protocol will be based on the judgment and discretion of the investigator. All data collected 
will be used in the conduct of the study. 
 
 
 
 


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Figure 1. 
Study and Treatment Schema 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
*Specific P2Y12 inhibitor drugs and doses will be administered as per the investigator’s discretion/standard of 
care (e.g., clopidogrel, prasugrel or ticagrelor) 
 
 
ASA=aspirin; IP=investigational product; LMH=low molecular weight heparin; UFH=unfractionated heparin 
 
Each subject randomized in this trial will participate for approximately 15 weeks, including a 
screening period of up to 14 days prior to the administration of the study drug and cardiac 
catheterization, the hospitalization phase, and a 90-day follow-up phase after the study drug 
administration as follows:    
• Screening/Enrollment Period:  up to 14 days prior to cardiac 
catheterization/PCI and study drug administration    
• Hospitalization Phase:  inpatient or outpatient period of hospitalization for 
care associated with the study drug administration and cardiac catheterization 
± PCI through discharge  
• Outpatient follow-up visit:  14 days (± 5 d)  post study drug administration 
• Telephone follow-up contact:  30 days (± 5 d) post study drug administration 
• Telephone follow-up contact:  90 days (± 7 d) post study drug administration 
 
 
 
PZ-128  
0.3 mg/kg 
 
PZ-128 
0.5 mg/kg 
 
Placebo 
0.3 mg/kg 
 
Placebo  
0.5 mg/kg 
 
Screening/ 
Baseline 
Angiography 
PCI 
PZ-128/Placebo IV infusion (2 h)† 
Randomization 
UFH or LMH 
Loading P2Y12* 
ASA 
Inpatient Hospitalization 
24 hours Post IP or 
prior to Discharge 
(whichever is sooner) 
14 days (± 5)  
Post IP 
Out-patient Visit 
30 days (± 5) 
Post IP  
Phone F/U 
90 days (±7)  
Post IP  
Phone F/U 
Maintenance 
ASA & P2Y12* 


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6.5.1 Screening (within 14 days prior to cardiac catheterization/study drug 
administration) 
 
Screening should occur as soon as a prospective study participant is identified. The 
investigator or qualified designee should ascertain as much as possible, and as allowed, that a 
subject would be eligible to participate before obtaining informed written consent.  All 
screening parameters for enrollment must be performed prior to randomization and must be 
within 14 days before the cardiac catheterization/PCI and study drug administration.  Subjects 
may or may not already be hospitalized due to their acute condition.  Any data collected and 
any procedure performed as part of standard of care preadmission testing or other testing 
before written consent has been obtained may be used as part of the assessment for eligibility 
as long as it would have been performed regardless of subject participation in the study and it 
is within the specified time frame for inclusion/exclusion criteria (this includes data/results 
collected from another facility).  All samples, tests, and evaluations collected/ performed/ 
recorded as part of the procedures specified in this protocol that are not part of standard of 
care may occur only after written informed consent has been obtained.   
 
A subject who signs the informed consent to participate in the study but does not progress to a 
randomization assignment (by decision of either the subject or investigator) will be considered 
as a screen failure.  Screen failure subjects will not be considered enrolled in the trial by the 
sponsor and will not be followed beyond the point it is determined that the subject will not be 
randomized- no further data will be collected, and the subject will not be included in any study 
safety and efficacy analyses. However, the investigator and/or designee will submit a log 
record of those subjects as per Section 8.2.   
The clinical laboratory at each study site will be used to perform all standard clinical labs 
according to its internal SOP’s unless otherwise stated.   
 
The following will be performed or obtained during the baseline screening period prior to 
randomization: 
 
1. 
Explain the study to the subject and obtain appropriate written informed consents (i.e., 
main study and optional PK/PD sub-study, exploratory biomarkers research and 
pharmacogenomics).  Review acceptable methods of contraception (birth control) while 
taking part in this study with both female subjects of child-bearing potential and male 
subjects. 
2. 
Obtain a complete medical history (medical, surgical and cardiovascular) and 
demographics. 
3. 
Review and record all previous and concomitant medications taken within the past 30 
days with particular attention to anti-platelet, anticoagulant and thrombolytic/ 
fibrinolytic therapy.  
4. 
Perform a complete physical exam (review of systems).  
5. 
Obtain vital signs, including heart rate, blood pressure, and height and weight. 
6. 
Record a standard 12-lead electrocardiogram (ECG). 


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7. 
Obtain blood samples from the subject for the following standard clinical laboratory 
evaluations to be performed locally: 
a. 
Hematology- complete blood count (CBC), differential white blood count and 
platelet count;  
b. 
Serum chemistry- sodium, potassium, chloride, carbon dioxide (CO2), glucose, 
blood urea nitrogen (BUN), creatinine, alkaline phosphatase, total bilirubin, 
alanine transaminase (ALT), and aspartate transaminase (AST); 
c. 
PT/INR and aPTT; 
d. 
Lipid panel- total cholesterol, high-density lipoprotein cholesterol, calculated low-
density lipoprotein cholesterol and triglycerides (does not have to be fasting); and  
e. 
Glycosylated Hemoglobin (HbA1c). 
8. 
Perform and document urine pregnancy test (urine beta-HCG point-of-care test) for all 
women of child-bearing potential (this must be completed during screening and also 
within the 24 hours prior to study drug administration).  Perform eligibility assessment 
(review of inclusion & exclusion criteria, See Section 6.3.1 and Section 6.3.2). 
 
Subjects may be randomized prior to the return of the baseline local clinical laboratory test 
results unless the test is specifically listed in the inclusion/exclusion criteria (i.e., hemoglobin, 
hematocrit, platelet count).  However, all baseline laboratory blood draws must be done prior 
to randomization and within the specified time frame (i.e., 14 days prior to study drug 
administration/cardiac catheterization ± PCI). 
 
6.5.2 Enrollment and Randomization  
 
Randomization must occur far enough in advance of the cardiac catheterization/PCI to allow 
the institution’s pharmacy staff to prepare and deliver the study drug to the catheterization lab 
and to ensure that the single dose, 2-hour IV infusion is started within one hour prior to the 
beginning of the coronary angiography following
 
 
 
1. 
When a subject qualifies for enrollment/randomization, the clinical site staff will access 
the web-based, randomization program (available 24 hours a day, 7 days a week) and 
enter confirmation that the subject meets all of the inclusion criteria and none of the 
exclusion criteria.  The clinical site will provide information on the urgency of the 
procedure to allow for proper stratification of study treatment assignment (i.e., elective 
versus urgent, See Section 6.3.1). Following a successful randomization process, the 
subject will be assigned a unique subject randomization number.   
 
2. 
The clinical site staff will notify the investigational pharmacy staff of the randomization 
and will coordinate the delivery of ready-to-infuse, blinded study drug per the 
appropriate time/date of the anticipated procedure.   
 
Appropriate eCRFs must be completed for all randomized subjects regardless of whether they 


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receive study drug. Randomized subjects cannot be considered screen failures.  
 
 6.5.3 Pre-Cardiac Catheterization Procedure  
 
1. 
Prepare study drug for administration in investigational/research pharmacy (see 
Investigational Product Instruction Manual-IPIM). 
2. 
Record any changes to concomitant medication(s). 
3. 
Confirm subject still meets eligibility criteria to receive study drug.  
4. 
Perform and document urine pregnancy test (urine beta-HCG point-of-care test) for 
women of child-bearing potential if screening assessment was not within the 24 hours 
prior to study drug administration. The result must be known and negative prior to 
administration of the study drug. 
5. 
Administer aspirin. 
 
 
7. 
Obtain vital signs, including heart rate and blood pressure just prior to study drug 
administration (i.e., Time=0). 
8. 
Collect blood sample (serum) for centralized research analysis of Cardiac Troponin I 
(cTnI) just prior to study drug administration (i.e., Time=0). 
9. 
Collect blood samples for optional research according to site participation and subject’s 
individual consent (see Section 6.6.3.2) just prior to study drug administration (i.e., 
Time=0): 
a. 
Samples for pharmacokinetics (plasma) and pharmacodynamics-platelet 
aggregation (whole blood) (PK/PD sub-study; participating sites only);  
b. 
Plasma sample for exploratory biochemical, inflammatory and metabolic markers; 
and  
c. 
Whole blood sample for pharmacogenomics. 
10. Start blinded PZ-128/placebo IV administration 0-60 min prior to start of coronary 
angiography and infuse continuously over 2 hours (infuse entire contents for complete 
dosing). Observe anaphylaxis precautions during the infusion and for at least 1 hour 
following cessation of study drug.  
11. Perform any additional standard of care assessments in the pre-cardiac 
catheterization/PCI setting. 
12. Assess and record adverse events, including bleeding and clinical efficacy endpoint 
events (MACE, stent thrombosis). 
 
 
 


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6.5.4 Cardiac Catheterization ± Percutaneous Coronary Intervention  
 
1. 
Perform diagnostic angiogram per institutional practices and determine if percutaneous 
coronary intervention (PCI) is indicated. Study drug infusion will be run through 
completion regardless of the outcome from the diagnostic angiography. 
2. 
Perform PCI per institutional guidelines and standards of care including parenteral anti-
coagulant (i.e., UFH or LMWH) and oral anti-platelet (i.e., P2Y12) if indicated (See 
Section 6.4.3 and Section 6.4.8 for standard of care treatment(s) and study protocol 
directives). PCI is deemed to have commenced when the guide wire crosses the lesion.  
If the randomized subject does not undergo PCI, the reason for non-intervention must be 
documented in the subject’s medical records by the operator (i.e., interventional 
cardiologist) making the decision to not perform PCI and entered into the eCRF.  
3. 
Following administration of the initial bolus of anti-coagulant (UFH or LMWH), ACT 
will be measured and documented (point-of-care testing) locally at “peak dose” and just 
prior to sheath removal, as well as according to the standard of care. 
4. 
Record all concomitant medications administered to the subject. 
Note, during PCI, a GPI for thrombotic bailout may be used (per the package insert) in 
subjects with new ischemia on telemetry or ECG, worsening of angiographic coronary 
flow during procedure, or thrombotic complication related to stenting during PCI, at the 
investigator’s discretion. The GPI used must be recorded on the case report form along 
with the indication and dose.  However, subjects in whom the administration of a GPI is 
planned must not be enrolled in the study. 
5. 
Assess and record adverse events, including bleeding and clinical efficacy endpoint 
events (MACE, stent thrombosis).  
 
6.5.5 Post-PZ-128/Placebo Infusion  
 
1. 
Obtain vital signs including heart rate and blood pressure immediately after the 
completion of the study drug administration (i.e., Time=2 h). 
2. 
Assess and record adverse events, including bleeding and efficacy endpoint events 
(MACE, stent thrombosis).  
3. 
Collect blood samples for optional research according to site participation and subject’s 
individual consent (see Section 6.6.3.2): 
a. 
Samples for pharmacokinetics (plasma) and pharmacodynamics- platelet 
aggregation (whole blood) (PK/PD sub-study; participating sites only) will be 
drawn at the following time points:  30 min ± 5 min, 1 h ± 5 min, 2 h + 15 min 
(immediately after completion of infusion), and 6 h – 2 h (4 to 6 h) after the start of 
the PZ-128 infusion; and 
b. 
Plasma sample for exploratory biochemical, inflammatory and metabolic markers 
will be drawn at the following time points: 2 h + 15 min (immediately after 
completion of infusion) and 6 h – 2 h (4 to 6 h) after the start of the PZ-128 
infusion. 


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6.5.6 Post-Cardiac Catheterization/PCI 
 
1. 
Collect blood sample (serum) for centralized research analysis of Cardiac Troponin I 
(cTnI) at 4 to 8 h and 12 to 24 h after the completion of PCI.  In addition, if applicable, 
collect samples immediately after occurrence of symptoms suggestive of acute coronary 
syndrome, and again 4 to 8 h and 12 to 24 h after symptoms if the subject has not yet 
been discharged from the hospital. 
2. 
Assess and record adverse events, including bleeding and clinical efficacy endpoint 
events (MACE, stent thrombosis). 
3. 
Record concomitant medications.  
4. 
Perform vital signs including heart rate and blood pressure (timing as per standard of 
care). 
5. 
Record a standard 12-lead ECG (timing as per standard of care). 
6. 
Obtain blood sample for the following standard clinical laboratory evaluations (timing as 
per standard of care): 
a. Hematology- complete blood count (CBC), differential white blood count and 
platelet count;  
7. 
Perform other post-procedural tests and evaluations in accordance with institutional 
guidelines and standards (e.g., arterial access sheath removal).  
 
6.5.7 24 hours (± 2 h) Post Start of Study Drug Infusion or At Discharge from Hospital 
(whichever occurs sooner) 
 
Perform the following at 24 hours ± 2 h post start of the IP infusion, or Prior to Discharge, 
whichever occurs sooner. 
 
1. 
Review and record all concomitant medications taken during hospitalization.  
2. 
Perform a physical examination (note, the clinical site’s standard of care, cardiac 
catheterization nursing assessment may be performed to evaluate the subject’s clinical 
status in lieu of a complete physical exam at this time point). 
3. 
Obtain vital signs, including heart rate and blood pressure. 
4. 
Obtain blood samples from the subject for the following standard clinical laboratory 
evaluations: 
a. 
Hematology- complete blood count (CBC), differential white blood count and 
platelet count;  
b. 
Serum chemistry- sodium, potassium, chloride, carbon dioxide (CO2), glucose, 
blood urea nitrogen (BUN), creatinine, alkaline phosphatase, total bilirubin, 
alanine transaminase (ALT), and aspartate transaminase (AST); and 
c. 
PT/INR and aPTT. 
 


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5. 
Assess and record adverse events, including bleeding and clinical efficacy endpoint 
events (MACE, stent thrombosis). 
6. 
Collect blood sample (serum) for centralized research analysis of Cardiac Troponin I 
(cTnI) if a sample was not already collected at 12 to 24 h after the completion of PCI. 
7. 
Collect blood samples for optional research according to site participation and subject’s 
individual consent (see Section 6.6.3.2): 
a. Samples for pharmacokinetics (plasma) and pharmacodynamics- platelet 
aggregation (whole blood) (PK/PD sub-study; participating sites only); and 
b. Plasma sample for exploratory biochemical, inflammatory and metabolic 
markers. 
8. 
Perform other tests and evaluations in accordance with institutional guidelines and 
standards (e.g., start maintenance anti-platelet regimen, aspirin and P2Y12, if indicated).  
9. 
Provide subject with discharge instructions, wallet medication card for study drug and 
schedule follow-up study office visit appointment for 14 days ± 5 d post study drug 
administration.  
 
6.5.8 Hospitalization lasting >24 Hours 
 
If the subject remains in the hospital >24 hours, perform the following daily until discharge: 
 
1. 
Obtain routine clinical tests and evaluations in accordance with institutional guidelines 
and standard of care (e.g., vital signs, blood samples for standard clinical laboratory 
evaluations, ECG, etc.). 
2. 
Assess and record adverse events, including bleeding and clinical efficacy endpoint 
events (MACE, stent thrombosis). 
3. 
Review and record all concomitant medications taken during hospitalization. 
 
If the subject remains in the hospital for ≥48 hours, collect blood samples for optional 
research according to site participation and subject’s individual consent (see Section 6.6.3.2) 
just prior to discharge:  
a. 
Samples for pharmacokinetics (plasma) and pharmacodynamics- platelet 
aggregation (whole blood) (PK/PD sub-study; participating sites only); and 
b. 
Plasma sample for exploratory biochemical, inflammatory and metabolic markers. 
 
6.5.9 14 days (± 5 d) Post Study Drug Infusion Follow-Up Outpatient Visit  
 
The subject will return to the investigational site approximately 14 days following their dosing 
with the study drug. 
 
1. 
Review and record interval history since discharge including any concomitant illnesses, 
procedures, therapies (e.g., transfusions), adverse events, including bleeding and clinical 


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efficacy endpoint events (MACE, stent thrombosis).  The subject should be questioned 
regarding any hospitalization and/or medical visits relating to episodes of ischemia or 
bleeding or adverse events that may have occurred since discharge. Original source 
documents must be collected for any events.  Should a subject be re-admitted or undergo 
care at an outside facility, all possible efforts should be made to obtain the original 
source documents.  
2. 
Review and record concomitant medications (including maintenance anti-platelet 
treatment) taken since discharge.  
3. 
Perform a complete physical examination.  
4. 
Obtain vital signs, including heart rate and blood pressure. 
5. 
Record a standard 12-lead ECG. 
6. 
Obtain blood sample from the subject for the following standard clinical laboratory 
evaluations: 
a. 
Hematology- complete blood count (CBC), differential white blood count and 
platelet count. 
7. 
Perform and document urine pregnancy test (urine beta-HCG point-of-care test) for all 
female subjects of child-bearing potential. 
8. 
Additional clinical laboratory tests and/or other evaluations may be performed for 
standard of care.   
9. 
Collect blood samples for optional research according to site participation and subject’s 
individual consent (see Section 6.6.3.2): 
a. 
Samples for pharmacokinetics (plasma) and pharmacodynamics- platelet 
aggregation (whole blood) (PK/PD sub-study; participating sites only); and 
b. 
Plasma sample for exploratory biochemical, inflammatory and metabolic markers. 
10. Schedule follow-up telephone contact 30 days (± 5 d) post study drug administration. 
 
6.5.10   30 days (± 5 d) Post Study Drug Infusion Follow-Up Telephone Contact  
 
The subject will be contacted approximately 30 days following dosing with the study drug. 
 
1. 
Review and record interval history since the 14-day study visit including any 
concomitant illnesses, procedures, therapies (e.g., transfusions), adverse events, 
including bleeding and clinical efficacy endpoint events (MACE, stent thrombosis). The 
subject should be questioned regarding any hospitalization and/or medical visits relating 
to episodes of ischemia or bleeding or adverse events that may have occurred since 
discharge. Original source documents must be collected for any events.  Should a subject 
be re-admitted or undergo care at an outside facility, all possible efforts should be made 
to obtain original source documents.  
2. 
Review and record concomitant medications (including maintenance anti-platelet 
treatment) taken since 14-day study visit.  


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3. 
Schedule follow-up phone contact for 90 days (± 7 d) post study drug administration. 
6.5.11   90 days (± 7 d) Post Study Drug Infusion Follow-up Telephone Contact 
  
The subject should be contacted approximately 90 days following dosing with the study drug. 
 
1. 
Review and record interval history since the 30-day study telephone call including any 
concomitant illnesses, procedures, therapies (e.g., transfusions), adverse events, 
including bleeding and clinical efficacy endpoint events (MACE, stent thrombosis). The 
subject should be questioned regarding any hospitalization and/or medical visits relating 
to episodes of ischemia or bleeding or adverse events that may have occurred since 
discharge. Original source documents must be collected for any events.  Should a subject 
be re-admitted or undergo care at an outside facility, all possible efforts should be made 
to obtain original source documents.  Note that non-serious adverse events (bleeding and 
non-bleeding) will not be collected in the eCRF beyond the 30-day contact. All serious 
adverse events and clinical efficacy endpoint events will be collected through the 90-day 
contact. 
2. 
Review and record concomitant medications (including maintenance anti-platelet 
treatment) taken since 30-day study telephone call.  
 
Appropriate treatment for each subject after completing the study shall be at the investigator’s 
discretion. 
 
6.5.12 Non-PCI Subjects:  Catheterization to Study Completion 
 
Non-PCI subjects will receive medical management or CABG.  The following provisions 
apply to all subjects when it is determined that PCI will not commence: 
• Subjects should receive all subsequent care according to local standards.   
• All post cardiac catheterization protocol-specified tests, evaluations and collections 
should be performed as per Section 1.2 and Section 6.5 and Section 6.6 as usual.  
Additional information/documentation for medical management: 
• During the subject’s hospitalization, the investigator or qualified designee should be 
sure to record the methods of medical management in source documentation/medical 
records and in the eCRF.   
 
Additional information/documentation for CABG: 
Every effort must be taken to obtain and record in source documentation and in the eCRF the 
following information for subjects who undergo CABG: 
• Postoperative bleeding volume, measured by 
o chest tube drainage for the first 24 hours after completion of the procedure, and 
o total chest tube drainage; 


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• type and number of units of transfused blood products within a 48 hour period; 
• reoperation following closure of the sternotomy incision for the purpose of controlling 
bleeding; 
• abnormalities in laboratory tests for cardiac enzymes and CBC; and  
• ECG abnormalities. 
 
