Conditions: Thrombosis
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 21
Healthy volunteers: yes

Brief summary:
The purpose of this study is to assess the safety, tolerability and pharmacodynamics of a single iv dose of E-WE Thrombin in healthy adult subjects.

Detailed description:

Arms:
arm 1: Participants will receive a single intravenous dose of 0.5 mcg/kg E-WE Thrombin. arm 2: Participants will receive a single intravenous dose of 1.0 mcg/kg E-WE Thrombin. arm 3: Participants will receive a single intravenous dose of 2.0 mcg/kg E-WE Thrombin. arm 4: Participants will receive a single intravenous dose of 4.0 mcg/kg E-WE Thrombin. arm 5: Participants will receive a single intravenous dose of placebo.

Interventions: intervention 1: E-WE Thrombin- Dose 1 intervention 2: E-WE Thrombin- Dose 2 intervention 3: E-WE Thrombin- Dose 3 intervention 4: E-WE Thrombin- Dose 4 intervention 5: Placebo
Intervention descriptions: intervention 1: Participants received a single intravenous dose of 0.5 mcg/kg E-WE Thrombin. intervention 2: Participants received a single intravenous dose of 1.0 mcg/kg E-WE Thrombin. intervention 3: Participants received a single intravenous dose of 2.0 mcg/kg E-WE Thrombin. intervention 4: Participants received a single intravenous dose of 4.0 mcg/kg E-WE Thrombin. intervention 5: Participants received a single intravenous dose of placebo.

Protocol document:
Prot_001.pdf: 
 
CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
 
 
 
 
 
 
 
Celerion Project No.:  CA19169 
 
Sponsor Project No.:  EWE-17-01 
 
US PIND No.:  PTS #PS003017; CRMTS #10353  
  
A Phase 1, Single Ascending Dose, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of E-WE Thrombin 
as an Intravenous Bolus in Healthy Adult Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
GCP Statement 
This study is to be performed in full compliance with the protocol, Good Clinical Practices 
(GCP), and applicable regulatory requirements. All required study documentation will be 
archived as required by regulatory authorities. 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Aronora Inc., and/or 
Celerion. Any viewing or disclosure of such information that is not authorized in writing by 
Aronora Inc., and/or Celerion is strictly prohibited. Such information may be used solely for 
the purpose of reviewing or performing this study. 


E-WE Thrombin 
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Sponsor Project No.:  EWE-17-01 
SAD Study Protocol 
Celerion Project No.:  CA19169 
Aronora Inc. 
US PIND No.:  PTS #PS003017; CRMTS #10353 
 
CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
1. 
PROTOCOL REVISION HISTORY 
DATE/NAME 
DESCRIPTION 
14May2018 
by Caroline Engel 
Final Protocol, Amendment 2: 
Following on FDA recommendations, the following changes were 
made to the protocol: 
1. The dosing interval between the sentinel group and the 
remaining subjects was revised to at least 28 days in Cohort 1 
and 14 days in the remaining cohorts. The protocol was updated 
throughout to reflect this change. 
2. The following study stopping rules were added to bullet 
number 5 in Section 10.4.1.4 Dose Escalation and Stopping 
Rules: 
I.  ≥ 1 subject that receive drug in a cohort experience: 
a. Life-threatening hypersensitivity reactions (e.g., 
anaphylaxis, respiratory symptoms, hypotension etc.). 
b. Any grade thromboembolic event possibly related to the 
study drug. 
c. Any grade bleeding possibly related to the study drug. 
d. Presence of antibodies against human thrombin or 
prothrombin. 
e. Presence of ADA. 
In addition, for clarification purposes, the second to last 
paragraph of this section was corrected to read (added text in 
bold and deleted text in strickthrough): 
Safety aPTT, PT, thrombin time, and ADA (Day 14 only and 
mixing study if applicable) data from a cohort will be needed 
for a dose escalation decision. If aPTT and thrombin time are 
elevated at Day 14, a mixing study will be performed. If the 
mixing study does not normalize the aPTT and/or thrombin 
time, dose escalation will be postponed until ADA data is 
available. If either ADA assay are confirmed to be positive, 
the study will be stopped according to the dose escalation 
and stopping rules outlined above. APC-PCI complex level 
data will not be needed for a dose escalation decision. 
3. More intensive vital signs monitoring will be performed in the 
first few hours after dosing. Section 6 Study Envent Flow Chart 
was updated accordingly. 


E-WE Thrombin 
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Sponsor Project No.:  EWE-17-01 
SAD Study Protocol 
Celerion Project No.:  CA19169 
Aronora Inc. 
US PIND No.:  PTS #PS003017; CRMTS #10353 
 
CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
DATE/NAME 
DESCRIPTION 
4. If aPTT and/or thrombin time values do not reach ± 10% of the 
baseline value or within the normal range by Day 14, sampling 
will continue every 7 days (± 2 days) until the ± 10% of 
baseline value or the normal range is reached. Subjects will 
return for a FU visit (i.e., follow-up procedures and AE 
evaluation listed on Day 28 will be repeated) 7 days (± 2 days) 
after aPTT and thrombin time values reach ±10% of the 
baseline value or within the normal range. The protocol was 
updated throughout to reflect this change. 
5. To be consistent with the Coagulation panel, “Fibrinogen” was 
added to the list in the Coagulation row in Section 6 Study 
Event Flow Chart. 
In addition, the following updates were made: 
6. The last sentence of the 4th paragraph in Section 10.4.3 Method 
of Assigning Subjects to Treatment Groups, was corrected for 
cnsistency troughout the protocol to read (added text in bold 
and deleted text in strickthrough): 
For Cohorts 2-4, tThe placebo will be randomized to either 
group. 
7. The name of the IRB was changed from Chesapeake IRB to 
Advarra. Section 13.1.1 Institutional Review Board was 
updated. 
8. Typographical and formating edits were performed throughout 
the protocol. 
27Mar2018 
by Tamara Moore 
Final Protocol, Amendment 1: 
This protocol was amended to correct a mathematical discrepancy 
in the total blood volume being drawn in this study. 
In Section 11.4 – Table 3: the frequency of blood draws and 
individual blood draw volumes were correct however, the total 
blood volumes (number of timepoints multiplied by volume drawn) 
was incorrect for the following rows: 
1) “On-study coagulation (aPTT, PT/INR, fibrinogen, and, if 
scheduled at the same time, thrombin time)”, the volume 
was decreased from 38.5 to 35 mL. 
2) “Blood for APC-PCI (Celerion)”, the volume was increased 
from 24 mL to 32 mL. 
3) Therefore the sum of all blood volumes, indicated in the 
rwo “Total Blood Volumes” was increased from 177.8 mL 


E-WE Thrombin 
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Sponsor Project No.:  EWE-17-01 
SAD Study Protocol 
Celerion Project No.:  CA19169 
Aronora Inc. 
US PIND No.:  PTS #PS003017; CRMTS #10353 
 
CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
DATE/NAME 
DESCRIPTION 
to 182.3 mL. 
In addition to the change above the reference list was updated to 
remove an extraneous reference Chow et al., 1992 and Gough K., et 
al., 1995. 
19Feb2017  
by Tamara Moore 
Final  
 


E-WE Thrombin 
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Sponsor Project No.:  EWE-17-01 
SAD Study Protocol 
Celerion Project No.:  CA19169 
Aronora Inc. 
US PIND No.:  PTS #PS003017; CRMTS #10353 
 
CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
2. PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES 
 
A Phase 1, Single Ascending Dose, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of E-WE Thrombin 
as an Intravenous Bolus in Healthy Adult Subjects 
 
 
SPONSOR: 
Aronora, Inc.  
4640 SW Macadam Avenue, Suite 200A  
Portland, Oregon 97239, USA 
Tel.:  +1 503 964-0250 
 
SPONSOR’S  
REPRESENTATIVE: 
 
Norah Verbout, PhD 
Senior Scientist 
4640 SW Macadam Avenue, Suite 200A  
Portland, Oregon 97239, USA 
Tel.:  +1 503 964-0250 
E-mail:  norah.verbout@aronorabio.com 
 
 
 
 
 
Signature 
 Date 
CELERION PRINCIPAL INVESTIGATOR 
AND CLINICAL SITE: 
 
2420 West Baseline Road 
Tempe, Arizona 85283, USA 
Tel.:  +1 602 437-0097 
Fax:  +1 602 437-3386  
 
 
 
 
Signature 
 Date 
 
 
 
 
  
 
Printed Name 
 


E-WE Thrombin 
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Sponsor Project No.:  EWE-17-01 
SAD Study Protocol 
Celerion Project No.:  CA19169 
Aronora Inc. 
US PIND No.:  PTS #PS003017; CRMTS #10353 
 
CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
3. ADDITIONAL KEY CONTACTS FOR THE STUDY 
Sponsor Contact for Serious 
Adverse Events 
Andras Gruber, MD 
President and CEO  
4640 SW Macadam Avenue, Suite 200A  
Portland, Oregon 97239, USA  
Tel.:  +1 503 530-6842 
Mobile:  +1 503 442-1213 
Fax:  +1 503 389-7330 
E-mail:  andras.gruber@aronorabio.com 
Celerion Protocol Author 
Tamara Moore, MSc 
Scientist I, Protocol Design & Development 
Celerion 
100 Alexis-Nihon Boulevard, Suite 360 
Montreal, Quebec H4M 2N8, Canada 
Tel.:  +1 514 744-8745 
Fax:  +1 514 744-8700 
E-mail:  tamara.moore@celerion.com 
Certified Clinical Laboratory for 
Safety and aPPT/PT 
Pharmacodynamic Samples 
Celerion 
2420 West Baseline Road 
Tempe, Arizona 85283, USA 
Contact: Ed Gritzfeld 
Tel.:  +1 602 437-0097 ext. 67172 
Fax:  +1 602 437-3386 
Bioanalytical Laboratory for 
APC-PCI samples 
Celerion 
621 Rose Street 
Lincoln, Nebraska 68502, USA 
Tel.:  +1 402 476-2811 
Fax:  +1 402 939-0428 
Immunogenicity Testing 
Laboratory 
 
Haemtech Biopharma Services, Inc. 
57 River Road, Unit 1010 
Essex Junction, Vermont 05452, USA 
Tel.:  +1 802 878-1777 
Fax:  +1 802 878-1776 


E-WE Thrombin 
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Sponsor Project No.:  EWE-17-01 
SAD Study Protocol 
Celerion Project No.:  CA19169 
Aronora Inc. 
US PIND No.:  PTS #PS003017; CRMTS #10353 
 
CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
Pharmacodynamic and Statistical 
Analyses  
Celerion 
100 Alexis-Nihon Boulevard, Suite 360 
Montreal, Quebec H4M 2N8, Canada 
Tel.:  +1 514 744-9090 
Fax:  +1 514 744-8700 
and/or 
621 Rose Street 
Lincoln, Nebraska 68502, USA 
Tel.:  +1 402 476-2811 
Fax:  +1 402 476-7598 
 