6.6 
Study Procedures 
 
The Study Flow Chart in Section 1.2 summarizes the study procedures to be performed at 
each protocol time point.  Individual study procedures are described below.  For details of the 
procedures for assessment and reporting of adverse events, see Section 6.7.2.2 (Assessment 
and Reporting of Adverse Events).  
 
In order to minimize variability of evaluations, it is recommended that the same individuals 
perform the same types of evaluations for all subjects at each clinical site.   
 
If a subject’s participation in the study is discontinued for any reason, every attempt should be 
made to obtain final information for each test and evaluation as shown in the Study Flow 
Chart in Section 1.2 pending the subject’s consent to undergo the study-directed procedures 
and permission to disclose the corresponding information/data.  
 
6.6.1 Standard Procedures and Clinical Evaluations 
 
• Explain Study and Obtain Written Informed Consent for the Main Study:  
Screening 
The investigator or qualified designee will explain the study to the prospective subject, 
answer all of his/her question (verbally or in writing), and obtain written informed 
consent before performing any study-related procedure. The investigator or qualified 
designee will also review acceptable methods of contraception (birth control) while 
taking part in this study with both female subjects of child-bearing potential and male 
subjects.  The execution of the informed consent will be documented in the subject’s 
medical records and a copy(s) of the informed consent(s) will be given to the subject. 
 
• Explain Optional Sampling for Pharmacokinetics/Pharmacodynamics, 
Exploratory Biomarkers and Pharmacogenomics: Screening 
The investigator or qualified designee will explain the optional sampling to the 
prospective subject, answer all of his/her question (verbally or in writing), and obtain 
written informed consent before performing any procedure related to the optional 
sampling. Written informed consent for the optional sampling for PK/PD sub-study 
(select sites only), exploratory biomarkers and pharmacogenomics (DNA and RNA) 
(See Sections 6.6.3.2, 6.7.3 and Appendix E) research may be contained in the same 
instrument as written informed consent for the rest of the study, or may be separate 
documents, at the discretion of the local Institutional Review Board (IRB). Regardless, 
separate signatures of informed consent are required to collect the optional samples for 


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PK/PD, exploratory biomarkers and pharmacogenomics research. Subjects who 
decline to sign the consent for optional research may still continue in the study.  The 
execution of the informed consent will be documented in the subject’s medical records 
and a copy(s) of the informed consent(s) will be given to the subject. 
 
• Review Inclusion/Exclusion Criteria (Including Prior and Current Medications 
and Therapies):  Screening 
The inclusion and exclusion criteria will be reviewed by the investigator or qualified 
designee to ensure that the subject qualifies for the study.  All medications and 
therapies during the 30 days prior to enrollment/randomization will be recorded in the 
source documentation and transcribed to the eCRF. 
 
• Medical History:  Screening 
A medical history will be obtained by the investigator or qualified designee.  Subject 
history should include information on family history and personal history.  Subject 
history should include information concerning family history of chest pain and/or heart 
attack, general cardiac history, alcohol intake, smoking, as well as other coronary risk 
factors such as diabetes, hypertension, dyslipidemia, and obesity. Particular attention 
and documentation should be given to the subject’s cardiac history, the clinical 
evaluation leading to the cardiac catheterization procedure (i.e., CAD presentation, 
Canadian Cardiovascular Society Classification for angina, Thrombolysis in 
Myocardial Infarction Risk Score for UA/NSTEMI, and New York Heart Association 
Classification of Functional Status for  heart failure), bleeding history and allergy 
history (drugs, IV contrast media, food, stings and atopic conditions and any required 
treatment/ medical intervention).  
 
• Physical Examination:  Screening, 24-hour/Discharge*, 14-day Visit 
The investigator or qualified designee will perform an examination to include skin, 
head, neck, pulses, lungs, heart, abdomen, extremities, and gross neurologic system.  
Abnormal findings not present at screening or abnormal findings that were present at 
screening but have become worse in severity/grading over baseline will be considered 
adverse events and recorded as per the AE procedures in Section 6.7.2.2.   
 
*Note, the clinical site’s standard of care, cardiac catheterization nursing assessment 
may be performed to evaluate the subject’s clinical status in lieu of a complete 
physical exam at the 24 hour/discharge time point.  This exam should be completed by 
qualified nursing staff with particular attention being paid to signs/symptoms related to 
the known side effects of PZ-128 (i.e., allergic reaction, injection site reaction and 
paresthesia) and other possible side effects from the procedure and/or concomitant 
medications (i.e., bleeding). 
 
• Vital Signs Assessment:  Screening, Just Before Study Drug Infusion, Just After 
Completion of Study Drug, After Catheterization/PCI, 24-hour/Discharge, 14-day 
Visit 
At screening, the investigator or qualified designee will measure blood pressure and 


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pulse (after the subject has been supine for at least 5 minutes), and measure body 
weight and height without shoes and heavy clothing.  Thereafter, only blood pressure 
and pulse will be measured.  Measurements will be made with the subject lying down 
just before study drug infusion, just after study drug completion, after 
catheterization/PCI and 24-hour/discharge.  Measurements will be made with the 
subject seated at the 14-day visit.   
 
• Assay- Pregnancy Test (Urine beta-HCG) for All Female Subjects of Child-
Bearing Potential: Screening (must be within 24 hour of study drug 
administration), 14-day Visit   
The investigator or qualified designee will record the point-of-care urine beta-HCG 
test. If more frequent pregnancy testing is required by local standards of care, perform 
the testing as required and report pregnancy as specified in Section 6.7.2.2.7. 
 
• Electrocardiogram:  Screening, After Catheterization/PCI, 14-day Visit 
A standard 12-lead ECG will be recorded by a qualified ECG technician or other 
qualified individual after the subject has been supine for at least 5 minutes.  All ECG 
reports in the study must include heart rate (HR) and QRS, QT, QTc (with method of 
correction) and PR intervals.  Timing after catheterization/PCI will be dictated by 
standard practice and clinical signs/symptoms of cardiac ischemia.  
 
• Record Previous and Concomitant Medications and Therapies:  Screening, 24-
hour/Discharge, 14-day Visit, 30-day Phone Call, 90-day Phone Call 
Concomitant medications will be recorded in the subject’s source documents and the 
appropriate section of the eCRF (See Section 6.4.3, Other Required Treatments and 
Section 6.4.8, Non-Study Treatments).  
 
The following medications/therapies are exempt from being reported to the sponsor, 
unless they are deemed the cause of or contributor to an adverse event or used in the 
treatment of an adverse event: 
o Electrolyte or nutritional replacement 
o IV fluids 
o Contrast media 
o Anesthetic medications that are inhaled or topical 
o Medications for surgical or nonsurgical procedures (e.g., sedatives, anesthestic) 
o Mediations/therapies that are not directly administered to the subject, such as 
cardioplegic solution or antithrombin used in conjunction with the 
cardiopulmonary bypass pump 
o Nonsystemic bowel prep (e.g., enema) 
o Vaccines 
 
• Adverse Events Assessment (Bleeding and Non-Bleeding):  Continually During 
Hospitalization Following Enrollment/Randomization, 14-day Visit, 30-day Phone 
Call 
 


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• Serious Adverse Events Assessment (Bleeding and Non-Bleeding):  Continually 
During Hospitalization Following Enrollment/Randomization, 14-day Visit, 30-
day Phone Call, 90-day Phone Call 
 
• Suspected Clinical Efficacy Endpoint Events (MACE & Stent Thrombosis):  
Continually During Hospitalization Following Enrollment/Randomization, 14-day 
Visit, 30-day Phone Call, 90-day Phone Call 
 
All adverse events (AEs) (bleeding and non-bleeding) will be reported to the sponsor 
in the eCRF from the time of randomization through 30 days after study drug 
administration. Only AEs which are classified as serious adverse events (SAEs) 
(bleeding and non-bleeding) will be reported to the sponsor in the eCRF after 30 days 
up until 90 days after study drug administration. All clinical efficacy endpoint events 
(MACE, stent thrombosis) will be reported to the sponsor from the time of 
randomization through 90 days after study drug administration.   
 
Recording of adverse events, including reports by subjects, observations by study staff, 
and results of laboratory tests or other procedures, is described in Section 6.7.2.2 
(Assessment and Reporting of Adverse Events).  Endpoint events (and associated 
symptoms) are identified as part of Section 6.7.1 (Safety/Activity/Efficacy Endpoints) 
and are defined specifically in Appendix B, and will be detailed in the separate CEC 
charter for purposes of adjudication.   
 
Note that clinical efficacy endpoint events- major adverse cardiac events (MACE) 
(any of cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke, 
recurrent ischemia requiring hospitalization or urgent coronary revascularization) and 
definite or probable stent thrombosis- as well as bleeding events (safety) are 
considered “Clinical Endpoint Events” and will be adjudicated periodically during the 
conduct of the trial.  The clinical endpoint events will be monitored in aggregate by the 
DSMB at appropriate intervals (i.e., quarterly).  As such, these clinical endpoint events 
will not be reported separately in an expedited manner as “serious adverse events” to 
the sponsor’s SAE contact (see Section 6.7.2.2.10- Protocol-Specific Exceptions to 
SAE Reporting).  
 
6.6.2 
Standard Laboratory Tests 
 
The investigator or qualified designee will collect all appropriate samples for analysis which 
will be then be performed at the local clinical laboratory on site. The values from Screening 
(Enrollment/Randomization) will be considered Baseline values for all standard laboratory 
tests.  Results of testing should be reviewed by the investigator/qualified designee in a timely 
manner for pertinent clinically significant values. If any abnormal test result is considered to 
be clinically significant, the test should be repeated at appropriate time intervals until it returns 
to Baseline or becomes a clinically insignificant finding or the investigator/qualified designee 
decides it is not appropriate to continue.  
 


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• Hematology:  Screening, After Catheterization/PCI, 24-hour/Discharge, 14-day 
Visit 
Blood samples will be collected to quantify red blood cell (RBC) count, total and 
differential white blood cell (WBC) count, hemoglobin concentration, hematocrit, and 
platelet count.  Timing after catheterization/PCI will be dictated by standard of care.  
 
• Serum Chemistry:  Screening, 24-hour/Discharge  
Blood samples will be collected to quantify the following variables:   
Sodium, potassium, chloride, carbon dioxide, glucose, blood urea nitrogen 
(BUN), creatinine, alkaline phosphatase, total bilirubin, alanine aminotransferase 
(ALT) and aspartate aminotransferase (AST). 
 
• PT/INR and aPTT:  Screening, 24-hour/Discharge  
 
• Activated Clotting Time:  During and After PCI 
Following administration of the initial bolus of anti-coagulant, point-of-care testing of 
the activated clotting time (ACT) should be measured at “peak dose” and just prior to 
sheath removal, as well as according to the standard of care and local routine practice.  
 
• Lipid Panel:  Screening 
Blood samples (does not need to be fasting) will be collected to quantify total 
cholesterol, high-density-lipoprotein cholesterol (HDL-C), calculated low-density-
lipoprotein cholesterol (LDL-C) and triglycerides.   
 
• Glycosylated Hemoglobin:  Screening 
Blood sample (does not require fasting) will be collected to quantify glycosylated 
hemoglobin (HgA1c) levels. 
 
6.6.3 Research Laboratory Tests and Collections 
 
 
Detailed procedures for collection, handling/processing, packaging, and shipment of samples 
associated with the various tests mentioned in this section will be included in a separate 
Research Laboratory Manual and will be provided to each clinical site.  The investigator or 
qualified designee will collect all appropriate samples for analysis.  Results from the analyses 
will be transmitted electronically from the sponsor/sponsor’s designated laboratory into a 
research laboratory study database and will not be individually reported back to the clinical 
site. Therefore the results will not become part of the subject’s medical records or be used by 
the investigator for medical management/clinical decision-making. 
 
6.6.3.1 Mandatory 
 
Samples will be collected from all subjects who sign the consent to participate in the main 
research study. The time points provided for the collection of blood samples for the Cardiac 
Troponin I (cTnI) will be indexed from the completion of the PCI. 
 


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• Cardiac Troponin I (Serum):  Just Prior to Study Drug Infusion, After PCI 
Blood samples will be collected to quantify the Cardiac Troponin I (cTnI) marker just 
before the administration of the study drug, 4 to 8 hours and 12 to 24 hours after 
completion of the PCI (Note, PCI subjects only). In addition, samples will be collected 
immediately after the occurrence of symptoms suggestive of acute coronary syndrome 
(ACS), and again 4 to 8 hours and 12 to 24 hours after symptoms if the subject has not 
yet been discharged from the hospital. 
 
Note, the evaluation of cardiac biomarker(s) (i.e., Cardiac Troponin I, Cardiac 
Troponin T, Creatine Kinase or Creatine Kinase-Myocardial Band) done locally for the 
clinical management of the subject will be performed as per standard of care and local 
routine practice.  The results from those standard clinical laboratory tests should be 
recorded in the appropriate section of the eCRF. 
 
6.6.3.2 Optional 
 
Samples will be collected only from subjects who sign the appropriate section in the consent 
form(s) for these optional collections and analysis. The time points provided for the collection 
of blood samples for exploratory biomarkers research, pharmacogenomics and 
pharmacokinetics/pharmacodynamics-platelet aggregation will be indexed from the start of 
the PZ-128/placebo infusion (i.e., Time=0). 
 
These blood samples and any other components may be retained by the sponsor for analysis 
until the study-specific scientific objectives have been completed. The subject retains the right 
to have the sample material destroyed at any time by contacting the investigator. The sponsor 
will be the exclusive owner of any data, discoveries, or derivative materials from the sample 
materials and is responsible for the destruction of the sample(s) at the request of the research 
subject through the investigator or at the end of the storage period. Following the request from 
a research subject, the investigator will provide the sponsor with the required study and 
subject number so that any remaining blood samples and any other components can be located 
and destroyed.  If a commercial product is developed from this research, the sponsor will own 
the commercial product. The subject will have no commercial rights to such product and will 
have no commercial rights to the data, information, discoveries, or derivative materials gained 
or produced from the samples.  See Section 8.2 and Appendix E for subject confidentiality.  
 
Subjects at All Centers  
 
• Exploratory Biomarkers Research (Plasma):  Just Prior to Study Drug Infusion, 
Select Times During Hospitalization, 24-hour/Discharge, 14-day Visit  
Blood samples for exploratory research of systemic markers of thrombosis and platelet 
reactivity, inflammation, and metabolomics will be collected just before the 
administration of the study drug, then 2 hours + 15 min (immediately after completion 
of infusion), 6 hours – 2 h (4 to 6 h) and 24 hours ± 2 h or discharge (whichever occurs 
sooner) after the start of the study drug infusion and at the 14-day visit.  After the 24-
hour collection, if a subject remains in the hospital for ≥48 hours, a blood sample will 


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be collected just prior to discharge. The samples will be analyzed by the sponsor under 
non-GLP conditions. 
 
• Pharmacogenomics (DNA and RNA) (Whole Blood):  Just Prior to Study Drug 
Infusion  
One blood sample for DNA, RNA and microRNA analysis will be collected just before 
the administration of the study drug. Pharmacogenomics analysis will be undertaken to 
investigate whether DNA polymorphisms, RNA levels and microRNAs correlate with 
the expression of genes involved in thrombosis, inflammation, and cardiometabolic 
diseases and whether these genetic components correlate with PZ-128 outcomes.  The 
samples will be analyzed by the sponsor and/or at one of the participating clinical sites 
under non-GLP conditions.   
 
Subjects at Select Clinical Site(s) Participating in the PK/PD Sub-study 
 
• Pharmacodynamics- Platelet Aggregation (Whole Blood):  Just Prior to Study 
Drug Infusion, Select Times During Hospitalization, 24-hour/Discharge, 14-day 
Visit 
Blood samples will be collected just before the administration of the study drug, then 
30 minutes ± 5 min, 1 hour ± 5 min, 2 hours + 15 min (immediately after completion 
of infusion), 6 hours – 2 h (4 to 6 h) and 24 hours ± 2 h or discharge (whichever occurs 
sooner) after the start of the study drug infusion and at the 14-day visit.  After the 24-
hour collection, if a subject remains in the hospital for ≥48 hours, a blood sample will 
be collected just prior to discharge. The samples will be analyzed using light 
transmission aggregometry (LTA) on-site under non-GLP conditions. 
 
• Pharmacokinetics (Plasma):  Just Prior to Study Drug Infusion, Select Times 
During Hospitalization, 24-hour/Discharge, 14-day Visit 
Blood samples will be collected just before the administration of the study drug, then 
30 minutes ± 5 min, 1 hour ± 5 min, 2 hours + 15 min (immediately after completion 
of infusion), 6 hours – 2 h (4 to 6 h) and 24 hours ± 2 h or discharge (whichever occurs 
sooner) after the start of the study drug infusion and at the 14-day visit.  After the 24-
hour collection, if a subject remains in the hospital for ≥48 hours, a blood sample will 
be collected just prior to discharge. The samples will be analyzed by the 
sponsor/sponsor’s designee under non-GLP conditions. 
 
The PK/PD sub-study will also include the collection of plasma for exploratory biomarkers 
research, meaning that subjects at select clinical site(s) participating in the PK/PD sub-study 
will be asked in one question whether they will allow additional blood to be collected for the 
PK/PD samples and exploratory biomarkers samples.  Subjects at clinical site(s) not 
participating in the PK/PD sub-study will be asked in one question whether they will allow 
additional blood to be collected just for the exploratory biomarkers samples.  
 
Approximately 54-64 mL of blood will be collected from each subject during their 
participation in the main portion of the study.   


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Subjects in whom informed consent has been obtained will have approximately 25-30 mL of 
additional blood collected during their participation in the exploratory biomarkers research 
component of the study. 
 
Subjects in whom informed consent has been obtained and are participating at a clinical site 
that has the capability to perform LTA will have approximately 200-230 mL of additional 
blood collected during their participation in this PK/PD sub-study (includes the PK/PD and 
exploratory biomarkers samples).  
 
Subjects in whom informed consent has been obtained will have approximately 5 mL of 
additional blood collected one time during their participation in the pharmacogenomics 
component of the study.  
 
Table 1 summarizes the collection of blood samples for the protocol-directed tests and 
optional research evaluations. 
 Table 1. Summary of Total Blood Sampling 
 
Number of Samples per Visit 
Volume (mL) 
Screening 
Enrollment 
Pre- 
Study 
Drug 
Post-
Cath 
± PCI 
24 hours 
/ 
Discharge 
14 
Days 
Total 
Draws 
Blood 
Volume 
per Test 
Sub- 
total 
Hematology 
1 
 
1 
1 
1 
4 
4.5 
18 
Serum Chemistry 
1 
 
 
1 
 
2 
8.5 
17 
Lipid Panel 
1 
 
 
 
 
1 
1 
1 
Hemoglobin A1C 
1 
 
 
 
 
1 
3 
3 
PT/INR, aPTT 
1 
 
 
1 
 
2 
4.5 
9 
ACT 
 
 
2 
 
 
2 
2 
4 
Cardiac Troponin I 
(Sample for Centralized 
Research Analysis) 
 
1 
0-1^ 
0-1^ 
 
1-6^ 
2 
2-12^ 
Volume per Visit (mL) 
21.5 
2 
10.5 
19.5 
4.5 
 
TOTAL 
54-64^ 
Optional  
 
 
 
 
 
 
 
 
Exploratory Biomarkers 
 
 
1 
2 
1-2* 
1 
5-6* 
5 
25-30* 
Pharmacogenomics  
 
1 
 
 
 
1 
5 
5 
Sub-Study (site specific) 
 
 
 
 
 
 
 
 
 
Pharmacodynamics-
 
Platelet Aggregation  
 
1 
4 
1-2* 
1 
7-8* 
20 
140-160* 
 
Pharmacokinetics 
 
1 
4 
1-2* 
1 
7-8* 
5 
35-40* 
^ depending upon performance of PCI, length of stay and the occurrence of symptoms suggestive of ACS  
*depending upon total length of stay 


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6.7 
Study Assessments 
 
Study assessments that require adjudication by the CEC are defined in Appendix B and will be 
detailed in a separate CEC charter. 
 