E-WE Thrombin 
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Sponsor Project No.:  EWE-17-01 
SAD Study Protocol 
Celerion Project No.:  CA19169 
Aronora Inc. 
US PIND No.:  PTS #PS003017; CRMTS #10353 
 
CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
4. TABLE OF CONTENTS 
1. PROTOCOL REVISION HISTORY ............................................................................2 
2. PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES ..........................5 
3. ADDITIONAL KEY CONTACTS FOR THE STUDY ...............................................6 
4. TABLE OF CONTENTS ...............................................................................................8 
5. SYNOPSIS ...................................................................................................................12 
6. STUDY EVENTS FLOW CHART .............................................................................17 
7. ABBREVIATIONS .....................................................................................................20 
8. BACKGROUND AND RATIONALE ........................................................................22 
8.1 
Introduction ........................................................................................................22 
8.2 
Background ........................................................................................................22 
8.2.1 
Preclinical Trials ..................................................................................22 
8.2.2 
Pharmacology ......................................................................................23 
8.2.3 
Pharmacokinetics .................................................................................23 
8.2.4 
Pharmacodynamics ..............................................................................23 
8.2.5 
Toxicology ...........................................................................................24 
8.3 
Rationale .............................................................................................................24 
8.3.1 
Purpose of the Study ............................................................................24 
8.3.2 
Dose Selection .....................................................................................24 
8.3.3 
Rationale for PD Markers ....................................................................25 
8.4 
Risk/Benefit ........................................................................................................25 
9. STUDY OBJECTIVES AND ENDPOINTS ...............................................................26 
9.1 
Study Objectives ................................................................................................26 
9.2 
Study Endpoints .................................................................................................26 
10. INVESTIGATIONAL PLAN ......................................................................................27 
10.1 Overall Study Design and Plan ..........................................................................27 
10.1.1 
Confinement, Return Visits, and Follow-Up .......................................27 
10.1.2 
Study Duration .....................................................................................28 
10.2 Study Conduct ....................................................................................................28 
10.2.1 
Screening..............................................................................................28 
10.2.2 
Check-in Procedures (Day -1) .............................................................28 
10.2.3 
Treatment Period (Day 1 to Day 2)......................................................28 
10.2.3.1 Single-dose Administration (Day 1) and Study Procedures 
(Days 1 to 2) ........................................................................28 
10.2.3.2 Meal Schedule .....................................................................29 


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US PIND No.:  PTS #PS003017; CRMTS #10353 
 
CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
10.2.4 
Follow-up Visits (Day 14 and 28) .......................................................29 
10.2.5 
Scheduled End of Study .......................................................................30 
10.3 Selection of Study Population ............................................................................30 
10.3.1 
Number of Subjects..............................................................................30 
10.3.2 
Inclusion Criteria .................................................................................30 
10.3.3 
Exclusion Criteria ................................................................................31 
10.3.4 
Early Termination of Subjects from the Study ....................................34 
10.3.5 
Study Restrictions ................................................................................34 
10.3.5.1 Prohibitions and Concomitant Therapy ..............................34 
10.3.5.2 Activity ................................................................................35 
10.4 Treatments ..........................................................................................................35 
10.4.1 
Treatments Administered .....................................................................35 
10.4.1.1 Drug Administration ...........................................................35 
10.4.1.2 Planned Dose Levels ...........................................................36 
10.4.1.3 Additional Dose Levels .......................................................37 
10.4.1.4 Dose Escalation and Stopping Rules ..................................37 
10.4.2 
Identity of Investigational Products .....................................................38 
10.4.3 
Method of Assigning Subjects to Treatment Groups ...........................39 
10.4.4 
Blinding................................................................................................39 
10.4.4.1 Maintenance of Randomization ..........................................39 
10.4.4.2 Procedures for Breaking the Blind Prior to Study 
Completion ..........................................................................40 
10.4.4.3 Interim Analysis ..................................................................40 
10.4.4.4 Revealing of Randomization ...............................................40 
10.4.5 
Treatment Compliance .........................................................................41 
11. STUDY PROCEDURES .............................................................................................42 
11.1 Safety Assessments ............................................................................................42 
11.1.1 
Body Height and Weight .....................................................................42 
11.1.2 
Physical Examination and Medical History .........................................42 
11.1.3 
Vital Signs ............................................................................................42 
11.1.3.1 Safety 12-Lead ECGs ..........................................................43 
11.1.4 
Clinical Laboratory Tests .....................................................................44 
11.1.5 
Check-In Questionnaire .......................................................................44 
11.1.6 
Injection Site Reaction Assessment .....................................................45 
11.1.7 
Immunogenicity ...................................................................................45 
11.1.7.1 Blood Sampling and Processing for Immunogenicity ........45 
11.1.7.2 Analytical Method ...............................................................46 


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Celerion Project No.:  CA19169 
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US PIND No.:  PTS #PS003017; CRMTS #10353 
 
CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
11.1.8 
Adverse Events ....................................................................................46 
11.1.8.1 Adverse Event Definition ....................................................46 
11.1.8.2 Monitoring ..........................................................................46 
11.1.8.3 Reporting .............................................................................47 
11.1.8.4 Serious Adverse Events.......................................................48 
11.2 Pharmacodynamic Assessment – APC-PCI .......................................................49 
11.2.1 
Blood Sampling and Processing ..........................................................49 
11.2.2 
Analytical Method ...............................................................................49 
11.3 Pharmacodynamic Assessments – Real-Time aPTT and protein C ...................49 
11.3.1 
Blood Sampling and Processing ..........................................................49 
11.3.2 
Analytical Method ...............................................................................49 
11.4 Blood Volume for Study Assessments ...............................................................50 
12. DATA ANALYSIS ......................................................................................................51 
12.1 Statistical Analysis .............................................................................................51 
12.1.1 
Sample Size Calculation ......................................................................51 
12.1.2 
Subjects to Analyze..............................................................................51 
12.1.3 
Safety Analysis ....................................................................................51 
12.2 Pharmacodynamics .............................................................................................52 
12.2.1 
Pharmacodynamic Parameters .............................................................52 
12.2.2 
Statistical Methods for Pharmacodynamic Analyses ...........................52 
12.3 Assessment of Pharmacokinetics .......................................................................52 
13. STUDY ADMINISTRATION.....................................................................................53 
13.1 Ethics ..................................................................................................................53 
13.1.1 
Institutional Review Board ..................................................................53 
13.1.2 
Ethical Conduct of the Study ...............................................................53 
13.1.3 
Subject Information and Consent.........................................................53 
13.2 Termination of the Study ....................................................................................53 
13.3 Data Quality Assurance ......................................................................................53 
13.4 Direct Access to Source Data/Documents .........................................................54 
13.5 Study Supplies ....................................................................................................54 
13.6 Data Handling and Record Keeping ...................................................................54 
13.7 Report Format ....................................................................................................55 
13.8 Protocol Amendments ........................................................................................55 
13.9 Publication Policy ..............................................................................................55 
14. REFERENCES ............................................................................................................56 
 


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SAD Study Protocol 
Celerion Project No.:  CA19169 
Aronora Inc. 
US PIND No.:  PTS #PS003017; CRMTS #10353 
 
CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
LIST OF TABLES 
 
Table 1: 
Dosing Duration .............................................................................................. 36 
Table 2: 
Product Descriptions ....................................................................................... 39 
Table 3: 
Blood Volume during the Study ..................................................................... 50 
 
 
 


E-WE Thrombin 
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SAD Study Protocol 
Celerion Project No.:  CA19169 
Aronora Inc. 
US PIND No.:  PTS #PS003017; CRMTS #10353 
 
CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
5. SYNOPSIS 
Compound 
E-WE thrombin 
Active ingredient: E-WE thrombin (0.1 mg/mL) 
Buffer: 16.2 mM sodium citrate, 3.8 mM citric acid, 150 mM 
sodium chloride, 0.1% polysorbate 80, at pH 6  
Clinical Indication 
Prevention and treatment of arterial thrombosis and 
thromboembolism 
Study Phase and Type Phase 1, single ascending dose (SAD) study, first-in-human study 
Study Objectives 
The primary objective of the study is to assess the safety and 
tolerability of single intravenous (IV) bolus doses of E-WE 
thrombin when administered to healthy adult subjects. 
The secondary objective is to assess the pharmacodynamics (PD) 
of single IV bolus doses of E-WE thrombin when administered to 
healthy adult subjects. The activated protein C/protein C inhibitor 
complex (APC-PCI) will be used as a surrogate biomarker for 
drug exposure. 
Study Design 
This is a randomized, double-blind, placebo-controlled, SAD 
study conducted at one study center in the United States (US). 
Four (4) cohorts of either 6 subjects (Cohort 1 [4 active and 
2 placebo]) or 5 subjects (Cohorts 2, 3, and 4 [4 active and 
1 placebo]) are planned for evaluation. In each cohort, subjects 
will receive a single IV bolus of E-WE thrombin or placebo. 
Subjects will participate in only 1 cohort.  
Two (2) sentinel subjects will be dosed (1 placebo and 1 active) 
in Cohort 1 and data will be collected through Day 28. The 
remaining subjects in the cohort will be dosed after evaluation of 
the sentinel subjects’ Day 28 safety data and will be dosed in 
2 groups separated by at least 14 days (2 subjects in the first 
group and 2 subjects in the second group). The placebo will be 
randomized to either group. 
The Cohorts 2, 3, and 4 will be dosed in 2 groups separated by at 
least 14 days (2 subjects in the first group and 3 subjects in the 
second group). The placebo will be randomized to either group.  
Safety (i.e., physical examinations, vital signs, 
electrocardiograms (ECGs), clinical laboratory tests [including 
coagulation], thrombin time, immunogenicity, injection site 
reaction, and adverse events [AEs]) will be assessed throughout 
the study. 


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SAD Study Protocol 
Celerion Project No.:  CA19169 
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US PIND No.:  PTS #PS003017; CRMTS #10353 
 
CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
Blood samples will be collected for PD assessment (i.e., 
APC-PCI) of E-WE thrombin at scheduled time points listed in 
the Study Events Flow Chart (Section 6) predose and for 24 hours 
postdose.  
Dose escalation to the next dose level (i.e., next cohort) will not 
take place until after the Principal Investigator (PI) has reviewed 
the safety data and informed the Sponsor of the findings. If any 
findings in the safety data are of concern, then the Safety Review 
Committee (SRC) comprised of but not limited to, the Sponsor, 
medical monitor, and the PI will convene to determine if adequate 
safety and tolerability from the previous cohorts, including 
activated partial thromboplastin time (aPTT), has been 
demonstrated to permit proceeding to the next cohort. 
For each cohort, 14 days of safety data will be used and reviewed 
for a dose escalation decision. Data from all subjects in the 
appropriate cohort will be used and reviewed for a dose 
escalation decision. aPTT and thrombin time should be in the 
normal range (unless it is still within ± 10% of individual’s 
baseline value taken at check-in) at Day 14 to rule out early 
cross-reacting antibodies to thrombin/prothrombin. A minimum 
of 4 subjects in each cohort must complete the study (up to 
Day 14) before proceeding to the next higher dosing cohort. 
Subjects dosed on the same day will be dosed with an interval of 
at least 1 hour between subjects. 
Subjects (including those who terminate early) will return on 
Days 14 and 28 for follow-up procedures (coagulation sample 
collection, thrombin time measurement, and immunogenicity 
sample collection) and to determine if any AE has occurred since 
the last study visit. If thrombin time and/or aPTT are found to be 
elevated beyond normal range (unless it is still within ± 10% of 
individual’s baseline value at check-in) at Day 14, both tests will 
be repeated. If aPTT and/or thrombin time are elevated beyond 
normal range in the retest, a mixing study will be performed. The 
mixing study will be performed on Day 14 by mixing the 
subjects’ plasma 1:1 with normal human pooled plasma. aPTT 
and thrombin time will be evaluated. If the aPTT and/or thrombin 
time does not correct to normal range, the presence of anti-drug 
antibodies (ADA) and cross-reacting prothrombin/thrombin 
antibodies will be presumed, and will be directly assessed before 
dose escalation decision.  
Subjects who terminate the study early will be asked to continue 
aPTT and thrombin time monitoring as scheduled until Day 28. 
Any subjects for whom aPTT and/or thrombin time did not reach 


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Celerion Project No.:  CA19169 
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US PIND No.:  PTS #PS003017; CRMTS #10353 
 
CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
± 10% of the baseline value or within the normal range by 
Day 14, will return every 7 days (±2 days) until aPTT and 
thrombin time reach ±10% of the baseline value or within the 
normal range and for a FU visit (i.e., follow-up procedures and 
AE evaluation listed on Day 28 will be repeated) 7 days 
(± 2 days) after it was reached. 
Study Population 
Subjects will be healthy male subjects and healthy female 
subjects of non-childbearing potential. 
Number of Subjects 
The study is planned to enroll up to 21 subjects in 4 cohorts 
[i.e., dose levels] with 6 subjects in Cohort 1 [4 subjects 
randomized to receive the active drug and 2 subjects to receive 
the placebo] and 5 subjects in Cohort 2, 3, and 4 [4 subjects 
randomized to receive the active drug and 1 subject to receive the 
placebo]. 
In each cohort, an attempt will be made to have at least 30% of 
the subjects be of a race/ethnicity minority group. An attempt will 
be made to include at least 2 females in each cohort. 
Additional subjects (up to 6 subjects per cohort) may be enrolled 
if it is deemed appropriate by the PI and the Sponsor to repeat a 
dose level or to study an intermediate dose level (lower than those 
planned) in a new cohort of subjects. 
Duration of 
Participation for 
Subjects 
The total planned duration of subject participation is 
approximately 56 days from screening to last visit, with clinical 
research unit (CRU) confinement from check-in on Day -1 to 
Day 2. Subjects will return to the CRU on Day 14 and Day 28 for 
follow-up procedures. 
Study Products 
E-WE thrombin will be supplied as sterile, non-pyrogenic, 
preservative-free liquid for IV administration. 
E-WE thrombin will be supplied as 0.1 mg/mL for IV use and 
given as a single IV bolus, according to the planned dose 
(mcg/kg) for each cohort, as noted below. 
Matching placebo will be supplied as sterile formulation buffer 
for injection via IV route. 
An unblinded pharmacist will be responsible for providing E-WE 
thrombin or placebo to the blinded study personnel for IV bolus 
administration. 
Planned Dose Levels 
On Day 1, subjects in each cohort will receive an IV bolus over 
15 seconds up to 1 minute of E-WE thrombin or matching 
placebo on one occasion. 
Planned doses will be as follows: 


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SAD Study Protocol 
Celerion Project No.:  CA19169 
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US PIND No.:  PTS #PS003017; CRMTS #10353 
 
CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
Cohort 1: 0.5 mcg/kg E-WE thrombin or matching placebo 
Cohort 2: 1.0 mcg/kg E-WE thrombin or matching placebo 
Cohort 3: 2.0 mcg/kg E-WE thrombin or matching placebo 
Cohort 4: 4.0 mcg/kg E-WE thrombin or matching placebo 
Dosing will not exceed 4.0 mcg/kg without a protocol 
amendment. 
Safety Assessments 
Safety will be monitored through vital signs, ECGs, clinical 
laboratory tests (including, but not limited to, hematology, serum 
chemistry profile, coagulation, and urinalysis), immunogenicity, 
injection site reaction, and AEs. 
Safety Analysis 
No formal inferential statistics will be done on safety 
assessments. 
The placebo subjects from all cohorts will be pooled into a single 
placebo group for all summaries and presentations. 
Descriptive statistics will be calculated for quantitative safety 
data and frequency counts will be compiled for classification of 
qualitative safety data, as appropriate. 
Adverse Events: 
AEs will be coded using the most current version of Medical 
Dictionary for Regulatory Activities® (MedDRA®) available at 
Celerion. 
A by-subject AE data listing, including verbatim term, preferred 
term, treatment, severity, and relationship to drug, will be 
provided. 
The number of subjects experiencing treatment-emergent adverse 
events (TEAEs) and number of TEAEs will be summarized by 
treatment using frequency counts. 
Injection site reaction will be assessed.  
Medical History and Physical Examination: 
Medical history will be listed by subject. 
Changes in physical examinations will be described in the text of 
the final report. 
Clinical Laboratory Results, Electrocardiograms, and Vital 
Signs Measurements: 
All clinical laboratory results (including coagulation), 12-lead 
ECGs, vital signs measurements, and their change from baseline, 
will be summarized by dose level and time point of collection. 
A shift table describing out-of-normal range shifts will be 