6.7.1 Safety/Activity/Efficacy Endpoints 
 
6.7.1.1 Primary Endpoint (Safety) 
 
The primary endpoint of the study will be the incidence of TIMI major plus minor bleeding 
not related to CABG through 30 days after treatment with the study drug.  Definitions are as 
follows: 
• TIMI Major bleeding is defined as  
o intracranial hemorrhage, or  
o clinically significant overt signs of bleeding associated with a decrease in 
hemoglobin concentration of ≥5 g/dL (or hematocrit ≥15%), or  
o fatal bleeding within 7 days.   
 
• TIMI Minor bleeding is defined as clinically overt signs of bleeding (including 
imaging) associated with a decrease in hemoglobin concentration of 3 to <5 g/dL (or 
hematocrit of 9 to <15%) that does not otherwise meet criteria for major bleeding.   
 
Hemoglobin concentration and hematocrit will be adjusted for any transfusion of packed red 
blood cells or whole blood given between enrollment/randomization and the post-transfusion 
measurements by Landefeld and coworkers as follows: 
Δ Hemoglobin (Hgb) = [Baseline Hgb – post-transfusion Hgb] + [number of transfused units] 
Δ Hematocrit (Hct) = [Baseline Hct – post-transfusion Hct] + [number of transfused units x 3] 
 
6.7.1.2 Key Secondary Endpoint (Efficacy) 
 
The key secondary endpoint is the incidence of any component of the MACE composite 
through 30 days and 90 days after treatment with the study drug.  
 
6.7.1.3 Other Secondary Endpoints Related to Safety 
 
Other secondary safety endpoints include the incidences of the following: 
1. TIMI minimal bleeding not related to CABG (defined as clinically significant overt 
signs of bleeding associated with a drop in hemoglobin concentration of <3 g/dL (or 
hematocrit of <9%)  that does not otherwise meet criteria for major or minor bleeding) 
through 30 days after treatment; 
2. “clinically significant” bleeding (defined as TIMI major or minor bleeding or bleeding 
requiring medical attention) through 30 days after treatment; and 


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3. TIMI bleeding related to CABG through 30 days after treatment (subjects who undergo 
CABG will specifically have assessment of (a) surgical wound bleeding using 
quantitative total chest tube drainage in the first 24 hours; (b) need for transfusion of 
blood products in the first 48 hours; and (c) need for surgical re-exploration). 
 
6.7.1.4 Other Secondary Endpoints Related to Efficacy 
 
Other secondary efficacy endpoints will include the following: 
1. incidence of the individual components of the MACE composite through 30 days and 90 
days after treatment; 
2. incidence of definite or probable stent thrombosis through 30 days and 90 days after 
treatment; 
3. inhibition of platelet aggregation induced by SFLLRN, thrombin, ADP, collagen and 
AYPGKF relative to baseline at several time points following treatment at select sites; 
4. population pharmacokinetics at baseline and at several time points following treatment; 
and  
5. effect of the investigator choice of P2Y12 inhibitor (i.e., clopidogrel versus 
prasugrel/ticagrelor) on the individual components of the MACE composite. 
 
6.7.1.5 Exploratory Endpoints 
 
These endpoints are not part of the formal objectives and are included as additional ways to 
evaluate bleeding and to gather information for future research.  
1. incidence of bleeding events according to the BARC (Bleeding Academic Research 
Consortium) classification through 30 days after treatment;  
2. change from baseline in select systemic markers of thrombosis and platelet reactivity, 
inflammation, and metabolomics at select time points; and 
3. population pharmacogenomics at baseline. 
 
6.7.1.6 Appropriateness of Measurements 
 
The study design is appropriate for the indication studied.  Validated methods of data 
collection, analysis, and evaluation will be used for the study. 
 
6.7.2 Additional Safety Assessment 
 
6.7.2.1 Specification of Safety Variables 
 
In addition to bleeding, safety variables to be assessed include all other adverse events, and 
results of physical examination, ECG, and standard clinical laboratory tests.  
 
 


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6.7.2.2 Assessment and Reporting of Adverse Events 
 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug related. An AE can be any unfavorable 
and unintended sign (e.g., an abnormal laboratory finding), symptom or disease temporally 
associated with the use of a drug, and does not imply any judgment about causality.  An 
adverse event can arise with any use of the drug (e.g., use in combination with another drug) 
and with any route of administration, formulation, or dose, including an overdose.   
 
AEs may include the onset of new illness and the exacerbation of pre-existing medical 
conditions. Worsening indicates the pre-existing medical condition (e.g., diabetes, headaches) 
has increased in severity, frequency, and/or duration, and/or has an association with a 
significantly worse outcome.  A pre-existing condition that has not worsened during the study, 
and involves an intervention such as elective cosmetic surgery or a medical procedure while 
on study is not considered an adverse event.   
 
All AEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means, and the 
treatment provided must be assessed by the investigator or qualified designee and recorded in 
the subject’s source documents/medical records. 
 
All adverse events (AEs) (bleeding and non-bleeding) will be reported to the sponsor in the 
eCRF from the time of randomization through 30 days after study drug administration. Only 
AEs which are classified as serious adverse events (SAEs) (bleeding and non-bleeding) will 
be reported to the sponsor in the eCRF after 30 days up until 90 days after study drug 
administration. All clinical efficacy endpoint events (MACE, stent thrombosis) will be 
reported to the sponsor from the time of randomization through 90 days after study drug 
administration.   
 
The investigator must assign the following adverse event attributes: 
• Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• Dates of onset and resolution, 
• Severity, 
• Assessment of relatedness to PZ-128 or PZ-128 placebo, and 
• Action taken and/or outcome (e.g., discontinuation of study drug administration, 
hospitalization, etc.). 
 
Subjects will be questioned and/or examined by the investigator or a qualified designee for 
evidence of AEs.  Overall, the questioning of subjects with regard to the possible occurrence 
of adverse events will be generalized such as, “How have you been feeling since your last 
visit/contact?”  The presence or absence of specific AEs should not be elicited from subjects.  
However, subjects will be questioned about the occurrence of any study-specific safety 
(bleeding) and efficacy (MACE, stent thrombosis) endpoint events (e.g., overt signs of 


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bleeding, chest pain, need for interim medical care, procedure(s) or hospital admission). 
 
The investigator is responsible for reviewing laboratory and other test (e.g., ECG) results and 
determining whether an abnormal value in an individual subject represents a change from the 
subject’s baseline values.  In general, only abnormal laboratory findings that represent a 
change from the subject’s baseline values that have clinical significance (based on the 
investigator’s judgment) should be recorded as adverse events.  A clinically significant lab 
value is one that indicates a new disease process, an exacerbation or worsening of an existing 
condition or requires further action(s) to be taken.   Where applicable, clinical sequelae (not 
the laboratory value) should be recorded as the adverse event.  
 
In particular, the following laboratory results must be captured as AEs: 
• decrease from Baseline in platelet count to a value <75,000/mm3 (note, <50,000 is a 
serious adverse event- see Section 6.7.2.2.5); 
• increase from Baseline in ALT or AST activity to a value greater than three times the 
upper limit of the reference range (i.e., >3 x ULN);   
• increase from Baseline in total bilirubin concentration to a value greater than one and 
a half times the upper limit of the reference range (i.e., >1.5 x ULN); and 
• increase from Baseline in serum creatinine to a value greater than one and a half 
times the upper limit of the reference range (i.e., >1.5 x ULN) or greater than one 
and a half times the baseline value (i.e., >1.5 x baseline). 
 
6.7.2.2.1 Assessment of Adverse Event Severity and Relationship to Treatment 
 
Where the determination of adverse event severity rests on medical judgment, the 
determination of severity must be made with the appropriate involvement of a medically-
qualified investigator. 
 
The descriptions and grading scales found in National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) version 4.0 will be used for all events with an 
assigned CTCAE grading. For events without assigned CTCAE grades, the recommendation 
is that the CTCAE criteria that convert the severity description into CTCAE grades should be 
used (see guideline below).  For each episode on an adverse event, the highest attained CTC 
grade should be reported.  All appropriate treating areas should have access to a copy of the 
CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded: 
 http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 
This version of CTCAE is MedDRA v12.0 (Medical Dictionary for Regulatory Activities 
Terminology) compatible at the AE (Adverse Event) term level where each CTCAE term is a 
MedDRA LLT (Lowest Level Term). CTCAE v4.0 includes 764 AE terms and 26 'Other, 
specify' options for reporting text terms not listed in CTCAE. Each AE term is associated with 
a 5-point severity scale.  For events without corresponding CTCAE terms, the MedDRA 
online resource should be consulted for the LLT:  
http://bioportal.bioontology.org/ontologies/MEDDRA?p=classes&conceptid=10063933 


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The CTCAE displays Grade 1 through 5 with unique clinical descriptions for severity for each 
AE based on this general guideline:   
Grade 0 
No AE (or within normal limits). 
Grade 1  
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2  
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL). 
Grade 3  
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL. 
Grade 4  
Life-threatening consequences; immediate risk of death; urgent intervention 
indicated. 
Grade 5  
Death related to AE. 
 
After naming and grading the event, a medically qualified investigator must assess the 
relationship of any AE to the use of study drug (i.e., PZ-128/ placebo), based on available 
information, using the following guidelines:  
Unlikely related: 
no temporal association, or the cause of the event has been identified, or 
the investigational drug cannot be implicated; 
Possibly related: 
temporal association, but other etiologies are likely to be the cause; 
however, involvement of the investigational drug cannot be excluded; 
Probably related: 
temporal association, other etiologies are possible, but unlikely. 
  
For purposes of regulatory reporting, AEs listed as “possibly” and “probably” related to the 
investigational drug will be considered to have a suspected “reasonable causal relationship” to 
the investigational drug.  For serious events that are unexpected, the sponsor will consider the 
investigator’s causality assessment when reporting to regulatory authorities, but ultimately the 
sponsor will determine if there is a reasonable possibility that the drug caused the event. For 
SAEs, causal relationship will also be assessed for other medication and study procedures.  
Further guidance to the interpretation of the causality question is found in Appendix C.  
 
The expectedness of an adverse event shall be determined according to the reference 
document.  The reference document for this current study is to be the current version of the 
sponsor’s investigator brochure (IB).  An adverse event is considered “unexpected” if it is not 
listed in the IB or is not listed at the specificity or severity that is observed.  Adverse events 
listed in the IB as occurring with members of the same class of drugs, or as anticipated from 
the pharmacological properties of the drug, are considered unexpected until they have been 
observed with the drug under investigation.  
 
 
 


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6.7.2.2.2 Monitoring Adverse Events 
 
Subjects experiencing AEs should be followed clinically until their health has returned to 
baseline status or until all parameters have returned to normal or have otherwise been 
explained.  It is expected that the investigator will provide or arrange appropriate supporting 
care for the subject if necessary.  The investigator or qualified designee is expected to report 
ongoing AEs at the subject’s completion of the clinical study to the subject’s primary care 
physician or referring cardiologist who will determine the need for and provide standard 
medical care.  
 
Any actions taken and follow-up results must be recorded either on the appropriate page of the 
eCRF or in a follow-up letter to the sponsor, as well as in the subject’s source 
documentation/medical records.  
 
For all AEs that require the subject to be discontinued from the study drug or the study 
procedures, relevant clinical assessments and laboratory tests will be repeated as clinically 
appropriate until final resolution or stabilization of the event(s).  
 
The sponsor, Tufts Medical Center, retains the right to request additional information for any 
subject with ongoing AEs/SAEs at the end of the study, if judged necessary. 
 
6.7.2.2.3 Known Adverse Events Relating to the Underlying Clinical Condition 
 
The underlying clinical condition in the subjects in the current trial is coronary artery disease 
and non-ST-segment-elevation ACS (NSTE-ACS).  Therefore, any signs and symptoms 
associated atherosclerosis, NSTE-ACS and/or subjects undergoing cardiac catheterization/PCI 
may be expected/ anticipated.  These may include (but are not limited to) coronary, cerebral or 
peripheral ischemia, ACS, stroke/transient ischemic attack (TIA), MI, and life-threatening 
ischemic events and any signs and symptoms associated with these conditions, such as (but 
not limited to) chest/jaw/arm pain, dyspnea, diaphoresis, hypotension, nausea, vomiting, 
dizziness, changes in ECG pattern, hemiparesis, and claudication.  
 
  
 
 
   
 
 


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No bleeding risk (i.e., bleeding or any other coagulation abnormalities) has been observed in 
animal or human investigations with PZ-128 to date and therefore bleeding should be 
considered unexpected for PZ-128.  However, bleeding is anticipated to occur in this trial with 
some frequency, regardless of PZ-128 exposure, due to it being a known consequence of the 
underlying standard of care procedures for the study population (cardiac catheterization/PCI) 
and background drug regimen (i.e., anti-coagulant and anti-platelet drugs).  Bleeding is a 
known risk of other PAR1 inhibitors [Zontivity® Full prescribing information].  The AEs 
mentioned under this section still need to be recorded in the subject’s source documents/ 
medical records and on the eCRF, regardless of causality. 
 
The current Investigator’s Brochure (IB) for PZ-128 is the reference document containing 
safety information for the investigational product (IP) in this study, PZ-128.  Adverse events 
expected for the IP are those described as such in the most recent IB.   
 
6.7.2.2.5 Definition of Serious Adverse Events  
 
A serious adverse event (SAE) is any adverse drug experience occurring at any dose and any 
study phase (e.g., treatment, follow-up) that results in any of the following outcomes (as 
determined by either the investigator or sponsor): 
• death; 
• life-threatening AE (i.e., one that places the subject, in the view of the 
investigator or sponsor, at immediate risk of death from the AE as it occurs;  
it does not include an adverse event that, had it occurred in a more severe 
form, might have caused death); 
• requires in-patient hospitalization (i.e., admission) or prolongs existing 
hospitalization (for ≥24 hours);  
• persistent or significant disability/incapacity (i.e., substantial disruption of the 
ability to conduct normal life functions); 
• congenital anomaly or birth defect;  
• an important medical event that may not result in death, be life-threatening, 


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or require hospitalization may be considered a serious adverse event 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 in-patient 
hospitalization, or the development of drug dependency or drug abuse.   
 
In addition to the general definitions above for SAEs, the following specific events will be 
considered as SAEs in the context of this study: 
• 
Anaphylaxis:  defined as ≥CTCAE Grade 3 or meeting Sampson criteria 
(Appendix C); 
• 
Decrease from Baseline in platelet count to a value <50,000/mm3 (=CTC 
Grade 3) 
 
Clarification should be made between the terms “serious” and “severe” since they are not 
synonymous. The term “severe” is often used to describe the intensity (and defined by the 
grading/severity scale) of a specific event (as in mild, moderate, or severe pain); the event 
itself, however, may be of relatively minor medical significance.  This is NOT the same as 
“serious,” which is based on the strict definition listed above and is based on subject or event 
outcome or action criteria usually associated with events that pose a threat to a subject’s life or 
functioning. A severe AE does not necessarily need to be considered serious. Investigators 
should assess adverse event severity and seriousness independently.  
 
Since the criteria for CTCAE severity differs from the regulatory criteria for serious adverse 
events, if adverse events correspond to grade 4 “life-threatening” CTCAE severity criteria 
(e.g., laboratory abnormality reported as grade 4 without manifestation of life-threatening 
status), it will be left to the investigator’s judgment to also report these abnormalities as 
serious adverse events.  For any adverse event that applies to this situation, comprehensive 
documentation of the event’s severity status must be recorded in the subject’s medical record.  
 
All SAEs, whether or not deemed study drug-related or expected, must be reported by the 
investigator or qualified designee to the sponsor within 24 hours of first becoming aware of 
the event.  The investigator/qualified designee will enter the required information about the 
SAE into the appropriate module of the eCRF, which will automatically result in distribution 
of the information to the appropriate sponsor contact(s).  If the eCRF system is temporarily 
unavailable, then a full description of the event and any sequelae should be provided as a 
telefacsimile (FAX).  If both the eCRF and FAX are not available, the event should be 
reported by telephone.    
 
 
 
 
 


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SAE Reporting Contact Information 
 
 
 
 
 
 
 
 
  
 
If the report is initially given to the sponsor via telephone, a full description of the event and 
any sequelae, including the investigator-determined causality to study drug must be provided 
in writing (by FAX or eCRF) as soon as possible, so that the appropriate written report can be 
completed by the sponsor.  If the report is initially given by FAX or telephone, then the 
required information about the SAE will be entered into the appropriate module of the eCRF 
immediately after the eCRF system is available.  
 
The investigator is responsible for ensuring that all SAEs that occur at any time after the 
subject has been randomized up through 90 days following the study drug administration are 
reported to the sponsor. New information relating to a previously reported SAE must be 
submitted to the sponsor within 24 hours of receipt.  The investigator may be asked to provide 
additional follow-up information, which may include a discharge summary or extracts from 
the medical record.  Information provided about the SAE must be consistent with that 
recorded on the applicable eCRF.  
 
Any SAE (including those which are ongoing when a subject completes his/her participation 
in the trial) must be followed by the site investigator (and will be followed by the sponsor) 
until one of the following occurs: 
• the event resolves or stabilizes; or 
• the event returns to baseline condition or value (if a baseline value is available). 
 
Events which are ongoing at the time the clinical database is closed will be recorded as 
unresolved.   
 
Reports of all SAEs must be communicated as soon as possible by the investigator to the 
appropriate IRB and/or reported in accordance with local law and regulations. 
 
Federal regulations require that the sponsor, Tufts Medical Center, to report any suspected 
adverse reactions (“reasonable possibility” that the drug caused the event) that are both serious 
and unexpected (21 CFR 312.32). Such events must be reported to the Food and Drug 
Administration (FDA), the NHLBI/NIH and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its IND) within 15 calendar days 
after the sponsor receives the information and determines that it qualifies for reporting. Such 
notification must occur within 7 calendar days if the serious unexpected suspected adverse 
reaction (SUSAR) was fatal or life-threatening. The sponsor is also required to report other 
serious adverse events and qualifying adverse events in an expedited manner to its IRB in 


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compliance with local institutional and IRB policies. Therefore, once the investigator has 
determined that an SAE has occurred, it is important to adhere to the reporting timeframes 
outlined above. After receiving the investigator’s SAE report, including the investigator’s 
assessment of causality, the sponsor will also assess the event for seriousness and the 
relationship to PZ-128/Placebo, and will determine if the event was unexpected. 
Investigational New Drug Safety Reports (INDSRs) will be reported to the FDA and 
NHLBI/NIH by Tufts Medical Center and copies of the report(s) will be distributed to all 
participating clinical investigators. The investigator is responsible for notifying the relevant 
IRB of all INDSRs in accordance with institutional and IRB policies in addition to any other 
safety information which has been provided by the sponsor throughout the duration of the 
trial.  
 
To comply with reporting regulations for serious adverse events, the treatment assignment of 
subjects who develop serious, unexpected, and related adverse events may be unblinded by the 
sponsor before submission to regulatory authorities. 
   
6.7.2.2.6 Reporting of Subject Death 
 
The death of any subject after enrollment/randomization up through 90 days following the 
study drug administration, regardless of the cause, must be reported by the investigator or 
qualified designee to the sponsor within 24 hours of first becoming aware of the death.  If 
the report is given to the sponsor via telephone rather than in writing on the form designated 
for SAE reporting, a full description of the event and any sequelae, including the investigator-
determined causality to study drug must be provided, so that the appropriate written report can 
be completed by the sponsor.  If an autopsy is performed, the report must be provided to the 
sponsor.  Reports of all deaths must be communicated as soon as possible to the appropriate 
IRB and/or reported in accordance with local law and regulations.  
 