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provided for clinical laboratory results. 
Thrombin time will be assessed. 
Concomitant Medications: 
Concomitant medications will be listed by subject.  
Immunogenicity: 
ADA detection will be reported and summarized descriptively. 
Pharmacodynamic 
Sample Collection 
Serial blood samples will be collected prior to and for 24 hours 
following the dose on Day 1 to determine APC-PCI levels, which 
will be performed by Celerion. The Sponsor will assess the 
real-time aPTT on-site, and also evaluate protein C. 
The sampling schedule may be modified based on the results 
from previous cohorts. 
Pharmacodynamic 
Analysis 
APC-PCI values will be listed and presented graphically.  
 
 


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6. STUDY EVENTS FLOW CHART 
Study Procedures a 
Scr b 
Study Days in Each Cohort c 
FU d 
Days → 
-1 
1 
2 e 
14  
28 
Hours → 
C-I f 
P 
0 
0.083 
0.25 
0.5 
1 
2 
4 
24 
 
 
Administrative Procedures 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations 
Full Physical Examination g 
x 
  
 
 
 
 
 
 
 
 
 
 
 
Injection Site Assessments  
 
 
x 
 
 
 
 
x 
 
 
x 
 
 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (heart rate, blood pressure, respiratory 
rate and temperature) 
x 
 
x h 
 
 
x 
x 
x 
x 
x 
x 
 
 
Safety 12-Lead Electrocardiogram 
x 
 
x h 
 
 
 
 
 
 
 
x 
 
 
Hem, Serum Chem i, and UA  
x 
x 
 
 
 
 
 
 
 
 
x 
 
 
Coagulation (Fibrinogen, aPTT j, and PT/INR) 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Thrombin Time j 
 
x 
 
 
 
 
 
 
 
 
 
x 
x 
Serum Pregnancy Test (females only) 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH (postmenopausal females only) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Alcohol and Drug Screen 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis Screen 
x 
 
 
 
 
 
 
 
 
 
 
 
 
AE Monitoring 
 
x 
Concomitant Medication Monitoring 
x 
x 
 
 
Study Drug Administration / Pharmacodynamics 
E-WE Thrombin Administration k 
 
 
 
x 
 
 
 
 
 
 
 
 
 
Blood for PD: Plasma for APC-PCI  
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 


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Study Procedures a 
Scr b 
Study Days in Each Cohort c 
FU d 
Days → 
-1 
1 
2 e 
14  
28 
Hours → 
C-I f 
P 
0 
0.083 
0.25 
0.5 
1 
2 
4 
24 
 
 
Other Procedures 
Plasma and Serum Immunogenicity l 
 
x 
 
 
 
 
 
 
 
 
 
x 
x 
Blood for protein C (Aronora)  
 
 
x 
 
 
 
 
x 
x 
 
x 
 
 
Blood for Real-Time aPTT (Aronora) 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Confinement in the CRU 
 
x 
 
 
Visit and Return Visits 
x 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
a 
For details on Procedures, refer to Section 11. 
b 
Within 28 days prior to study drug administration. 
c 
Cohort 1 will include a sentinel group of 2 subjects randomized in a 1:1 ratio for active to placebo who will be dosed at least 28 days before the remaining subjects. 
The remaining subjects in Cohort 1 will be dosed in two groups separated by at least 14 days (2 subjects in the first group and 2 subjects in the second group). The 
Cohorts 2, 3, and 4 will be dosed in two groups separated by at least 14 days (2 subjects in the first group and 3 subjects in the second group). The placebo will be 
randomized to either group. 
d 
Subjects (including those who terminate early) will return on Days 14 and 28 for follow-up procedures (coagulation sample collection, thrombin time measurement, 
and immunogenicity sample collection) and to determine if any AE has occurred since the last study visit. Subjects who terminate the study early will be asked to 
continue aPTT and thrombin time monitoring as scheduled until Day 28.  
Any subjects for whom aPTT and/or thrombin time did not reach ± 10% of the baseline value or within the normal range by Day 14, will return every 7 days 
(±2 days) until aPTT and thrombin time reach ±10% of the baseline value or within the normal range and for a FU visit (i.e., follow-up procedures and AE evaluation 
listed on Day 28 will be repeated) 7 days (± 2 days) after it was reached. 
e 
To be performed prior to discharge from the CRU or prior to early termination from the study. 
f 
Subjects will be admitted to the CRU on Day -1, at the time indicated by the CRU. 
g 
Full physical examination will be performed at screening. A symptom-driven physical examination may be performed at other scheduled times, at the PI’s or 
designee’s discretion. 
h 
To be performed within 24 hours prior to dosing. 
i 
Samples for serum chemistry will be obtained following a fast of at least 8 hours, however, in case of dropouts or rechecks, subjects may not have fasted for 8 hours 
before the serum chemistry sample is taken. 
j 
If thrombin time and/or aPTT are found to be elevated at Day 14, both tests will be repeated. If aPTT and/or thrombin time are elevated beyond the normal range 
(unless it is still within ± 10% of individual’s baseline value at check-in) in the retest, a mixing study will be performed. The mixing study will be performed on Day 
14 by mixing the subjects’ plasma 1:1 with normal human pooled plasma. aPTT and thrombin time will be evaluated. If the aPTT and/or thrombin time do not 
correct to normal range, the presence of ADA cross-reacting prothrombin/thrombin antibodies will be presumed. The applicable subject will remain at the CRU until 