6.7.2.2.7 Reporting of Pregnancies 
 
Pre-clinical genotoxicity studies with PZ-128 were negative and the reproductive and 
developmental risk of PZ-128 is likely low.  However, reproductive and teratogenicity studies 
have not been performed and therefore the risks to the human embryo or fetus or sperm are 
unknown at this time. Women of child-bearing potential recruited into the study must have a 
negative urine pregnancy test (urine beta-HCG) prior to randomization and within 24 hours of 
treatment with the study drug.  Women of child-bearing potential must agree to use a 
medically accepted method of contraception during the study from the time of providing 
written informed consent through 90 days after dosing with the study drug and will undergo a 
post study drug infusion pregnancy test (urine beta-HCG) at the 14-day Follow-Up Visit. If a 
female subject becomes pregnant or suspects she is pregnant while participating in this study, 
she must inform her treating obstetrician and principal investigator immediately. Pregnancy 
information on female clinical study subjects will be collected by the sponsor.  If a female 
subject becomes pregnant during the course of the study, the study drug must be discontinued 
(if not already administered) and the investigator or qualified designee must contact the 
sponsor within 5 working days of the investigator or qualified designee first becoming aware 


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of the pregnancy.  If a serious adverse event occurs in conjunction with the pregnancy, then 
the reporting time frame for an SAE (1 working day) and method of reporting must be met. 
The sponsor’s representative will provide instructions on how to collect pregnancy 
information (i.e., Pregnancy Notification Form) including follow-up data on the outcome of 
the pregnancy.  
 
Male participants will be advised to use a medically accepted method of contraception during 
the study from the time of study drug administration through 90 days after dosing with the 
study drug.  Written information will be provided to the participating male subjects at the time 
of enrollment in the study’s informed consent document which may be shared with their 
female partner(s) as to the unknown risks to a future pregnancy.    If a female partner 
conceives and becomes pregnant while the male subject is participating in this study, the 
sponsor should be notified as per the procedures described above.  However, information 
about the pregnancy may only be collected by the investigator and released to the sponsor if 
the female partner of the male subject provides written consent to release such information via 
an IRB-approved authorization/ consent form.  A female partner of a male subject should only 
be presented with the authorization/consent form if a pregnancy or suspected pregnancy 
occurs. The sponsor will provide clinical sites with templates for these related documents to 
use as a model and the local IRB guidelines and approval process will be adhered to.  
 
6.7.2.2.8 Preplanned Hospitalizations or Procedures 
 
Hospitalization for SAE reporting purposes is defined as an inpatient hospital stay equal to or 
greater than 24 hours.  Emergency room visits that do not result in admission to the hospital 
should be evaluated for one of the other “serious” outcomes.  
 
Hospitalization admissions and/or surgical procedures/operations scheduled to occur during 
the entire study period, but planned prior to study enrollment/randomization are not 
considered AEs if the illness or disease existed before the subject was enrolled/randomized in 
the trial, provided that it did not deteriorate in an unexpected manner during the trial (e.g., 
surgery performed earlier than planned). If the event/condition worsens during the study, 
however, it must be reported as an AE (or SAE, if the event/condition results in a “serious” 
outcome).  
 
As per the exclusion criteria (Section 6.3.2), major surgical procedures should not be planned 
to take place within 30 days following the study drug administration/catheterization/PCI.   
 
6.7.2.2.9 Reports of Overdose 
 
The doses of 0.3 mg/kg and 0.5 mg/kg are expected to be well-tolerated. The half-life of PZ-
128 ranged from 1.3 to 1.8 hours in volunteers with CAD risk factors, so the blood levels of 
PZ-128 will be substantially lower in 8 hours (i.e., 3 to 4 half-lives). 
 
Overdose is defined as any single dose above the maximum dose allowed by the clinical 
protocol. 


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The effects of overdose of PZ-128 in humans are not known. Potential adverse effects include 
bleeding, anaphylaxis and thrombophlebitis/injection site irritation based upon the experience 
in the previous phase 1 study which involved the administration of PZ-128 at dose levels up to 
and including 2 mg/kg. Although there are no known antidotes to overdose, in case of 
overdose, the subject should be closely monitored, and supportive treatment should be 
administered to treat the presenting clinical manifestations. Bleeding events should be treated 
according to standard clinical practice, depending upon the location and severity of the bleed. 
In severe cases, the administration of platelets may be considered, as it may counteract the 
pharmacologic effect of PZ-128.  
 
Information on overdoses in clinical subjects will be collected by the sponsor. Should a 
subject experience an overdose during the course of the study (whether symptomatic or not), 
the investigator or qualified designee must contact the sponsor within 5 working days of the 
investigator or qualified designee first becoming aware of the overdose.  Follow-up 
information on the outcome of the overdose should be forwarded to the sponsor.   
 
Any event associated with, or observed in conjunction with, a product overdose (whether 
accidental or intentional) or a product abuse and/or withdrawal is considered an AE should be 
reported as such (Section 6.7.2.2).  If a serious adverse event occurs in conjunction with the 
overdose, then the reporting time frame for an SAE (24 hours) must be met.  The sponsor’s 
representative will provide instructions on how to collect this information.  
 
6.7.2.2.10 Protocol-Specific Exceptions to SAE Reporting to Sponsor 
 
Suspected clinical endpoint events that are also serious adverse events are to be recorded in 
the subject’s eCRF (bleeding or clinical efficacy endpoint modules), but will not be reported 
in an expedited manner to the sponsor’s SAE contact as serious adverse events.  The suspected 
endpoint events recorded in the eCRF will be monitored in aggregate by the DSMB at 
appropriate intervals in order to detect any potential imbalance between the study arms which 
would suggest that the events are occurring more frequently or at higher severity in the study 
drug treatment group than the control group. 
 
Specifically, the following events will not be reported in an expedited manner to the sponsor’s 
SAE contact: 
• activity/efficacy endpoints- MACE- any of cardiovascular death, non-fatal MI, non-
fatal stroke, recurrent ischemia requiring hospitalization, or urgent coronary 
revascularization with PCI or CABG; and stent thrombosis 
• safety endpoints- any bleeding that does not result in death, regardless of severity  
 
Note that death unrelated to cardiovascular disease and death attributable to bleeding will be 
reported in an expedited manner to the sponsor’s SAE contact.  
 
 
 


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6.7.2.2.11 Reporting of Investigational Medicinal Product Quality Complaints 
 
Any defect or possible defect in an investigational drug product (defined as a pharmaceutical 
form of an active substance or placebo being tested or used as a reference in a clinical trial) 
must be reported by the investigator or qualified designee to the sponsor within 24 hours of 
first becoming aware of the possible defect.  This report to the sponsor may be made by 
telephone to the designated sponsor representative.  The product and packaging components in 
question, if available must be stored in a secure area under specified storage conditions until it 
is determined whether the product is required to be returned for investigation of the defect.  If 
the product complaint is associated with an SAE, the SAE must be reported separately in 
accordance with the protocol, and the SAE report should mention the product quality 
complaint.  
 
6.7.2.3 Guidelines and Management of Special Situations  
 
The principal investigator(s) is responsible for ensuring that procedures and expertise are 
available to handle medical situations including emergencies during the study.  A medical 
emergency usually constitutes an SAE and should be reported as such (Section 6.7.2.2). 
 
The Sponsor Representative/Medical Director may be contacted with any questions/concerns: 
 
 
 
 
 
 
 
  
 
Management of Coronary Artery Bypass Surgery (CABG) 
If the investigator determines that a subject requires CABG, the subject should be treated as if 
they had received PZ-128.  Pre-surgical prep and treatment (e.g., administration of blood 
products) and the timing of the CABG should be based on a sufficient washout of 48 hours.  
The need for CABG should not require unblinding of study drug.  However, in the event that 
it becomes medically necessary to unblind the subject, the procedures are outlined in Section 
6.4.6. 
 
Management of Bleeding Events 
Bleeding complications should be managed according to usual clinical practice and may 
include the administration of blood products.  While high levels of platelet inhibition are 
achieved, especially after the IV infusion of PZ-128, the effects of the drug are readily 
reversible and decline with declining blood concentrations. After a single dose with 0.3 or 0.5 


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mg/kg IV administration, the effects are ≥50% recovered within about 24 hours.  If a clinically 
significant bleeding event occurs, the following data should be obtained immediately: 
• Complete blood count 
• Platelet count 
• Prothrombin time (PT) / INR 
• Activated partial thromboplastin time (aPTT) for bleeding not associated with 
PCI, or peak ACT (if available) for bleeding associated with PCI 
 
Transfusions of blood products (packed red blood cells, whole blood, platelets, fresh frozen 
plasma, cryoprecipitate, etc.) may be necessary for subjects with clinically significant bleeding 
events and these decisions are left to the discretion of the investigator. The type of blood, 
number of units, site of bleeding (if any), and hemoglobin value at the time of transfusion will 
be recorded on the case report form. 
 
Management of Drug Allergic Reactions 
 
   
 
Anaphylaxis precautions must be observed during PZ-128/placebo administration and for at 
least 1 hour following the completion of the infusion. Medical equipment and supplies needed 
for resuscitation (pharmacologic agents including epinephrine, anti-histamines, 
corticosteroids, intravenous fluids, and aerosolized bronchodilators, oxygen, 
devices for intubation and mechanical ventilation, tracheostomy equipment, and a 
defibrillator) will be readily available in the treatment area where the study drug is 
administered. An anesthesiologist will be available 24 hours/day at the facility for assistance 
with intubation, mechanical ventilation and advanced life support. 
 
Subjects will be observed carefully for possible infusion reactions and managed appropriately 
if indicated. The investigator may use his/her discretion in determining the regimen to be used 
according to standard clinical practice and tailored to the specific clinical situation (i.e., 
symptoms and severity of the reaction and responsiveness). Management may include, but is 
not limited to the following: 
• Interruption and/or discontinuation of the study drug infusion 
• Antihistamine(s) (e.g., Diphenhydramine (H1), Ranitidine (H2)) 
• Corticosteroid (s) (e.g., Methylprednisolone) 
• Brochodilator(s) (e.g., Albuterol) 
• Adrenergic Agonist(s) (e.g., Epinephrine) 
• Inotropic Agent(s) (e.g., Glucagon) 
• Vasopressor(s) (e.g., Dopamine) 
• Intubation 


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• IV fluids 
• Oxygen 
 
Mild to moderate symptoms include localized skin reactions (pruritus, flushing, rash) and 
usually can be controlled with symptom management (e.g. administration of antihistamines 
and/or corticosteroids) and if necessary, temporary interruption of the study drug infusion. The 
study drug infusion may be interrupted and/or restarted at the discretion of the investigator 
depending upon the type and severity of the reaction and the responsiveness to the symptom 
management and/or the brief (no longer than 1 hour) interruption of the infusion.  Any 
recurrence of symptoms following an initial improvement and/or following drug re-challenge 
is cause for discontinuation of the study drug. 
  
Severe symptoms, such as clinically significant hypertension or hypotension, dyspnea, 
bronchospasm, angioedema or generalized urticaria require immediate discontinuation of the 
study drug and aggressive symptom management.  The criteria for the diagnosis of 
Anaphylaxis [48] is attached in Appendix C.  Anaphylaxis is a medical emergency that 
requires prompt recognition and immediate discontinuation of the study drug and 
intervention/treatment.  A subject who experiences anaphylaxis will not be re-challenged with 
the study drug. 
 
Prompt and accurate documentation of any allergic reaction should include the following: 
• Initial symptoms and course of progression 
• The timing of symptom onset 
• Intervention, timing and subject response 
• Time of symptom resolution 
• Discharge instructions (e.g., follow-up plans, prescribed medications, 
appropriate allergy referral, etc.) or transfer to emergency services. 
 
The disposition and follow-up of subjects with an allergic reaction depends on the severity of 
the initial reaction, the response to treatment and the clinical judgment of the investigator and 
medical staff. Subjects with non-life-threatening symptoms should be observed for 4-6 hours 
after successful treatment (resolution of symptoms) if discharge is being considered. Subjects 
who have severe reactions/anaphylaxis with cardiovascular and/or respiratory symptoms or 
refractory symptoms should be admitted or treated and observed for a longer prior of time 
especially if the condition is not promptly resolved by therapy. Other high-risk groups include 
those on beta-blocker therapy who have significant reactions and those with severe late-phase 
or prolonged reaction.  Some subjects who have problematic social situations (e.g., no phone) 
or live far from medical care may also require admission or prolonged observation.   
 
Subjects experiencing any allergic reaction should be provided with education regarding risk 
with future exposure to agents that might initiate an allergic response and precautions at the 
time of discharge including instructions for seeking emergency medical care upon recurrence 


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of signs/symptoms. 
 
Need for Administration of Prohibited Medications  
There are no anticipated prohibitive medications in the case of a medical emergency.  
 
6.7.3 Other Assessments 
 
6.7.3.1 Optional Sampling for Pharmacogenomics (DNA and RNA) Analysis 
 
Platelets, endothelium and atherosclerotic plaques express and secrete a large number of 
diverse pro-thrombotic and anti-thrombotic components. Prothrombotic and hemorrhagic risk 
may be influenced in large part by the individual’s genetic make-up and accordingly, the study 
will explore whether DNA polymorphisms (specific DNA sequences that differ among 
individuals), RNA levels and microRNAs correlate with the expression of genes involved in 
thrombosis, inflammation, and cardiometabolic diseases and whether these genetic 
components correlate with PZ-128 clinical outcomes in subjects providing informed consent 
for the whole blood collection. A number of CAD-related genetic loci have been recently 
identified (n=198), but it is essentially unknown how these genetic variants are related to 
cardiovascular outcomes in PCI/ACS patients or whether the variants influence platelet 
reactivity and thrombotic risk. In particular, the newly identified PAR1 agonist, MMP-1 is 
significantly elevated in plasma from patients following acute myocardial infarction. A 
commonly occurring MMP-1 promoter polymorphism will be assessed for increased risk of 
myocardial infarction in subjects with high promoter activity haplotypes versus significantly 
decreased risk in subjects with low promoter activity haplotypes. It has also been suggested 
that polymorphisms in the PAR4 gene region may be associated with platelet reactivity and 
cardiovascular outcomes.  Therefore, in an effort to determine if DNA sequence variability in 
PAR4 is associated with disease status and response to PZ-128, genotype for single nucleotide 
polymorphisms (SNPs) in PAR4 will be determined. In addition, genome-wide association 
studies may be performed to identify genetic factors predisposing subjects to cardiometabolic 
diseases which are associated with the population under study in this trial (i.e., obesity, lipid 
metabolism, CVD, diabetes). 
 
In all cases of genetic analysis of DNA and gene expression analysis from the whole blood 
samples provided by the subjects participating in the TRIP-PCI study, strict confidentiality 
will be maintained.  No subject names or initials will be associated with the whole blood, the 
derived samples (DNA, RNA, or microRNA) or the corresponding laboratory research data.  
More information appears in Appendix E. 
 
6.7.3.2 Optional Sampling for Pharmacokinetics, Pharmacodynamics (Platelet 
Aggregation), Exploratory Biomarkers 
 
Thrombin is the major protease in the coagulation cascade.  Its pleiotropic activity can 
ultimately lead to thrombosis and tissue injury.  Thrombin also has numerous direct effects on 
vascular cells and is the most potent activator of platelets identified to date.  The purpose of 
this optional sampling is to gather data to further investigate the effects of PAR1 blockade on 


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platelet and other vascular reactivities and to continue to characterize the pharmacokinetic 
profile.  
 
6.7.4 Criteria for Termination of the Trial 
 
The DSMB (see Section 7.8 and Section 9.3.1) will retain responsibility for recommending 
early termination of the study to the sponsor, who will have ultimate authority/responsibility 
for making the decision.  The criteria that the DSMB will follow to determine when to 
terminate the study will be described in the separate DSMB charter.  
 
 
 


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7.0 
STATISTICAL AND ANALYTICAL PLAN 
 
7.1 
Study Design 
 
This is a multi-center, prospective, randomized, double-blind, placebo-controlled, balanced-
parallel-groups study to evaluate the safety of PZ-128 compared with placebo, given in 
addition to standard of care, in subjects undergoing non-emergent PCI or non-emergent 
cardiac catheterization with the intention to perform PCI.   
 
Prior to coronary angiography, approximately 600 subjects are expected to be randomized in a 
2:2:1:1 parallel, double-blind fashion to a single, 2-hour continuous intravenous infusion of 
either: PZ-128 0.3 mg/kg, PZ-128 0.5 mg/kg, or Placebo 0.3 mg/kg, or Placebo 0.5 mg/kg (the 
two placebo groups will be merged for the purposes of data analysis). The study drug infusion 
will be initiated within one hour prior to the start of the cardiac catheterization procedure (i.e., 
angiography).  
 
The planned administration of GPI for a subject excludes that subject from participation in this 
study. During PCI, bail-out GPI may be used, at the investigator’s discretion, in subjects with 
new ischemia on telemetry or ECG, worsening of angiographic coronary flow during 
procedure, or thrombotic complication related to stenting during PCI. 
 
Subjects meeting the inclusion/exclusion criteria (Section 6.3.1 and Section 6.3.2) will follow 
the randomization procedures (Section 6.4.4 and Section 6.5.2). The randomization code and 
starting seed will be generated and maintained by RTI. It will not be provided to the sponsor, 
or sites until the database has been locked with the exceptions of parties listed in Section 
6.4.6.  The randomization will be generated using random permuted blocks, stratified by 
clinical site according to the urgency of the procedure at the time the operator decides to 
perform the cardiac catheterization (i.e., elective versus urgent).   
 
7.2 
General Aspects of Statistical Evaluation 
 
Statistical analyses will be performed using SAS version 9.23 and, where appropriate (e.g., 
specific pharmacokinetic analyses) other validated software.  Statistical analyses will be 
performed in accordance with the study protocol, and a comprehensive Statistical Analysis 
Plan (SAP) which will be prepared before unmasking of the data.  The SAP will provide 
further details of the analyses and presentation of the data and will contain ground rules and 
data handling conventions used to perform the analyses. Both the data and the proposed 
methods of analyses will be reviewed continuously during the study by the study team, which 
includes input from statistical, clinical and data management personnel. Before database lock, 
a masked review will take place during which all important protocol deviations will be 
discussed and agreed by the team and any ambiguities in study outcomes will be adjudicated 
in a masked fashion by the protocol team. 
 
The primary and secondary outcome measures will be treated as binary outcomes with any 
individual experiencing the event within the specified time frame after treatment classified as 


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positive for the outcome and other individuals classified as negative. Details of the measures 
will be included in the SAP.     
 
7.3 
Data Sets 
 
Safety analysis set 
Safety evaluations will include subjects who have been randomized and who have received 
any amount of study drug treatment.  Subjects will be evaluated according to treatment 
actually received. The safety analysis set will be used as the primary analysis dataset for the 
reporting of both the primary and secondary safety analyses as described below.  
 
Intention-to-treat analysis set 
Efficacy analyses will be carried out on an intent-to-treat basis, and all evaluations will 
include all subjects who receive randomization assignment, irrespective of initiation of 
treatment, who provide at least one outcome assessment.  Subjects will be analyzed according 
to the assigned study treatment irrespective of any treatment allocation errors.  
 
Per-protocol analysis sets 
Per-protocol analysis sets will also be defined during the masked review for total bleeding 
events, and key efficacy outcome measures. Subjects will be excluded from the per protocol 
analysis sets as a result of protocol deviations likely to influence the outcome variables (exact 
details of possible protocol deviations will be detailed in the SAP). Similar conclusions from 
both the safety analysis set and per protocol analysis set are required for a robust interpretation 
of the bleeding event results. 
 
7.4 
Demographic and Other Baseline Characteristics 
 
Demographic variables (e.g., sex, race, age, weight) and baseline clinical characteristics will 
be summarized by treatment group to assess comparability of treatment groups.  No formal 
statistical analyses of these data comparing treatment arms are planned. 
 
7.5 
Safety Analyses 
 
All safety endpoints for bleeding are defined in Appendix B. Only bleeding events 
adjudicated by the Clinical Events Committee (CEC) will be used in the primary and 
secondary analyses.  
 
7.5.1 Primary Endpoint 
 
The overall objective of this study is to evaluate the safety of two dose levels of PZ-128 
compared to placebo.  The outcome used to assess the safety of PZ-128 will be the incidence 
of major and minor bleeding events, as assessed by the TIMI system of classification, when 
PZ-128 or placebo is added to the standard of care (dual anti-platelet therapy with aspirin and 
P2Y12 inhibitor) in subjects undergoing non-emergent PCI or non-emergent cardiac 
catheterization with the intent to perform PCI.  