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these test results are obtained. Subjects for whom aPTT and/or thrombin time did not reach ± 10% of the baseline value or within the normal range by Day 14, will 
return every 7 days (±2 days) until aPTT and thrombin time reach ±10% of the baseline value or within the normal range. 
k 
Subjects in the sentinel group (Cohort 1 only) will be dosed at least 28 days prior to remaining subjects. The remaining subjects in Cohort 1 and subjects in the 
Cohorts 2, 3, and 4 will be dosed in two groups separated by at least 14 days. Dosing in each group will be staggered by at least 1 hour.  
l: 
Immunogenicity testing for ADA will be first performed on blood samples taken on Days 14 and 28. If ADA are found, the check-in sample of ADA will be 
evaluated.  
 
Abbreviations: ADA = Anti-drug antibodies, AE = Adverse event, APC-PCI = Activated protein C with protein C inhibitor, aPTT = Activated partial thromboplastin 
time, C-I = Check-in, Chem = Chemistry, CRU = Clinical research unit, FSH = Follicle-stimulating hormone, FU = Follow-up, Hem = Hematology, HIV = Human 
immunodeficiency virus, INR = International normalized ratio, PD = Pharmacodynamic, PI = Principal Investigator, PT = Prothrombin time, Scr = Screening, 
UA = Urinalysis. 


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7. ABBREVIATIONS 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
APC 
Activated protein C 
APC-PCI 
Activated protein C with protein C inhibitor 
aPTT 
Activated partial thromboplastin time 
BMI 
Body mass index 
bpm 
Beats per minute 
°C 
Degrees Celsius 
CFR 
Code of Federal Regulations 
cm 
Centimeter 
CRF 
Case report form 
CRU 
Clinical Research Unit 
ECG 
Electrocardiogram 
FDA 
Foods and Drug Administration 
FSH 
Follicle-stimulating hormone 
FU 
Follow-up  
g 
Gram 
GCP 
Good clinical practice 
GLP 
Good laboratory practice 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HED 
Human equivalent dose 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 


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kg 
Kilogram 
m2 
Meters squared 
mcg 
Microgram 
MedDRA® 
Medical Dictionary for Regulatory Activities® 
mg 
Milligram 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
msec 
Millisecond 
n 
Sample size 
No. 
Number 
ng 
Nanogram 
NOAEL 
No observed adverse effect level 
oz. 
Ounce 
PAR 
Protease activated receptors 
PD 
Pharmacodynamic(s) 
PI 
Principal Investigator 
PIND 
Pre-Investigational New Drug 
PK 
Pharmacokinetic(s) 
PT 
Prothrombin time 
QA 
Quality assurance 
QTcF 
Corrected QT interval using Friderica’s correction 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SRC 
Safety Review Committee 
TEAE 
Treatment-emergent adverse event 
US 
Unites States of America 
USA 
United States of America 
WT 
Wild type 
 


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8. BACKGROUND AND RATIONALE 
8.1 
Introduction 
This study is being conducted as the first in a series of studies for the clinical development of 
E-WE thrombin. The trial will be conducted in compliance with the protocol, GCP, and 
applicable regulatory requirements. The subject population will be comprised of healthy 
adult males and/or female (non-childbearing potential) subjects. 
E-WE thrombin is a recombinant antithrombotic protein C activator enzyme analog of human 
alpha thrombin that generates endogenous activated protein C (APC) on intravascular cell 
surfaces, while at pharmacological doses does not cleave fibrinogen or activate protease 
activated receptors (PARs) on platelets. Due to avid binding of E-WE to thrombin receptors, 
predominantly thrombomodulin and GPIb on cells, therapeutic doses of the active enzyme 
are likely cleared from the circulation in seconds to minutes. Free E-WE thrombin, if any, 
that is not associated with a thrombin receptor after the minimum effective dose, is unlikely 
to exhibit measurable pharmacological activity. 
E-WE thrombin was developed by Aronora, Inc. and is intended for single dose intravenous 
administration. The proposed indication for E-WE thrombin is arterial thrombosis and 
thromboembolism, including those associated with acute cerebrovascular accidents, acute 
coronary syndrome and other severe acute thrombus formation-associated ischemic events. 
A brief overview of available information regarding E-WE thrombin (AB002) follows below. 
Details can be found in the E-WE thrombin, AB002 Investigator’s Brochure of 29 March 
2017 [1]. 
8.2 
Background 
8.2.1 Preclinical Trials  
The molecular mechanism by which E-WE thrombin exerts its antithrombotic activity is the 
selective activation of endogenous plasma protein C under intravascular shear flow. 
Antithrombotic treatment with E-WE thrombin utilizes an endogenous targeting system via 
cell-surface associated thrombin receptors including, among others, thrombomodulin, 
glycoprotein Ib [2], and PARs, which are variably expressed on the luminal surfaces of blood 
vessels, platelets, and other cells. One of the putative mechanisms of action, in vivo, is 
binding of E-WE thrombin to circulating platelets, which deliver and concentrate E-WE 
thrombin on the thrombus, which is the site of desired pharmacological activity. At the 
thrombus interface, E-WE thrombin cleaves protein C, generating the potent endogenous 
antithrombotic and anti-inflammatory enzyme APC, thereby downregulating thrombin 
generation and interrupting thrombogenesis. APC exerts additional protective effects by 
upregulating cytoprotective mechanisms and promoting anti-apoptotic signaling through 
cleavage of the transmembrane receptors, such as PAR 1 and 3. 