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The primary safety outcome variable is the incidence of TIMI major plus minor bleeding not 
related to CABG through 30 days after treatment.   
 
7.5.2 Secondary Safety Endpoints 
 
The secondary safety outcome variables will be the following: 
• incidence of bleeding that does not meet the TIMI criteria for major or minor 
(i.e., minimal bleeding) through 30 days after treatment; 
• incidence of “clinically significant” bleeding through 30 days after treatment 
(TIMI major or minor or bleeding requiring medical attention); 
• incidence of TIMI bleeding related to CABG through 30 days after treatment;  
 
7.5.3 Exploratory Safety Endpoints 
 
The following exploratory safety endpoint is not part of the objectives of the trial and is 
included as an additional way to evaluate bleeding for future consideration:   
• incidence of bleeding events according to the BARC (Bleeding Academic 
Research Consortium) classification through 30 days after treatment. 
 
7.5.4 Methodology 
 
The primary objective of this study is to evaluate the safety of two dose levels of PZ-128 
compared to placebo as measured by the incidence of TIMI major plus minor bleeding not 
related to CABG through 30 days after treatment.  Specifically, the study will is designed to 
test the hypothesis that from a safety perspective, PZ-128 is non-inferior to placebo, where 
non-inferiority is demonstrating that the difference in risk of bleeding incidence between the 
two treatments is less than a specified clinically important margin; the acceptable safety 
margin will depend in part on the efficacy benefit found for PZ-128.  Specifically, the analysis 
of the bleeding outcome variables will assess the risks of bleeding on the two treatment 
regimens by generating point and one-sided 95% confidence interval estimates of the risk 
difference using the following formula: 
 
 
 
 
 
Risk Difference = πPZ-128 - πPbo  
where πPZ-128 is the bleeding incidence across the two PZ-128 arms and πPbo is the bleeding 
incidence for the placebo arm.  The point and interval estimates for this risk difference will be 
obtained using a generalized linear model with the binomial distribution assumption and an 
identity link.  To address the potential underlying risk differences associated subpopulations 
defined by underlying subject risk and whether or not the subject received CABG, those 
factors will be included in the model.  The robust variance estimator as defined by Liang and 
Zeger [49] will be used to generate the interval estimates. Comparable models will be used to 
generate estimates for both the primary outcome and the secondary outcomes defined above. 
 
 
 


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Adverse Events 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 4.0 will be used for AE/SAE reporting in the trial database.  This version of CTCAE is 
MedDRA v12.0 (Medical Dictionary for Regulatory Activities Terminology) compatible at 
the AE (Adverse Event) term level where each CTCAE term is a MedDRA LLT (Lowest 
Level Term).  All adverse events will be captured from the time of randomization up until 30 
days after study drug administration and all serious adverse events will be captured from the 
time of randomization up until 90 days after study drug administration.  AEs will be 
summarized by system organ class and preferred term using MedDRA, with summaries 
reported separately for the 3 treatment arms aggregated across all participants in those 
treatment arms, and stratified by the four risk groups defined by the cross-classification of 
whether subjects received CABG or not and the urgency of the procedure at the time the 
operator decides to perform the cardiac catheterization (i.e., elective versus urgent). All 
adverse event data will be listed for all subjects. Separate listings of all SAEs, deaths and 
discontinuations due to AEs will be presented. Adverse event data will be summarized by 
relationship and severity. All AEs relating to bleeding will be summarized separately. 
 
Laboratory data 
All laboratory data will be listed and absolute values outside the normal range will be flagged 
if applicable. Changes from pre-dose baseline at Screening may also be summarized. 
Numerical laboratory data will be summarized using standard summary statistics and will be 
presented by treatment group. 
 
Other safety data 
Physical examination, ECG, and vital signs data will be listed and summarized using standard 
summary statistics by treatment group. 
 
7.6 
Efficacy Analyses   
 
Efficacy endpoints are defined in Appendix B.  Only efficacy endpoint events adjudicated by 
the CEC will be used in the secondary efficacy analyses.   
 
7.6.1 Secondary Efficacy Endpoints 
 
While the primary objective of this study is to determine the safety of PZ-128, secondary 
analyses will be used to evaluate potential efficacy signals that will allow an assessment of the 
comparative risk/benefit calculus of the treatment in determination of a future Phase 3 study.  
 
Specific secondary efficacy outcome measures include:  
• incidence of the composite endpoint of major adverse cardiac events 
(MACE)- any of cardiovascular death, non-fatal myocardial infarction, non-
fatal stroke, recurrent ischemia requiring hospitalization or urgent coronary 
revascularization with either CABG or subsequent PCI evaluated through 30 
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• incidence of the individual components of the MACE composite as measures 
of potential clinical benefit evaluated through 30 days and 90 days after 
treatment: 
o cardiovascular death 
o non-fatal MI 
o non-fatal stroke 
o recurrent ischemia requiring hospitalization 
o urgent coronary revascularization 
• incidence of definite or probable stent thrombosis evaluated through 30 days 
and 90 days after treatment; 
• effect of the investigator choice of P2Y12 inhibitor (i.e., clopidogrel versus 
prasugrel/ticagrelor) on the individual components of the MACE composite 
measure through 30 days and 90 days post treatment. 
 
7.6.2 Methodology 
 
The proposed phase 2 study is not of sufficient size or of sufficient follow-up duration to 
allow analysis of clinical event rates.   
 
Two alternative approaches will be used to evaluate the differences in risk of the various 
secondary outcome measures.  The first will utilize generalized linear models analogous to 
those used for the safety outcomes.  In addition because each of these outcome measures can 
be evaluated using a time to event approach, survival analyses will be used to examine those 
outcomes.  Kaplan-Meier estimates of the cumulative risk of each outcome will be calculated 
to investigate differences between the treatment groups in the time to occurrence, and a Cox 
Proportional hazard model that accounts for the risk stratification variables described above 
will be used to assess risk differences in the 3 treatment groups. All of these analyses will be 
interpreted descriptively, with no adjustment for multiple comparisons.  We anticipate that 
some analyses will be conducted for specific subgroups (e.g., influence of baseline risk 
factors, concomitant therapies), but these subgroup analyses will again be considered 
exploratory and treated as descriptive analyses.  Details will be provided in the SAP.  
Generalized linear models comparable to those used for the safety outcomes will also be used 
to evaluate the effect of investigator choice of P2Y12 inhibitor on each of the MACE 
components. 
 
7.7 
Determination of Sample Size/Power  
 
Power calculations were used to evaluate the size of non-inferiority margins that were able to 
be detected from a study of 600 participants, 400 of whom are randomized to PZ-128 and 200 
of whom are randomized to placebo.  Available data on bleeding rates from previous studies 
[29, 32, 33] suggest that the incidence of bleeding in the placebo arm is likely to be in the 
range of 2% to 6%.  Furthermore, the sponsor assumes that the true difference in the incidence 


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of the participants on the PZ-128 arms and those in the placebo arms are likely to be in the 
range of 0% to 2%.  Based on these assumptions, the table below shows the minimum non-
inferiority margin that could be demonstrated with at least 80% power, where that non-
inferiority margin is based on the upper limit of the 95% confidence interval identified above.  
This sample size is adequate to demonstrate acceptable upper safety bounds. 
 
True Incidence or Risk of 
Bleeding for placebo 
Minimum Demonstrable Non-inferiority margin 
True Incidence 
Difference of 0% 
True Incidence 
Difference of 2% 
2% 
2.6% 
5.0% 
3% 
3.2% 
5.5% 
4% 
3.7% 
5.9 % 
5% 
4.1% 
6.3% 
6% 
4.4% 
6.6% 
 
7.8 
Interim Analysis 
 
Although no formal stopping boundaries will be utilized, one interim safety analysis will be 
performed at approximately 1 year following the enrollment of the first subject, or after 
enrollment of 50% of the study population, whichever occurs first.  The Data and Safety 
Monitoring Board (DSMB) will be provided point and interval estimates of PZ-128 benefit at 
the time of that analysis based on survival estimates, and will evaluate evidence of bleeding 
risk in light of the potential efficacy benefits in making recommendations about stopping the 
trial.  
 
An independent DSMB, as described in Section 9.3.1, will monitor safety data on an 
ongoing basis to ensure that subject safety is not compromised.   The DSMB-supporting 
statistician will have access to the randomization code to allow grouping of the safety data.  
The DSMB will receive blinded data but has the option to unblind the data if deemed 
warranted.    The DSMB will make safety recommendations for the alteration or 
termination of the study to the study sponsor. 
 
7.9 
Other Analyses 
 
7.9.1 Pharmacokinetics 
 
The plasma portion of the blood samples from each consenting participant will be assayed at a 
centralized lab for PZ-128 under non-GLP conditions at baseline and select time points 
following the start of the study drug administration as specified in Section 6.6.3. PK 
parameters will be calculated over time (Cmax, AUC, t1/2, Clearance and Distribution) and will 
be summarized by dose level. Data will be presented using graphical summaries and 
descriptive statistics.  
 
 
 


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7.9.2 Pharmacodynamics 
 
At select sites, blood samples from each consenting participant will be analyzed onsite using 
Light Transmission Aggregometry (LTA) under non-GLP conditions at baseline and select 
time points following the start of the study drug administration as specified in Section 6.6.3.   
The following will be measured:    
• Inhibition of platelet aggregation (maximum and final) induced by SFLLRN 
5-20 μM (or SFLLRN of equivalent potency) using blood collected in 0.4% 
sodium citrate. 
• Inhibition of platelet aggregation (maximum and final) induced by AYPGKF 
160 μM using blood collected in 0.4% sodium citrate. 
• Inhibition of platelet aggregation (maximum and final) induced by collagen 
4-20 μg/mL using blood collected in 0.4% sodium citrate. 
• Inhibition of platelet aggregation (maximum and final) induced by 5-20 μM 
ADP using blood collected in 0.4% sodium citrate. 
• Inhibition of platelet aggregation (maximum and final) induced by thrombin 
1 nM-1 µM using blood collected in 0.4% sodium citrate (with GPRP added 
for 1mM final concentration). 
 
Maximal and final extent inhibition of platelet aggregation (IPA) from pre-dose baseline at 
Screening will be calculated at all subsequent time points using  
Percentage of Inhibition= 100%  x  (PAs - PA)  
 
 
 
 
 
    (PAs) 
Where PA is the mean response at the given time point, and PAs is the mean response at pre-
dose baseline (Screening).  Percentage inhibition will be restricted to the closed interval 
[0,100]; any data falling outside this range will be truncated to the appropriate limit.  
Individual peak inhibition of platelet aggregation (IPAmax) will be estimated as the highest 
IPA within the collection time period and TIPAmax will be the time to IPAmax for final extent 
and maximum extent of IPA.  
 
The percentage inhibition of the specific agonist-induced platelet aggregation (final and 
maximum extent) will be summarized at the scheduled protocol time points using standard 
summary statistics for each treatment group.  Mean plots showing changes within treatment 
groups across time will be presented. The derived PK and PD parameters will be summarized 
using standard summary statistics and graphical presentations.  
 
7.9.3 Exploratory Biomarkers 
 
The plasma portion of the blood samples from each consenting participant will be assayed at a 
centralized lab under non-GLP conditions for systemic biomarkers of platelet reactivity, 
inflammation and metabolomics at baseline and at select time points following the start of the 
study drug administration as specified in Section 6.6.3.  This will include two PAR1 agonists, 


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thrombin (in complex with anti-thrombin III: TAT) and MMP-1. Changes from the pre-dose 
baseline (Screening) to each of the subsequent time points will be compared between 
treatment groups using descriptive statistics and correlated with outcomes.  
 
 


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8.0 
ADHERENCE TO ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
 
The ethical and regulatory requirements that must be observed to comply with Principles of 
Good Clinical Practice (GCP) for the conduct and monitoring of clinical investigations are 
presented in this section and Appendix D, General Requirements for Clinical Trials.  
 
The study must be conducted in accordance with GCP as outlined in the International 
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals 
for Human Use (ICH) Guidelines, E6 Good Clinical Practice:  Consolidated Guidance and 
other applicable laws and regulations.  In addition, the study must be conducted in accordance 
with the USA Code of Federal Regulations (CFR) since the study is conducted under a USA 
IND (Investigational New Drug Application).   
 
By signing this protocol (Appendix A), the investigator agrees to adhere to these 
requirements.  
 
8.1 
Ethical Conduct of the Study 
 
8.1.1 Institutional Review Board 
 
Prior to initiation of the study at any site, the study, including the protocol, informed consent 
form, other written subject information, and any proposed advertising material must be 
approved by an appropriate Institutional Review Board (IRB).  The IRB must be constituted 
according to applicable regulatory requirements. The IRB approval must be obtained in 
writing, clearly identifying the trial, the documents reviewed (e.g., IB, informed consent, 
advertisement), the Principal Investigator’s name and the date of the review/approval. In the 
event that the IRB requires changes in the protocol, the sponsor shall be advised and must 
approve the changes prior to implementation.  The investigator shall not modify the study 
described in the protocol once finalized and after approval by the IRB without the prior 
written approval of the sponsor. A copy of the written approval of the protocol and informed 
consent form must be received by Tufts Medical Center before recruitment of subjects into the 
study and shipment of investigational product to the site. The investigator or qualified 
designee will forward all subsequent IRB approvals to the sponsor.   
 
Protocol amendments, except where necessary to eliminate an immediate hazard to subjects, 
must be made only with the prior approval of the sponsor.  Agreement from the investigator 
must be obtained for all amendments relating to the protocol, Investigator’s Brochure and 
informed consent document(s) issued by the sponsor.  The IRB must be informed of all 
amendments and give written approval before implementation at the site.  
 
The investigator will be responsible for obtaining annual IRB approval/renewal throughout the 
duration of the study. Copies of the IRB’s continuance of approval must be sent to Tufts 
Medical Center.  The investigator will submit a report to the IRB (with a copy to the sponsor) 
upon notification by the sponsor of the completion of study enrollment (study closure) and the 


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overall termination of the study.  
 
All investigators will be responsible for notifying their IRB of deviations from the protocol 
and AEs/SAEs occurring at their site according to local procedures. All other AE/SAE reports 
received by the investigator from Tufts Medical Center should be processed by the site in 
accordance with ICH GCP Guidelines, CFR and local procedures. 
 
8.1.2 Subject Information and Consent 
 
The investigator is responsible for obtaining written informed consent from the subject after 
adequate explanation of the aims, methods, anticipated benefits, and potential risks of the 
study and before any protocol-specific screening procedures or any investigational products 
are administered.  In obtaining informed consent, the information must be provided in 
language and terms understandable to the subject. The execution of informed consent 
(acquisition of informed consent and the subject’s agreement or refusal) must be documented 
in the subject’s medical records, and the informed consent form must be signed and personally 
dated by the subject and by the person who conducted the informed consent discussion. The 
original signed and dated consent form must be retained by the investigator as part of the trial 
records in accordance with institutional policy and a copy of the signed and dated consent 
form must be given to the subject. 
 
The consent form must include all of the required elements of informed consent in accordance 
with ICH Guidelines E6 and the USA FDA as set forth in Title 21 CFR, Part 50.  In addition, 
the sponsor specifically requests that the consent form identify it as the sponsor and state that 
use of the drug is investigational/ experimental and the side effects of the drug are not 
completely known.  The sponsor will provide a suggested model generic informed consent 
document for the investigator to prepare the informed consent form to be used at his/her site. 
The consent form must be approved by the appropriate IRB and sponsor before study 
initiation at a clinical site.  Updates to the template will be communicated in writing from the 
sponsor to the investigator.  Any subsequent changes to the approved informed consent form 
must be reviewed and approved by the appropriate IRB and sponsor before implementation.   
 
8.1.3 Protocol-Related Regulatory Issues 
 
The investigator is responsible for forwarding the following documents to the sponsor for 
review before study initiation can occur: 
• Signed and dated protocol signature page (Investigator’s Agreement, 
Appendix A) 
• Signed and dated Investigator’s Brochure signature page 
• Copy of approved/validated IRB informed consent form (and HIPAA Form if 
not included in the ICF), other written subject information, and any proposed 
advertising material 
• Copy of the IRB approval letter of the protocol and informed consent form 


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• The IRB composition or written statement and assurance number (FWA) that 
IRB is in compliance with regulations 
• Completed Form FDA 1572 
• Up-to-date curriculum vitae (signed and dated within one year) and medical 
license number of Principal Investigator and all Sub-Investigators listed on 
the Form FDA 1572, if applicable 
• Laboratory normal ranges and documentation of laboratory certification (or 
equivalent license) for clinical labs 
• Completed Financial Disclosure statements for the Principal Investigator 
and all Sub-Investigators listed on Form FDA 1572 
• Delegation of Authority (signed study staff log) 
• Signed study contract 
 
 8.2 
Reporting to Sponsor and Subject Confidentiality 
 
Contact with the investigator will be maintained by the sponsor and sponsor’s monitor who 
will visit the investigator at the initiation and closure of the study and at periodic intervals 
during the study to assess the conduct of the study. 
 
The investigator must ensure that the subject’s confidentiality is maintained: 
• On the eCRFs or other documents submitted to the sponsor/sponsor’s designee, 
subjects should be identified by their initials and a subject identification number only, 
with a complete and accurate date of birth on the demographics eCRF.  
• Documents that are not for submission to the sponsor (e.g., signed informed consent 
forms) should be kept in strict confidence by the investigator. 
• All optional pharmacokinetic, pharmacodynamics, exploratory biomarkers research 
and pharmacogenomics blood samples (for subjects who sign separate consent) 
submitted to the sponsor should be identified by the subject’s unique study number 
only and the collection date/time. All results will be coded by the sponsor/sponsor’s 
designee with the subject’s unique study number (or a random genetics sample code in 
the case of the pharmacogenomics) and stored in a secure database to ensure 
confidentiality while enabling destruction of the samples upon completion of the 
study’s objectives or the subject’s request (i.e., withdrawal of consent for further 
analysis). Since the research laboratory evaluations are not expected to benefit the 
subject directly or to impact medical management, the results will not be individually 
reported back to the investigator, will not be placed in the subject’s medical record and 
will not be made available to the subject or third parties (e.g., medical providers).  See 
Appendix E for information relating to pharmacogenomics.  
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the sponsor, of the regulatory 
agency(s), and the IRB direct access to review the subject’s original medical records for 


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verification of study-related procedures and data.  Direct access includes examining, 
analyzing, verifying and reproducing any records and reports that are important to the 
evaluation of the study.  The investigator is obligated to inform and obtain the consent of the 
subject to permit named representatives to have access to his/her study-related records, 
including personal health information, without violating the confidentiality of the subject.  
 
An entire eCRF will be completed for all subjects who give informed consent and undergo 
successful randomization (i.e., considered “enrolled” by the sponsor), whereas subjects who 
give informed consent but do not subsequently undergo successful randomization will be 
registered in the interactive web-based system as screen failures and will have the following 
information completed:  1) demographics (date of birth, sex/gender, race, ethnicity) and 2) 
subject status including the reason for failure to be randomized.  Any other institutional 
screening/enrollment logs used by the clinical site staff should be securely maintained and any 
identifying fields should be removed if the log is accessible to the sponsor/sponsor’s monitor. 
 
All eCRF screens should be completed soon after the evaluation has occurred. 
 
It is essential that all dates appearing on the sponsor’s subject data collection forms for 
laboratory tests, evaluations, etc. be the dates on which the samples/specimens were obtained, 
or the procedures performed. The investigator will acknowledge in writing that he/she has 
verified the accuracy of the recorded data.  
 
Further details are provided in Appendices D and E. 
 
8.3 
Publications and Other Rights 
 
A.  The investigator has the right to publish or publicly present the results of the study in 
accordance with this Section 8.3 of the protocol.  Since this protocol is a part of a 
multicenter study, it is understood that it is the intent of the sponsor and the investigator to 
initially only publish or present the study results together with the other centers, unless 
specific written permission is obtained in advance from the sponsor to publish separate 
results.  The sponsor shall advise as to the implications of timing of any publication in the 
event clinical trials are still in progress at centers other than the investigator’s center.  
 
The investigator agrees not to publish or publicly present any interim results of the study 
without the prior written consent of the sponsor.  The investigator further agrees to provide 
to the sponsor 60 days prior to submission for publication or presentation, review copies of 
abstracts or manuscripts for publication (including, without limitation, slides and texts of 
oral or other public presentations and texts of any transmission through any electronic 
media (e.g., any computer access system such as the Internet) that report any results of the 
study. The sponsor shall have the right to review and comment with respect to 
publications, abstracts, slides, and manuscripts and the right to review and comment on the 
data analysis and presentation with regard to (1) proprietary information that is protected 
by the provisions contained in paragraph B below, (2) the accuracy of the information 
contained in the publication, and (3) to ensure that the presentation is fairly balanced and 


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in compliance with FDA regulations. 
 
If the parties disagree concerning the appropriateness of the data analysis and presentation, 
and/or confidentiality of the sponsor’s confidential information, the investigator agrees to 
meet with the sponsor’s representatives at the clinical site or as otherwise agreed, prior to 
submission for publication, for the purpose of making good faith efforts to discuss and 
resolve any such issues or disagreement.  
  
B.  No publication or manuscript shall contain any trade secret information of the sponsor or 
any proprietary or confidential information of the sponsor and shall be confined to new 
discoveries and interpretations of scientific fact.  If the sponsor believes there is patentable 
subject matter contained in any publication or manuscript submitted for review, the 
sponsor shall promptly identify such subject matter to the investigator.  If the sponsor 
requests and at the sponsor’s expense, the investigator shall use its best efforts to assist the 
sponsor to file a patent application covering such subject matter with the USA Patent and 
Trademark Office or through the Patent Cooperation Treaty prior to any publication. 
 
C.  The investigator is granted the right, subject to the provisions of this protocol, to use the 
results of all work provided by the investigator under this protocol, including but not 
limited to, the results of tests and any raw data and statistical data generated for the 
investigator’s own teaching, research, and publication purposes only.  The 
investigator/institution agrees, on behalf of itself and its employees, officers, trustees, and 
agents, not to cause said results to be knowingly used for any commercial purpose 
whatsoever except as authorized by the sponsor in writing.  
 
 


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9.0 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
 
9.1 
Sponsor 
 
The sponsor of this study is indicated in the Title Page.  
 
9.2 
Investigators 
 
The investigators of this study are indicated in the Title Page. 
 
Only investigators qualified by training and experience in interventional cardiology to perform 
a clinical investigation with PZ-128 in subjects undergoing cardiac catheterization/PCI are 
selected.  The sponsor will contact and select all investigators (i.e., the legally responsible 
party(s) at each clinical site).  It is the responsibility of each study-site investigator to select 
appropriately qualified persons to whom he/she will delegate study duties and document this 
on the study-specific Delegation of Authority Form.  The investigator will provide the current 
study protocol and other relevant study documents to all sub-investigators and other staff 
responsible for study conduct, as well as provide for the training of all sub-investigators or 
other staff involved in the conduct of this research. 
 
Both the sponsor and the investigator reserve the right to terminate the investigator’s 
participation in the study according to the study contract/agreement.  
 
A clinical study report (CSR) will be prepared by the sponsor or its qualified designee to 
describe the results of the study.  One of the investigators shall be selected by the sponsor to 
review the CSR and provide approval of the final CSR in writing.  The investigator chosen to 
review and approve the CSR is to be called the CSR Coordinating Investigator.  A second 
investigator shall be selected as the Alternate CSR Coordinating Investigator.  The Alternate 
CSR Coordinating Investigator is to review and approve the CSR should the first CSR 
Coordinating Investigator be unable to do so.  The sponsor is to select the CSR Coordinating 
Investigator and Alternate CSR Coordinating Investigator from the investigators using the 
following criteria: 
• must be the Principal Investigator at a clinical study site actively enrolling subjects and 
participating in the study; 
• must be willing and capable of completing the necessary reviews and providing 
approval of the CSR in writing; and  
• must have participated in clinical research prior to participating in this current study.  
 
9.3  
Committees and Central Organizations 
 
Addresses of central organizations will be identified on Forms FDA 1571.  
 
 
 


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9.3.1 Data and Safety Monitoring Board (DSMB) 
 
An independent DSMB will be established to further the rights, safety and well-being of 
subjects who will be participating in this study by monitoring the progress and results.  The 
DSMB will review in an aggregated and blinded fashion, with the option to unblind these 
data, if deemed warranted: 
o bleeding and associated data (aggregated) through 30 days, primarily to 
determine whether the type and occurrence of bleeding is in accord with 
anticipated results (i.e., no potential meaningful additional risk), and 
o MACE and stent thrombosis results. 
 
Reviewed data will not have been adjudicated by the CEC (see Section 9.3.2).  The DSMB 
will monitor SAEs and aggregated AEs and may also elect to review data on platelet 
aggregation, if deemed necessary.  The DSMB will perform one interim safety analysis to 
evaluate evidence of bleeding risk in light of any potential efficacy benefit(s) and to allow 
the DSMB to make recommendations to the sponsor (i.e., continuing the study under the 
current protocol, amending the current protocol, or stopping the study). Otherwise, the 
DSMB will meet quarterly or as required to perform its function.   The DSMB may request 
an unplanned review of all safety data if a concern arises. No formal statistical rule for 
stopping the trial will be defined.  
 
The DSMB will comprise scientifically inclined clinicians who are not investigators in the 
study and not otherwise associated with the sponsor and an independent statistician (i.e., not 
from the sponsor’s statistical designee, RTI and not otherwise associated with the sponsor or 
clinical sites).  The DSMB will be described in detail in the separate DSMB Charter, which 
will include a description of the interim analysis to be performed, including how the interim 
results will be analyzed and how the interim analysis will affect the overall study. All 
activities of the DSMB will be documented.  This documentation will include data 
summaries and analyses provided to the committee as well as minutes of the meetings.  The 
unmasked documentation will remain confidential within the DSMB until the study is 
unblinded.  
 
9.3.2 Clinical Events Committee (CEC) 
 
An independent CEC will be established to review and adjudicate each suspected bleeding 
event, MACE (CV death, non-fatal MI, non-fatal stroke, recurrent ischemia with 
hospitalization, urgent coronary revascularization) and probable/definite stent thrombosis 
identified by investigators or triggered by predefined criteria with the appropriate supporting 
documentation for the event.  The group will use the definitions of the endpoints of the 
protocol (Appendix B) and additional instructions for its interpretation so that the 
adjudication proceeds in consistent fashion overtime. The CEC will comprise physician 
personnel (interventional cardiologists) who are not investigators in the study and not 
otherwise directly associated with the sponsor.  The CEC judges will remain blinded to 
treatment throughout the adjudication process and the study.  The CEC-adjudicated data will 


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be used in the final analyses of certain endpoints. The CEC will be described in detail in a 
separate CEC Charter.  
 
 
9.3.3 Central Randomization Service (Medidata Rave®) 
 
Central randomization will be performed via an interactive web-based system within the 
Medidata Rave® platform which is available 24 hours a day, 7 days a week to facilitate real-
time enrollment/ randomization.   Investigators or designee will login to iMedidata under the 
specific study to enroll/randomize the subject and obtain the following:  unique subject study 
number and randomization number.  The designated unblinded pharmacist at the clinical site 
will login to iMedidata via a restricted access mechanism to obtain the randomized treatment 
assignment (active PZ-128 or placebo and dose level designation) in order to provide blinded 
IV solution for infusion.  The system will allow the study sponsor and designated parties to 
track the progress of the study closely.  
 
9.3.4 Research Triangle Institute, International (RTI) 
 
RTI will provide intellectual services with respect to the design and operation (regulatory 
consulting, biostatistics, computer programming and data management) of the clinical trial.   
 
9.3.5 Clinical Supplies Management (CSM) 
 
CSM is the sponsor’s designated partner for the labeling, packaging, storing, management of 
inventory of the investigational product(s) (IP) and the distribution of the IP to the approved 
clinical sites. 
  
9.3.6 Central Research Lab- Tufts Center for Hemostasis and Thrombosis Research 
 
Tufts Center for Hemostasis and Thrombosis Research at Tufts Medical Center (study 
sponsor) will serve as the recipient and processing/distribution center for samples for the 
following research tests and will perform the analysis on the samples unless otherwise 
indicated: 
• Cardiac Troponin I (sponsor will send samples to a designated laboratory for analysis 
and provide results to the CEC members for adjudication purposes related to suspected 
MI cases) 
• Exploratory Biomarkers- thrombin in complex with anti-thrombin III: TAT and  
MMP-1 
• Pharmacokinetics (sponsor will send samples to a designated laboratory for analysis) 
• Pharmacodynamics (sponsor will perform LTA only for the Tufts Medical Center 
clinical site) 
• Pharmacogenomics- DNA, RNA and microRNA analysis (sponsor may send samples 
to one of the participating clinical sites to perform analysis) 
 


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All of the above-listed tests are being conducted for research purposes only.  The subject’s 
individual results will not be returned to the corresponding investigator but will be transmitted 
electronically to the study’s research laboratory database by the sponsor.  
 
 


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and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy 
Clin Immunol 2006;117:391-7. 
 
49. Liang, KY, Zeger SL. Longitudinal data analysis using generalized linear models. 
Biometrika 1986;73:13-22. 
 
50. Wiviott SD, Antman EM, Gibson CM, et al.  Evaluation of prasugrel compared with 
clopidogrel in patients with acute coronary syndromes:  design and rationale for the Trial 
to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with 
prasugrel Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38). Am Heart J 
2006;152:627-35. 
 
51. Morrow DA, Scirica BM, Fox KA, Berman G, Strony J, Veltri E, Bonaca MP, Fish P, 
McCabe CH, Braunwald E. Evaluation of a novel antiplatelet agent for secondary 
prevention in patients with a history of atherosclerotic disease: design and rationale for the 
Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic 
Events (TRA 2 degrees P)-TIMI 50 trial. Am Heart J 2009;158:335-41 e3. 
 


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52. Mehran R, Rao SV, Bhatt DL., et al. Standardized bleeding definitions for cardiovascular 
clinical trials:  a consensus report from the Bleeding Academic Research Consortium. 
Circulation 2011;123:2736-47. 
 
53. Cannon CP, Brindis RG, Chaitman BR, et al.  2013 ACCF/AHA key data elements and 
definitions for measuring the clinical management and outcomes of patients with acute 
coronary syndromes and coronary artery disease:  a report of the American College of 
Cardiiology Foundation/American Heart Association Task Force on Clinical Data 
Standards (Writing Committee to Develop Acute Coronary Syndromes and Coronary 
Artery Disease Clinical Data Standards). Circulation 2013;127:1052-89. 
 
54. Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, FArb A, Fonarow GC, Jacobs 
JP, Jaff MR, Lichtman JH, Limacher MC, Mahaffey KW, Mehran R, Nissen SE, Smith 
EE, Targum SL. 2014 ACC/AHA key data elements and definitions for cardiovascular 
endpoint events in clinical trials:  a report of the American College of 
Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing 
Committee to Develop Cardiovascular Endpoints Data Standards). Circulation 
2015;131:000-000. 
 
55. Thygesen K, Alpert JS, Jaffe AS, on behalf of the Joint ESC/ACCF/AHA/WHF Task 
Force for the Universal Definition of Myocardial Infarction. Third universal definition of 
myocardial infarction. Circulation 2012;126:2020-35. 
 
56. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, 
Mauri L, Vranckx P, et al. Clinical end points in coronary stent trials: a case for 
standardized definitions. Circulation 2007;115:2344-51. 
 
  
 
 
 
 
 
 


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APPENDIX A:  SIGNATURES 
 
 


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INVESTIGATOR’S AGREEMENT 
 
 
I have read the accompanying protocol entitled, “A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the Safety of PZ-128 in Subjects Undergoing  
Non-Emergent Percutaneous Coronary Intervention- Thrombin Receptor Inhibitory 
Pepducin in PCI (TRIP-PCI) (Protocol No. TMC-PZ128-02)” and agree to abide by all 
provisions set forth therein. 
 
I agree to comply with the International Conference on Harmonisation Tripartite Guideline 
on Good Clinical Practice and applicable FDA regulations/guidelines set forth in 21 CFR 
Parts 11, 50, 54, 56, and 312. 
 
I agree to ensure that Financial Disclosure Statements will be completed by: 
 
• me (including, if applicable, my spouse [or legal partner] and dependent children) 
 
• my sub-investigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
 
before study initiation, during the study if there are changes that affect our financial 
disclosure status, and for one year following the completion of the study (i.e., one year after 
the last subject has completed the study as specified in the protocol). 
 
I agree to ensure that the confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of Tufts Medical Center, Inc. 
 
 
 
 
 
Signature 
 
 
 
 
 
Name of Principal Investigator 
Date (DD Month YYYY) 
 
 
 
 
 
Name of Investigational Site 
Investigational Site #  
 
 




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APPENDIX B:  DEFINITIONS OF CLINICAL ENDPOINTS 
 
 
 
 


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An Independent Clinical Events Committee (CEC) will adjudicate each suspected bleeding and 
efficacy endpoint event (MACE- any of CV death, non-fatal MI, non-fatal stroke, recurrent 
ischemia with hospitalization, or urgent coronary revascularization; and stent thrombosis), 
while blinded to treatment.   
 
SAFETY (BLEEDING)  
 
Bleeding will be classified according to 2 separate classifications.   
 
1.  Thrombolysis in Myocardial Infarction (TIMI) [26, 50, 51] 
Primary and secondary endpoints 
 
The following definitions apply to all settings outside of peri-CABG: 
 
Major: 
1.  Any intracranial (ICH)*, or 
2.  Clinically significant overt signs of hemorrhage associated with a drop in hemoglobin 
(Hgb) of ≥5 g/dL (or, when Hgb is not available, an absolute drop in hematocrit (Hct) of 
≥15%), or 
3.  Fatal bleeding (bleeding that directly results in death within 7 d) 
 
Minor: 
Any clinically significant overt sign of hemorrhage (including imaging) that is associated with 
a fall in Hgb of 3 to <5 g/dL (or, when Hgb is not available, a fall in Hct of 9 to <15%). 
 
Minimal: 
Clinically significant overt signs of hemorrhage associated with a drop in Hgb of <3 g/dL (or, 
when Hgb is not available, a fall in Hct of <9%) that did not otherwise meet criteria for minor 
or major bleeding. 
 
To account for transfusions, Hgb and Hct measurements will be adjusted for any packed red 
blood cells (PRBCs) or whole blood given between baseline (enrollment) and post-transfusion 
measurements by the method of Landefeld and coworkers. A transfusion of one unit of blood 
will be assumed to result in an increase by 1 g/dL in Hgb or by 3% in Hct. Thus, to calculate 
the true change in hemoglobin or hematocrit, if there has been an intervening transfusion 
between 2 blood measurements, the following calculations should be performed: 
 
Δ Hemoglobin (Hgb) = [Baseline Hgb – post-transfusion Hgb] + [number of transfused units] 
 
Δ Hematocrit (Hct) = [Baseline Hct – post-transfusion Hct] + [number of transfused units x 3] 
 
Bleeding events will also be classified as spontaneous or induced as defined below: 
• Spontaneous:  any bleeding which there is no relation to any cause or reason. 
• Induced:  any bleeding that is precipitated by a cause or cause reason. 
 
  


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Bleeding requiring medical attention: 
Any overt sign of hemorrhage that meets one of the following criteria and does not meet 
criteria for a major or minor bleeding event, as defined above: 
• Requiring intervention (medical practitioner-guided medical or surgical treatment to 
stop or treat bleeding, including temporarily or permanently discontinuing or 
changing the dose of a medication or study drug) 
• Leading to or prolonging hospitalization 
• Prompting evaluation (leading to an unscheduled visit to a healthcare professional 
and diagnostic testing, either laboratory or imaging)  
 
TIMI Clinically significant Bleeding: 
The presence of either TIMI major or TIMI minor bleeding, or bleeding requiring medical 
attention. 
 
For subjects experiencing a hemorrhage that occurs as a result of CABG, the following criteria 
will be used: 
 
Major: Any hemorrhage that meets any of the following criteria: 
a.  Fatal bleeding (i.e., bleeding that directly results in death), or 
b.  Perioperative intracranial bleeding*, or 
c.  Reoperation following closure of the sternotomy incision for the purpose of 
controlling bleeding, or 
d.  Transfusion** of ≥5 U of whole blood or PRBCs within a 48 hour period, or 
e.  Chest tube output >2 L within a 24-hour period. 
 
None: Not qualifying as a major bleed in setting of CABG. 
 
*In light of the increased sensitivity of brain imaging for microhemorrhages of uncertain 
clinical significance, brain imaging with an incidental finding of microhemorrage (<10 mm 
evident only on gradient-echo MRI)  in the absence of associated clinical symptoms/findings 
will not be considered to meet the protocol definition of intracranial hemorrhage.  
 
**Cell saver transfusion will not be counted in calculations of blood products. 
 
 
 
 
 


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2.   Bleeding Academic Research Consortium [52] 
  Exploratory endpoint 
 
Type 0: no bleeding 
 
Type 1: bleeding that is not actionable and does not cause the subject to seek unscheduled 
performance of studies, hospitalization, or treatment by a healthcare professional; may include 
episodes leading to self-discontinuation of medical therapy by the subject without consulting a 
healthcare professional 
 
Type 2: any overt, actionable sign of hemorrhage (e.g., more bleeding than would be expected 
for a clinical circumstance, including bleeding found by imaging alone) that does not fit the 
criteria for type 3, 4, or 5 but does meet at least one of the following criteria: (1) requiring 
nonsurgical, medical intervention by a healthcare professional, (2) leading to hospitalization 
or increased level of care, or (3) prompting evaluation 
 
Type 3 
Type 3a 
Overt bleeding plus hemoglobin drop of 3 to <5 g/dL* (provided hemoglobin drop is related 
to bleed) 
Any transfusion with overt bleeding 
 
Type 3b 
Overt bleeding plus hemoglobin drop ≥5 g/dL* (provided hemoglobin drop is related to bleed) 
Cardiac tamponade 
Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid) 
Bleeding requiring intravenous vasoactive agents 
 
Type 3c 
Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does 
include intraspinal) 
Subcategories confirmed by autopsy or imaging or lumbar puncture 
Intraocular bleed compromising vision 
 
Type 4: CABG-related bleeding 
Perioperative intracranial bleeding within 48 h 
Reoperation after closure of sternotomy for the purpose of controlling bleeding 
Transfusion of ≥5 U whole blood or packed red blood cells within a 48-h period† 
Chest tube output ≥2L within a 24-h period 
 
Type 5: fatal bleeding 
Type 5a 
Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious 
 
 


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Type 5b 
Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation 
 
Platelet transfusions should be recorded and reported but are not included in these definitions 
until further information is obtained about the relationship to outcomes. If a CABG-related 
bleed is not adjudicated as at least a type 3 severity event, it will be classified as not a bleeding 
event. If a bleeding event occurs with a clear temporal relationship to CABG (i.e., within a 48-
h time frame) but does not meet type 4 severity criteria, it will be classified as not a bleeding 
event. 
 
*Corrected for transfusion (1 U packed red blood cells or 1 U whole blood=1 g/dL 
hemoglobin). 
†Cell saver products are not counted. 
 
 


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EFFICACY   
 
Major Adverse Cardiac Event (MACE) 
Defined as the composite endpoint of cardiovascular death, non-fatal MI, non-fatal stroke, 
recurrent ischemia with hospitalization, or urgent coronary revascularization. 
  
Death [53, 54]  
Cardiovascular death is the endpoint defined in this trial (as opposed to all-cause death) and 
only suspected CV death cases will be submitted for adjudication to the CEC.  Death will be 
classified as cardiovascular, non-cardiovascular, or unknown/undetermined. All deaths will be 
assumed to be cardiovascular in nature unless a non-cardiovascular cause can be clearly 
shown, with the exception of death without any additional information, which will be 
classified as unknown/undetermined. 
 
The primary cause of death is determined by the principal condition that caused the death, not 
the immediate mode of death, as per the following: 
 
 
Cardiovascular death: 
 Acute MI  
Death by any cardiovascular mechanism (arrhythmia, sudden death, HF, stroke, 
pulmonary embolus, PAD) within 30 days after an acute MI, related to the immediate 
consequences of the MI, such as progressive HF or recalcitrant arrhythmia.  There may 
be assessable (attributable) mechanisms of cardiovascular death during this time 
period, but for simplicity, if the cardiovascular death occurs within 30 d of an acute 
MI, it will be considered a death due to MI.  
Note:  Acute MI should be verified to the extent possible by the diagnostic criteria 
outlined for acute MI or by autopsy findings showing recent MI or recent coronary 
thrombosis.  Death resulting from a procedure to treat an MI (PCI or CABG), or to 
treat a complication resulting from an elective coronary procedure to treat myocardial 
ischemia (i.e., chronic stable angina) or death due to an MI that occurs as a direct 
consequence of a cardiovascular investigation/procedure/operation should be 
considered as a death due to a cardiovascular procedure.  
  
 Sudden cardiac death 
Death that occurs unexpectedly and not within 30 d of an acute MI.  
Note:  Sudden cardiac death includes the following scenarios: 
-Death witnessed and occurring without new or worsening symptoms; 
-Death witnessed within 60 min of the onset of new or worsening cardiac symptoms 
unless the symptoms suggest acute MI; 
-Death witnessed and attributed to an identified arrhythmia (e.g., captured on an ECG 
recording, witnessed on a monitor, or unwitnessed but found on ICD review); 
-Death after unsuccessful resuscitation from cardiac arrest (e.g., ICD unresponsive 
sudden cardiac death, pulseless electrical activity arrest); 
-Death after successful resuscitation from cardiac arrest and without identification of a 
specific cardiac or noncardiac etiology; 


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-Unwitnessed death in a subject seen alive and clinically stable ≤24 h before being 
found dead without any evidence supporting a specific non-cardiovascular cause of 
death (information about the subject’s clinical status preceding death should be 
provided if available) 
Unless additional information suggests an alternate specific cause of death (e.g., death 
due to Other cardiovascular causes), if a subject is seen alive ≤24 h before being found 
dead, sudden cardiac death should be recorded (e.g., subject found dead in bed but who 
had not been seen by a family member for >24 h). 
 
 Death due to heart failure 
Death associated with clinically worsening symptoms and/or signs of HF, regardless of 
etiology. 
Note:  Deaths due to HF can have various etiologies, including singe or recurrent MIs, 
ischemic or nonischemic cardiomyopathy, hypertension, or valvular disease. 
 
 Death due to stroke 
Death after stroke that is either a direct consequence of the stroke or a complication of 
the stroke. 
Note:  Acute stroke should be verified to the extent possible by the diagnostic criteria 
outlined for stroke. 
 
 Death due to cardiovascular procedures 
Death caused by the immediate complication(s) of a cardiovascular procedure. 
 
 Death due to cardiovascular hemorrhage 
Death related to hemorrhage such as a nonstroke intracranial hemorrhage (e.g., 
subdural hematoma), nonprocedural or nontraumatic vascular rupture (e.g., aortic 
aneurysm), or hemorrhage causing cardiac tamponade. 
 
 Death due to other cardiovascular causes 
Cardiovascular death not included in the above categories but with specific, known 
cause (e.g., PE, PAD). 
   
Non-cardiovascular death:  defined as any death with a specific cause that is not thought to be 
cardiovascular in nature: 
 Pulmonary 
 Renal 
 GI 
 Hepatobiliary 
 Pancreatic 
 Infection (includes sepsis) 
 Inflammatory/immune (includes SIRS, immunological, autoimmune diseases and 
disorders, anaphylaxis from environmental allergies) 
 Hemorrhage that is neither cardiovascular bleeding nor a stroke 
 Non-cardiovascular procedure or surgery 


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 Trauma (includes homicide) 
 Suicide 
 Prescription drug reaction or overdose (includes anaphylaxis)  
 Nonprescription drug reaction or overdose 
 Neurological (excludes cardiovascular death from ischemic stroke, hemorrhagic 
stroke, or undetermined cause of stroke, or cardiovascular hemorrhage of central 
nervous system) 
 Malignancy 
 Other non-cardiovascular cause of death 
 
Unknown/Undetermined cause of death: refers to death not attributable to either 
cardiovascular or noncardiovascular cause 
 
Myocardial Infarction (MI) 
Third Universal Definition of Myocardial Infarction [55] 
 
Note:  cTnI or cTnT is the preferred biomarker.  If a cTnI or cTnT assay is not available, the 
best alternative is CK-MB (measured by mass assay).  In this study, the centralized cTnI 
results will be used to reduce intermarker and interassay variability.  The locally available 
results will be submitted by the clinical sites and may be used in the adjudication process as a 
secondary source.     
 
Acute MI 
The term acute myocardial infarction should be used when there is evidence of myocardial 
necrosis in a clinical setting consistent with acute myocardial ischemia. Under these 
conditions, any one of the following criteria meets the diagnosis for myocardial infarction:  
 
Type 1: Spontaneous 
Spontaneous clinical syndrome related to atherosclerotic plaque rupture, ulceration, fissuring, 
erosion, or dissection, with resulting intraluminal thrombus, and leading to decreased 
myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis. This 
classification requires: 
a) Detection of a rise and/or fall of cardiac biomarker values (preferably cTn) with at least 1 
value >99th percentile of the URL and  
b) At least one of the following:  
(i)  Symptoms of myocardial ischemia  
(ii) New or presumed new significant ST-segment–T wave (ST–T) changes or new left 
bundle branch block (LBBB) on the ECG  
(iii) Development of pathological Q waves on the ECG 
(iv) Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality  
(v) Identification of an intracoronary thrombus by angiography or autopsy.  
 
Notes:  One or more coronary arteries may be involved.  The subject may have underlying 
severe CAD but on occasion may have non-obstructive CAD.  


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Type 2:  Ischemic imbalance 
Spontaneous clinical syndrome where a condition other than CAD contributes to an imbalance 
between myocardial oxygen supply and/or demand (e.g., coronary endothelial dysfunction,  
coronary artery spasm, coronary embolism, tachy-/bradyarrhythmias, anemia, respiratory 
failure, hypotension, and hypertension with or without LVH).  This classification requires: 
a) Detection of a rise and/or fall of cardiac biomarker values (preferably cTn) with at least 1 
value >99th percentile of the URL and  
b) At least one of the following:  
(i)  Symptoms of myocardial ischemia  
(ii) New or presumed new significant ST-segment–T wave (ST–T) changes or new left 
bundle branch block (LBBB) on the ECG  
(iii) Development of pathological Q waves on the ECG 
(iv) Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality  
 
Type 3:  Death, no markers 
Death where symptoms suggestive of myocardial ischemia are present, and with (presumed) 
new ischemic changes or new LBBB on ECG, but where death occurs before cardiac 
biomarkers can be obtained or could rise or (in rare cases) were not collected.  
 
Type 4a:  Percutaneous coronary intervention (PCI)-related 
MI associated with and occurring within 48 h of PCI, with elevation of cardiac biomarker 
values to >5 × 99th percentile of the URL in subjects with normal baseline values (≤99th 
percentile URL), or a rise of biomarker values >20% if the baseline values are elevated and 
are stable or falling. This classification also requires at least 1 of the following: 
(i) Symptoms suggestive of myocardial ischemia (i.e., prolonged ischemia ≥20 minutes) 
(ii) New ischemic changes on ECG or new LBBB 
(iii) Angiographic loss of patency of a major coronary artery or a side branch or 
persistent slow flow or no flow or embolization 
(iv) Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality.  
 
Type 4b:  Stent thrombosis  
MI associated with stent thrombosis as detected by coronary angiography or at autopsy, where 
symptoms suggestive of myocardial ischemia are present, and with a rise and/or fall of cardiac 
biomarker values, with at least 1 value >99th percentile of the URL.  
 
Type 4c:  Stent restenosis 
MI associated with stent restenosis as detected by coronary angiography or at autopsy, 
occurring >48 h after PCI, without evidence of stent thrombosis but with symptoms suggestive 
of myocardial ischemia, and with elevation of cardiac biomarker values to >99th percentile of 
the URL.  This classification also requires the following: 
(i) Does not meet criteria for any other classification of MI 
(ii) Presence of a ≥50% stenosis at the site of previous successful stent PCI or a complex 
lesion and no other significant obstructive CAD of greater severity following 1) 


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Initially successful stent deployment, or 2) Dilation of a coronary artery stenosis with 
balloon angioplasty to <50% stenosis 
 
Type 5:  Coronary artery bypass grafting (CABG)-related 
MI associated with and occurring within 48 h of CABG surgery, with elevation of cardiac 
biomarker values to >10 × 99th percentile of the URL in subjects with normal baseline cardiac 
biomarker values (≤99th percentile URL).  This classification also requires at least 1 of the 
following: 
(i) New pathological Q waves, new LBBB on ECG 
(ii) Angiographic new graft or new native coronary artery occlusion 
(iii) Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality.  
 
Acute MI- Symptoms 
Presence of acute symptoms of myocardial ischemia, such as chest, upper extremity, 
mandibular, or epigastric discomfort, or an ischemic equivalent such as dyspnea or fatigue. 
This is one of the noncardiac marker criteria supporting the diagnosis of acute MI Types 1, 2, 
3, 4a, 4b, and 4c. 
 
Acute MI- Acute Ischemic Changes on ECG 
Presence of new or presumed new significant ST-segment-T wave (ST-T) changes or new 
LBBB consistent with acute myocardial ischemia. This is one of the noncardiac marker 
criteria supporting the diagnosis of acute MI Types 1, 2, 3, and 4. 
• Ischemic changes on ECG 
In the absence of LVH and LBBB pattern (or other confounder such as a paced 
rhythm) on ECG, either: 
 a) ST elevation 
New (or presumed new) ST elevation at the J point in 2 contiguous leads with the 
following cut points: ≥0.1 mV in all leads other than leads V2 to V3 where the 
following cut points apply: ≥0.2 mV in men ≥40 y of age; ≥0.25 mV in men <40 
y of age, or ≥0.15 mV in women; or  
 
b) ST depression and T-wave changes  
New (or presumed new) horizontal or downsloping ST-segment depression ≥0.05 
mV in 2 contiguous leads and/or T inversion ≥0.1 mV in 2 contiguous leads with 
prominent R wave or R/S ratio >1. 
 
• LBBB  
New (or presumed new) LBBB pattern on ECG. 
 
Acute MI- New Q Waves on ECG 
Presence of new or presumed new pathological Q waves consistent with MI. This is one of the 
noncardiac marker criteria supporting the diagnosis of acute MI Types 1, 2, 4, and 5. 
 


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 New (or presumed new):  
a) Any Q wave in leads V2 to V3 ≥0.02 s or QS complex in leads V2 and V3 
b) Q wave ≥0.03 s and ≥0.1 mV deep or QS complex in leads I, II, aVL, aVF, or V4 to V6 
in any 2 leads of a contiguous lead grouping (I, aVL; V1 to V6; II, III, aVF) 
The same criteria are used for supplemental leads V7 to V9.  
 
Acute MI- Coronary Thrombus Present 
Presence of thrombus in a major epicardial vessel consistent with an acute MI. This is one of 
the noncardiac marker criteria supporting the diagnosis of acute MI Type 1. 
 
• Thrombus on angiography  
In the patient with a presumed acute STEMI, the angiographic appearance of 
thrombus (typically a filling defect) on angiography. This includes the aspiration of 
thrombus from the infarct vessel before coronary intervention during primary PCI for 
acute STEMI. 
 
• Thrombus at autopsy 
Identification of thrombus in a major epicardial vessel at autopsy. 
 
Acute MI- Change in Noninvasive Imaging 
Demonstration of a new change in myocardial viability or function consistent with MI. This 
is one of the noncardiac marker criteria supporting the diagnosis of acute MI Types 1, 2, 4a, 
and 5. 
 
• New loss of viable myocardium 
Noninvasive imaging evidence of a loss of viable myocardium when compared with 
the most recent previous noninvasive imaging study. 
 
• New regional wall motion abnormality 
Noninvasive imaging evidence of a decrease in regional wall motion contractility 
compared with the most recent previous noninvasive imaging study. 
 
Acute MI- PCI Angiographic Complication 
Occurrence of an adverse angiographic finding during PCI consistent with acute 
myocardial ischemia. This is one of the noncardiac marker criteria supporting the diagnosis 
of acute MI Type 4a. 
• Loss of major coronary 
Angiographic loss of patency of a major epicardial vessel. 
 
• Loss of side branch 
Angiographic loss of patency of a side branch. 
 
• Slow flow/no flow/embolization 
Angiographic reduction of flow into the coronary microcirculation. 
 


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Acute MI- Acute Vessel Occlusion After CABG 
Angiographic documentation of a new CABG or new native coronary artery occlusion within 
48 h of CABG surgery. This is one of the noncardiac marker criteria supporting the diagnosis 
of acute MI Type 5. 
 
Prior MI 
Presence of any 1 of the following criteria meets the diagnosis for prior MI (before study 
initiation):  
• Pathological Q waves with or without symptoms in the absence of non-ischemic 
causes  
a) Any Q wave in leads V2 to V3 ≥0.02 s or QS complex in leads V2 and V3 
b) Q wave ≥0.03 s and ≥0.1 mV deep or QS complex in leads I, II, aVL, aVF, or 
V4 to V6 in any 2 leads of a contiguous lead grouping (I, aVL; V1 to V6; II, 
III, aVF) 
The same criteria are used for supplemental leads V7 to V9 
c) R wave ≥0.04 s in V1 to V2 and R/S ≥1 with a concordant positive T wave in 
the absence of a conduction defect 
• Imaging evidence of a region of loss of viable myocardium that is thinned and fails 
to contract, in the absence of a non-ischemic cause  
• Pathological findings of a prior MI  
 
Silent MI 
Asymptomatic patients who develop new pathologic Q wave criteria for MI detected during 
routine ECG follow-up, or reveal evidence of MI by cardiac imaging, that cannot be directly 
attributed to a coronary revascularization procedure, should be termed ‘silent MI’.  The 
diagnosis of a new silent Q wave MI should be confirmed by a repeat ECG with correct lead 
placement, or by an imaging study, and by focused questioning about potential interim 
ischemic symptoms. 
 
  
 
 


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Stroke [54]  
Stroke is defined as an acute episode of focal or global neurological dysfunction caused by 
brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction of sudden 
onset,  
(a) with persistence of symptoms for ≥24 hours or results in death (in <24 hours) and is 
not due to an identifiable non-vascular cause (i.e., brain tumor, trauma), or 
(b) with symptoms of short duration (<24 hours) but evidence of infarction on cerebral 
imaging. 
 
Stroke will be subclassified into 1 of 3 mutually exclusive categories:  
1. Ischemic 
An acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction 
of central nervous system tissue.   
Note:  Hemorrhage may be a consequence of ischemic stroke.  In this situation, the 
stroke is an ischemic stroke with hemorrhagic transformation and not a hemorrhagic 
stroke.   
 
2. Hemorrhagic 
An acute episode of focal or global cerebral or spinal dysfunction caused by 
intraparenchymal, intraventricular or subarachnoid hemorrhage.  
Note:  Subdural hematomas are intracranial hemorrhagic events and not strokes.  
 
3. Undetermined 
An acute episode of focal or global neurological dysfunction caused by presumed 
brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction 
but with insufficient information (brain image via CT/MRI or autopsy) to allow 
categorization as either ischemic or hemorrhagic (without documentation or if tests 
are inconclusive).  
 
As a matter of differentiation, transient ischemic attack (TIA) is a transient episode (resolves 
spontaneously without any evidence of residual deficit <24 hours) of focal neurological 
dysfunction caused by brain, spinal cord, or retinal ischemia, without acute infarction. TIAs 
will not be reported as endpoints but will be reported as an AE.  
 
Recurrent Ischemia with Hospitalization [26] 
Recurrent ischemia with hospitalization is defined as ischemic discomfort or equivalent 
meeting the following criteria:  
(a) lasting ≥10 minutes at rest, or repeated episodes at rest lasting ≥5 minutes, or an 
accelerating pattern of ischemic discomfort (episodes that are more frequent, severe, 
longer in duration, and precipitated by minimal exertion), considered to be 
myocardial ischemia upon final diagnosis, and  
(b) prompting hospitalization (including an overnight stay on an inpatient unit) within 48 
hours of the most recent symptoms, and  
(c) at least 1 of the following additional criteria for coronary artery disease and/or 


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ischemia:  
• new and/or dynamic ST depression ≥0.05 mV, ST elevation ≥0.1 mV, or 
symmetric T-wave inversion ≥0.2 mV on a resting ECG; or  
• definite evidence of ischemia on stress echocardiography, myocardial 
scintigraphy (e.g., an area of clear reversible ischemia), or ECG-only 
stress test (e.g., significant dynamic ST shift, horizontal or downsloping); 
or  
• angiographic evidence of epicardial coronary artery stenosis of ≥70% 
diameter reduction and/or evidence for intraluminal arterial thrombus. 
 
If subjects are admitted with suspected myocardial ischemia, and subsequent testing reveals a 
noncardiac or non-ischemic etiology, this will not be recorded as meeting this end point. 
Potential ischemic events meeting the criteria for myocardial infarction will not be adjudicated 
as ischemia requiring hospitalization. 
 
Urgent Coronary Revascularization [26] 
Urgent coronary revascularization is defined as ischemic discomfort or equivalent meeting the 
following criteria: 
(a) lasting ≥10 minutes at rest, or repeated episodes at rest lasting ≥5 minutes, considered 
to be myocardial ischemia upon final diagnosis, and  
(b) prompting coronary revascularization during an unscheduled visit to health care 
facility or during an unplanned (or prolonged) hospitalization for these symptoms or 
revascularization, which was either done emergently or not previously planned during 
the course of hospitalization.  
 
Attempted revascularization procedures, even if not successful, will be counted. Potential 
ischemic events meeting the criteria for myocardial infarction will not be adjudicated as 
urgent coronary revascularization. 
 
Coronary Stent Thrombosis [56] 
All cases of reported death, MI, recurrent ischemia with hospitalization and urgent coronary 
revascularization will be reviewed and adjudicated with respect to stent thrombosis according 
to the Academic Research Consortium definition below:  
 
Timing: 
Acute stent thrombosis*  
 
0 to 24 hours after stent implantation 
Subacute stent thrombosis*   
>24 hours to 30 days after stent implantation 
Late stent thrombosis†  
 
>30 days to 1 year after stent implantation 
Very late stent thrombosis†  
>1 year after stent implantation 
 
Stent thrombosis should be reported as a cumulative value over time and at the various 
individual time points specified below. Time 0 is defined as the time point after the guiding 
catheter has been removed and the subject has left the catheter laboratory. 
 
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thrombosis (0-30 days)  
†Includes primary as well as secondary late stent thrombosis; secondary late stent thrombosis 
is a stent thrombosis after a target lesion revascularization. 
 
Grading: 
Three categories of evidence define the probability that coronary artery stent thrombosis has 
occurred:  
 
1)  Definite stent thrombosis* 
a.  Angiographic confirmation of stent thrombosis† 
The presence of a thrombus‡ that originates in the stent or in the segment 5 mm 
proximal or distal to the stent and presence of at least 1 of the following criteria 
within a 48-hour time window: 
• Acute onset of ischemic symptoms at rest 
• New ischemic ECG changes that suggest acute ischemia 
• Typical rise and fall in cardiac biomarkers (refer to definition of 
spontaneous MI) 
• Nonocclusive thrombus 
Intracoronary thrombus is defined as a (spheric, ovoid, or irregular) 
noncalcified filling defect or lucency surrounded by contrast material 
(on 3 sides or within a coronary stenosis) seen in multiple projections, 
or persistence of contrast material within the lumen, or a visible 
embolization of intraluminal material downstream. 
• Occlusive thrombus 
TIMI 0 or TIMI 1 intrastent or proximal to a stent up to the most 
adjacent proximal side branch or main branch (if originates from the 
side branch). 
b.  Pathological confirmation of stent thrombosis 
Evidence of recent thrombus within the stent determined at autopsy or via 
examination of tissue retrieved following thrombectomy. 
2)   Probable stent thrombosis 
Clinical definition of probable stent thrombosis is considered to have occurred after 
intracoronary stenting in the following cases: 
• Any unexplained death within the first 30 days§ 
• Irrespective of the time after the index procedure, any MI that is 
related to documented acute ischemia in the territory of the implanted 
stent without angiographic confirmation of stent thrombosis and in the 
absence of any other obvious cause. 
 
3) Possible stent thrombosis 
Clinical definition of possible stent thrombosis is considered to have 
occurred with any unexplained death >30 days after intracoronary stenting.  
 
*Definite stent thrombosis is considered to have occurred by either angiographic or 
pathological confirmation. 
†The incidental angiographic documentation of stent occlusion in the absence of clinical signs 


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or symptoms is not considered a confirmed stent thrombosis (silent occlusion). 
‡Intracoronary thrombus. 
§For studies with ST-elevation MI population, one may consider the exclusion of unexplained 
death within 30 days as evidence of probable stent thrombosis. 
 
When available data support >1 classification, the highest level of certainty should be 
reported. 
 
 
 


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APPENDIX C:  ADDITIONAL SAFETY INFORMATION 
 
 
 


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A Guide to Interpreting the Causality Question 
 
The following factors should be considered when deciding if there is a “reasonable 
possibility” (i.e., “possibly” or “probably”) that an AE may have been caused by the drug. 
 
• Time Course. Exposure to suspect drug. Has the subject actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration 
of the suspect drug? 
• Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class?  OR could the AE be anticipated from its pharmacological 
properties? 
• Dechallenge experience.  Did the AE resolve or improve on stopping the suspect 
drug? 
• No alternative cause. The AE cannot be reasonably explained by another etiology 
such as the underlying disease, other drugs, other host or environmental factors. 
• Rechallenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped?   
• Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship? 
 
A “reasonable possibility” could be considered to exist for an AE where one or more of these 
factors exist. 
 
In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any de-
challenge (if performed) is negative or ambiguous or there is another more likely cause of the 
AE. 
 
In difficult cases, other factors could be considered such as: 
• Is this a recognized feature of overdose of the drug? 
• Is there a known mechanism? 
 
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this.  
 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 
 
 


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National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis 
Network criteria for anaphylaxis [48] 
 
 
Anaphylaxis is highly likely when any one of the following 3 criteria are 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 PEF, 
hypoxemia) 
b. Reduced 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 stimuli for that subject 
(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 symptoms (e.g., crampy abdominal pain, vomiting) 
3. Reduced BP after exposure to known stimuli for that subject  (minutes to several hours): 
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic BP 
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person's 
baseline 
PEF, Peak expiratory flow; BP, blood pressure. 
 
Modified from Sampson et al., 2006 
 
 
 
 
 


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APPENDIX D:  GENERAL REQUIREMENTS FOR CLINICAL TRIALS 
 
 
 


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1 
General Requirements for Clinical Trials 
Sponsor (which includes its affiliates/partners) and the investigator agree to conduct the trial as 
described in the protocol, according to applicable laws, regulations, and principles of good 
clinical practice.  It is the intention that the trial be conducted according to practices that will 
satisfy worldwide registration requirements.  Therefore, in addition to satisfying locally 
relevant requirements for the conduct of the trial, there may be a need to satisfy other 
requirements, as specified in this protocol.  These additional requirements may follow laws, 
regulations, and practices of health authorities and/or sponsor policies.  While health authorities 
may not directly oversee the conduct of the trial, they may be recipients of marketing 
applications that contain the report of the trial.  Sponsor will take into account the 
appropriateness of the trial site and facilities and be assured of the investigator’s qualifications 
and availability for the entire duration of the trial.  The investigator will ensure that there are 
sufficient time, staff and facilities available for the duration of the trial.  
 
Both sponsor (represented by the “sponsor representative”) and the investigator must sign the 
protocol (and subsequent versions of the protocol if amended) as an agreement of the details of 
the clinical trial.  The agreement will include the acceptance of procedures for source document 
verification, data collection, monitoring, audit, inspection, and quality assurance.  Any 
amendments to the protocol or changes to any trial documents must have the agreement of 
sponsor, the investigator, and when appropriate, the Institutional Review Board (IRB) before 
the amendment or change is implemented; any such agreement must be documented in writing. 
 
It is the responsibility of the investigator to ensure that all staff personnel who will be handling, 
packaging, and/or shipping clinical specimens or any other hazardous or dangerous goods act 
in conformance with International Air Transport Association (IATA) regulations relating to the 
handling and shipping of hazardous or dangerous goods.  
 
2 
Monitoring and Inspections  
The sponsor representative and regulatory authority inspectors are responsible for contacting 
and visiting the investigator for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the clinical study (e.g., eCRFs and other pertinent data) 
provided that subject confidentially is respected.   
 
The sponsor-appointed, study monitor is responsible for verifying the eCRFs at regular 
intervals throughout the study to verify adherence to the protocol-completeness, accuracy and 
consistency of the data- and adherence to local regulations on the conduct of clinical research. 
The monitor should have access to subject medical records, source documents and other study-
related records needed to verify the entries on the eCRFs.  
 
The investigator agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits, including delays in completing eCRFs, are resolved.  It is 
essential that the investigator and designated staff set aside a sufficient amount of time for 
these study monitoring visits to permit an adequate review of the trial’s progress and study 
data. 
 


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This study may be selected for audit by the sponsor or inspection by regulatory authorities 
(e.g., FDA, DHHS, NHLBI/NIH). Inspection of site facilities (e.g., pharmacy, drug storage 
areas, treatment areas, laboratories) and review of original study-related records will occur to 
evaluate the study conduct and compliance with the protocol and applicable regulatory 
requirements.  
 
3 
Recording Subjects’ Data 
The investigator must conduct the trial and maintain records and data during and after the term 
or early termination of the trial in compliance with all applicable legal and regulatory 
requirements, including any applicable requirements of the USA Code of Federal Regulations 
and specific local regulations, and in accordance with ICH. 
 
The investigator is to provide such subject data on completed Case Report Forms (CRFs) or via 
computer entry on an Electronic Data Capture (EDC) system.  The investigator must maintain a 
separate subject list containing the name and address for each participant so that all can quickly 
be contacted by the investigator, if necessary. 
 
Case Report Forms are an integral part of the trial and subsequent reports.  They need not be 
completed by the investigator, but all entries are the responsibility of the investigator.  The 
investigator is expected to review subject data before attesting in writing to the accuracy and 
completeness (and legibility when paper CRFs are used) of the information contained therein. 
 
Any records or documents used as the source of information in the CRF are to be maintained 
and readily available for review by authorized representatives of the sponsor or regulatory 
agency.  These records or documents are called the subject source data.  These include but are 
not limited to hospital records, clinical and office charts, laboratory and pharmacy records, 
diaries, microfiches, and radiographs and correspondence.  
 
Completed paper CRFs are to be collected by the study monitor after source document 
verification has been completed.  Paper and electronic CRFs and the electronic database shall 
be the exclusive property of sponsor.   
 
3.A 
Paper Case Report Forms 
All paper CRFs are to be filled out using a black ball-point pen.  Errors should be lined out but 
not obliterated and the correction inserted, initialed and dated.  
 
3.B 
Electronic Data Capture (EDC) 
Data collection and data management will be performed using the Medidata Rave® EDC 
System, developed by Medidata Solutions, Inc.  Medidata Rave® is an internet-based system 
that enables subject randomization, data collection through electronic CRFs, review of data 
through automated and manual data edit checks, and online source document verification.  
Electronic CRFs (eCRFs) are used in place of paper CRFs, for the transcription of source 
document data.  
 
 
 


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3.Bi 
Third Party Housing 
The Medidata Rave® application and the eCRF data for the clinical trial is installed and stored 
on a server in a central, secure facility where systems administration and backups can be 
performed regularly.  The central facility where the server is located is neither owned nor 
operated by Tufts Medical Center.  The data-hosting facility utilizes card-key access and video 
surveillance.  Redundant power supply, raised floors, disaster proofing, bulletproof glass/walls, 
motion detection, and servers inside locked cages are all security features. Data stored at the 
hosting facility is backed-up and stored at an offsite location on a frequent basis.  
 
3.Bii Authentication 
Each user of the system accesses the central application through a standard web browser (e.g., 
Internet Explorer).  At the beginning of each session, user authentication is performed through 
a unique and confidential combination of User identification (user ID) and password. Activities 
in the Medidata Rave® System are time, date, and user stamped in the database, along with 
duration of the sessions.  After login, the system establishes a user session, so that all data 
recorded by the user is stored in the database along with the user identification.  
 
3.Biii Data Collection 
Each user in Medidata Rave® is granted specific rights within the system, limiting the data that 
they can view or edit and the particular functions that they can perform.  Data consistency 
checks may be performed prior to data submission to ensure that the proper type of data is 
submitted in the field (e.g., alphabetic vs. numeric, number of significant digits, etc.).  Once 
data are submitted, an audit trail independently records the user ID, date and time of the entry 
and reason for change.  Any actions that create, modify, or delete an electronic record are 
recorded.  The audit trail is incremental and cannot be modified by any user. 
 
The Medidata Rave® System performs edit checks on submitted data and notifies users with 
the results of these checks.  In both cases, the user will be presented with a description of the 
discrepancy, and will be expected to address the problem.  As with paper CRFs, the 
investigator is expected to review eCRF data on an ongoing basis. 
 
To ensure the quality of clinical data across all subjects and sites, a clinical data management 
review will be performed on subject data received at the sponsor/designee.  During this review, 
subject data will be checked for consistency, omissions, and any apparent discrepancies. In 
addition, the data will be reviewed for adherence to the protocol and regulatory standards.  To 
resolve any questions arising from the clinical data management review process, data queries 
and/or site notifications will be created in the EDC system database for site resolution and 
closed by the sponsor/designee reviewer. 
 
3.B.iv Data Access 
During the conduct of the study, each investigative site can access all of its entered data, 
including complete audit information, through the Medidata Rave® System using a standard 
web browser.  At the completion of the study, each investigator will be required to sign an 
EDC memo attesting to the completeness and accuracy of the data for each subject at his/her 
site.  Also, each site will receive an archival copy on compact disc (CD) of the eCRFs, 


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representing all data entered for its subjects, in Adobe Acrobat (PDF) format.  The CDs can be 
accessed, search, and copied.  
 
4 
Trial Documents and Records Retention 
The investigator and designated staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for inspection 
at any time by representatives from the sponsor and/or applicable regulatory authorities.  
Elements include  but are not limited to:   the protocol with all amendments; Investigator’s 
Brochure with all amendments;  subject files containing completed eCRFs, original source 
documentation and informed consents;  correspondence to and from the sponsor, health 
authorities and IRB; investigator’s curricula vitae, license and financial disclosure; study 
monitor logs and reports; laboratory reference ranges and laboratory certifications; and 
pharmacy information pertaining to the accountability, handling and storage of the 
investigational product(s).   
 
Subject files and other source data must be kept for the maximum period of time permitted by 
the hospital, institution or private practice, or as specified below.  The study monitor must be 
consulted if the investigator wishes to assign the files to someone else, remove them to another 
location or is unable to retain them for the specified period. 
 
The investigator must retain trial records for the amount of time specified by applicable laws 
and regulations.  At a minimum, trial records must be retained for the amount of time specified 
by the Code of Federal Regulations, Title 21, Volume 5, which state that an investigator shall 
retain records required to be maintained under this part for a period of 2 years following the 
date a marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and FDA is notified.  All trial 
documents shall be made available if required by relevant health authorities.  The investigator 
should consult with the study monitor prior to discarding trial and/or subject files.  
 
Sponsor will retain all sponsor-required documentation pertaining to the trial for the lifetime 
of the product.  Archived data may be held on microfiche or electronic record, provided that a 
back-up exists and that a paper copy can be obtained from it, if required. 
 
The sponsor will post trial information, including the results, on public registries in which the 
sponsor participates (e.g., clinicaltrials.gov, a service of the United States National Institutes of 
Health).  The information on public registries may be transferred to other countries, as 
appropriate, for the uses described above. No subjects will be identified in this information.  
 
5 
FDA Financial Disclosure Requirement  
In connection with the clinical study described in the protocol, the investigator certifies that, if 
asked, the investigator will read and answer the Clinical Investigator Financial Disclosure 
Form truthfully and to the best of investigator’s ability.  Investigator also certifies that, if asked, 
the investigator will have any other applicable party(s) (e.g., sub-investigators) read and answer 
the Clinical Investigator Financial Disclosure Form as a condition of their participation in the 


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study.  
 
If the financial interests reported on the Clinical Investigator Financial Disclosure Form change 
during the course of the study or within one year after the last subject has completed the study 
as specified in the protocol, the investigator and the other applicable party(s) are obligated to 
inform the sponsor of such financial change.  
 
6 
Investigator Information 
The investigator agrees that the sponsor may store, in an electronic database, for sponsor’s 
ongoing and future processing and use, including for purposes of monitoring the conduct of 
this study and considering potential investigators for future studies, both administrative and 
qualitative information, including personal data (e.g., name, address, curriculum vitae, etc.), 
relating to the investigator’s conduct of the study.  The investigator further agrees that such 
information may be provided to FDA and/or other appropriate regulatory authority, consistent 
with sponsor’s obligations to same.  The investigator also agrees that the sponsor may post 
certain information concerning the investigator’s participation in the study (e.g., study site 
phone contact information and study site location) on public registries in which the sponsor 
participates (e.g., clinicaltrials.gov, a service of the United States National Institutes of Health).  
The information on public registries may be used to contact the investigator by prospective 
study subjects or referring physicians.  The information on public registries may be transferred 
to other countries, as appropriate, for the uses described above.  
 
 
 
 
 


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APPENDIX E:  CONFIDENTIALITY AND SECURITY OF PHARMACOGENOMICS 
RESEARCH  
 
 
 
 


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Confidential Subject Information for Pharmacogenomics Study 
All information in this trial will be treated as confidential.  The whole blood sample from 
randomized research subjects who have provided separate informed consent will be collected 
and sent to the sponsor (Tufts Center for Hemostasis and Thrombosis Research) for 
pharmacogenomics analysis. The sample will be labeled by the clinical site with the subject’s 
unique study identification number, the sample type code (i.e., PG), study time point and the 
date/time of collection. A corresponding eCRF will be entered by the clinical site and will 
contain certain standard subject identifiers that are normally collected in the course of this 
clinical trial, such as subject initials, subject study identification number, and date of birth. This 
will enable authorized study sponsor personnel to accurately track the collection, storage and 
processing of the blood sample. 
 
The sponsor, Tufts Center for Hemostasis and Thrombosis Research, will perform the DNA 
and RNA purification/extraction procedures and the subsequent genetic analysis utilizing the 
whole blood sample and derivative specimens (i.e., DNA and RNA). Upon receipt of the whole 
blood sample, the sponsor’s designated staff will enter the subject study identification number 
into a coded data base and assign a new identifier (genetic sample code) to each sample. This 
new identifier will be linked to the subject study identification number assigned to the subject. 
From that point on, the whole blood sample, its derivative specimens and any results from the 
genetic analysis will be labeled with the same genetic sample code for each subject. The 
genetic sample code or “key” will be stored separately from the subject’s eCRF and from the 
data resulting from the genetic analysis. This “key” will be maintained by the sponsor’s 
designated staff. The underlying clinical trial database for the study will be stored by the 
unique subject study identification number within the electronic data capture (EDC) system 
(i.e., Medidata Rave®) maintained by the sponsor and sponsor’s designee, RTI, International.   
The genetic research laboratory database will be stored according to the genetic sample code in 
a separate file (i.e., Microsoft Excel® spreadsheet) maintained by the sponsor. The sponsor will 
request certain clinical variables and outcomes collected during the entire course of the 
subject’s participation in the underlying trial (i.e., up to 90 days following study drug 
administration) from RTI at the time of data analysis.  The secure “key” will be used to match 
the genetic sample code to the original subject identification number to allow the sponsor to 
correlate the clinical variables and outcomes information collected during the course of the 
study (identified by unique subject identification number) with the information obtained from 
the genetic analysis (identified only by genetic sample code).  The genetic research laboratory 
data will not be merged into the main clinical trial database and the personal identifying 
information from the clinical trial database will not be sent to the sponsor by RTI.   The “key” 
could potentially be utilized to reconstruct the link between genetic information and 
identifiable clinical information, under other specific circumstances- verification of data 
accuracy, request for sample/specimen(s) destruction by the investigator on behalf of the 
subject or as mandated by regulatory authorities.  
 
The “key” will be destroyed at the conclusion of the pharmacogenomics study, after the clinical 
information has been associated with the subjects’ genetic sample code.  Once this “key” is 
destroyed, the sample/specimen(s) and associated data derived from the genetic analyses of 
these sample/specimen(s) will be rendered anonymous and it will be impossible to identify any 


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specific individual subject’s sample/specimen(s) and/or associated data.  
 
Genetic analysis utilizing the DNA and RNA sample/specimen(s) will be performed by the 
sponsor and may be performed at one of the participating clinical trial sites designated by the 
sponsor if expertise in a particular genetic/genetic expression test is indicated.  The 
pharmacogenomics sample/specimen(s) will not be used by investigators other than those 
conducting the original research protocol (main study), and will not be subjected to testing 
outside the stated purpose and objectives of the original research protocol (See Section 
6.7.3.1), and will not be disseminated to other researchers who are not part of the original 
protocol. If applicable, sample/specimen(s) shipped by the sponsor to a clinical trial site will be 
identified only by the genetic sample code.  If required for analysis, the sponsor may provide 
the clinical trial site with the clinical trial data set identified only by the genetic sample code.  
The clinical trial site will not have access to the “key” to link the genetic sample code to the 
individual’s identifiers.   Any sample/specimen(s) remaining with the clinical trial site after the 
genetic analysis has been performed will be returned to the sponsor or destroyed.  
 
The informed consent form will be kept under secure storage at the clinical site for regulatory 
purposes and cannot be traced to any samples, test results, or medical information once the 
specimens have been rendered anonymous.  Laboratory personnel performing the genetic 
testing will not have access to the informed consent document or the clinical trial database, nor 
will they be able to identify subjects from the coded sample/specimen(s). Sample/Specimen(s) 
will be identified to the laboratory staff only by the genetic sample code. Subjects who decline 
to sign the informed consent for the optional pharmacogenomics study will not have the whole 
blood sample collected, nor will they be excluded from participating in the underlying clinical 
trial. 
 
Withdrawal from Pharmacogenomics Study 
Subjects may withdraw their consent for the pharmacogenomics sample/specimen(s) to be 
archived for subsequent testing at any time. Subjects may request from the local principal 
investigator (in writing or by telephone) that their sample/specimen(s) be destroyed and the 
investigator will notify the sponsor. Sample/Specimen(s) which have not already been analyzed 
will be destroyed in a manner documented and prescribed by the sponsor.   If applicable, the 
sponsor will contact the clinical site performing any genetic analysis and request that those 
sample/specimen(s) be destroyed if they have not already been used. Any genetic or genetic 
expression data and clinical data that have been rendered from the sample/specimen(s) up until 
the time of the subject’s documented informed consent withdrawal will be utilized in the 
study’s analysis.  
 
Retention of Samples and Data  
The archived pharmacogenomics sample/specimen(s) (whole blood sample, DNA and RNA 
derivatives) will be analyzed within 15 years from the end of the underlying clinical trial (i.e., 
when the final subject completes the main study protocol), and then destroyed in a manner 
documented and prescribed by the sponsor.  It is possible that the sample/specimen(s) may be 
exhausted prior to that point in time.  
 


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It is anticipated that the data generated from the pharmacogenomics study will be retained by 
the sponsor for an indefinite period of time.  
 
Data Security 
The pharmacogenomics research database will be accessible only to authorized sponsor research 
personnel and/or designated collaborators, and will be stored and accessible by the genetic 
sample code.   Until the “key” is destroyed, there exists a means to decipher the genetic code 
which would enable linkage of the data to the identity and private information of the subject.   
However, this could only be achieved if an individual possessed both the “key” and the access 
to the underlying clinical trial database. This is limited to two designated staff members at the 
sponsor site. 
 
These data are collected for pharmacogenomics research purposes only as specified in Section 
6.7.3.1, and will not be used for any other purpose without explicit consent form the research 
subject.  
 


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APPENDIX F:  SUGGESTED MODEL INFORMED CONSENT DOCUMENT