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In both mice and primates, E-WE thrombin has potent antithrombotic effects, with 
concomitant hemostatic safety. The efficacy of E-WE thrombin has been established in 
several experimental models, including a mouse model of stroke [3], a mouse model of 
myocardial ischemia and reperfusion, and a well-established model of vascular graft 
thrombosis in baboons [4], alone and in combination with fibrinolysis. Importantly, while 
treatment with E-WE thrombin was efficacious in these experimental models, no 
demonstrable effect of E-WE thrombin on hemostasis was observed. These data indicate that, 
in contrast to currently marketed antithrombotics, which target elements of the coagulation 
cascade that participate in or are essential for both thrombosis and hemostasis, E-WE 
thrombin targets thrombosis without increasing bleeding. 
8.2.2 Pharmacology 
8.2.3 Pharmacokinetics 
Limited PK studies with E-WE thrombin have been performed in cynomolgus monkeys and 
in baboons. The PK assay used to detect active E-WE thrombin was only sensitive enough to 
detect high doses of E-WE thrombin (> 10 mcg/kg). The observed PK profile in theses 
animals closely mirrored the drug exposure PD biomarker assays (APC-PCI and aPTT), 
which were able to detect the magnitude and duration of action of E-WE thrombin. In blood, 
E-WE thrombin is inhibited by enzymatic interaction with serine protease inhibitors, and the 
reaction is accelerated by heparin. Therefore, it has been technically challenging to develop 
an ultrasensitive assay for the residual or trace free E-WE molecules that may have avoided 
binding or inhibition and remain circulating in plasma. Free E-WE thrombin does not exert 
demonstrable pharmacological, procoagulant, or platelet activating effects in fluid phase. 
8.2.4 Pharmacodynamics 
Injection of E-WE thrombin results in the temporal and selective generation of endogenous 
APC, and escape of some APC from the surface into the blood circulation. In the circulation, 
APC inactivates factor Va and factor VIIIa, resulting in a temporal prolongation of the aPTT. 
The activity of APC is regulated in part through its enzymatic interactions with serine 
protease inhibitors to form inactive enzyme inhibitor complexes, primarily APC-PCI and 
APC-antitrypsin complexes. The half-life of exogenous recombinant APC is 15 to 
25 minutes in blood, and data from baboons suggest that the half-life of endogenous APC is 
comparable. The rate of APC inhibition by PCI in plasma is significantly accelerated in the 
presence of heparin, and the APC-PCI complex is reported to have a half-life of 20 minutes 
in the circulation. 
In preclinical Study Report No. AB002.4, the APC-PCI complex was evaluated as a 
biomarker for E-WE thrombin activity in a baboon. The systemic effect of an IV bolus of 
E-WE thrombin (0.75 to 10 mcg/kg) on APC-PCI complex formation and corresponding 
aPTT was evaluated over 2 hours. Injection of E-WE thrombin caused a dose-dependent 
increase in APC-PCI plasma levels. Elevated levels of APC-PCI were present between 5 and 
120 minutes post administration at all four dose levels, with peak APC-PCI levels observed 
approximately 30 minutes after E-WE thrombin injection. By 120 minutes post injection, 
APC-PCI values were trending toward baseline.  


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In the same baboon, aPTT prolongation was also evaluated. E-WE thrombin caused a 
dose-dependent transient increase in the aPTT at all four dose levels, peaking at 
approximately 15 to 30 minutes post administration, with peak prolongation ranging from 
approximately 1.2-fold to 1.8-fold over baseline value. aPTT returned to baseline by 
120 minutes at all doses tested except the highest dose. The duration and magnitude of the 
aPTT elevation in response to E-WE thrombin correlated with plasma APC-PCI 
concentrations and the fold increase in aPTT prolongation significantly correlated with 
APC-PCI concentration:  
(R2 = 0.85, p ≤ 0.001 by linear regression). 
The APC-PCI profile of E-WE thrombin was also evaluated in a Good Laboratory Practice 
(GLP) single dose-acute study in cynomlogus monkeys. Administration of E-WE thrombin to 
cynomolgus monkeys (12.5, 25, 50 mcg/kg) caused a temporal increase in the concentration 
of APC-PCI complexes, in a dose-dependent manner. In addition, the anticipated temporal 
PD effect of aPTT prolongation occurred in all test article dose groups. By 24 hours, aPTT 
elevation returned to baseline. 
8.2.5 Toxicology 
The toxicity profile of E-WE thrombin was evaluated in two GLP single-dose acute toxicity 
studies in Sprague-Dawley rats and cynomolgus monkeys. In rats, a single dose of E-WE 
thrombin was administered at doses of 0, 30, 100, and 300 mcg/kg and animals were 
evaluated for 3 days (main study) and 29 days (recovery group) after dosing. In cynomolgus 
monkeys, a single dose of E-WE thrombin was administered at doses of 0, 12.5, 25, and 
50 mcg/kg and animals were evaluated for 4 days (main study) and 15 days (recovery study) 
after dosing. E-WE thrombin was well tolerated in both species and no E-WE thrombin-
related AE were observed. Based on these results, the no observed adverse effect level 
(NOAEL) was determined to be 300 mcg/kg/dose and 50 mcg/kg/dose, for rats and 
cynomolgus monkeys, respectively.  
Refer to the Investigator’s Brochure (IB) for detailed background information on study drug [1]. 
8.3 
Rationale 
8.3.1 Purpose of the Study 
This clinical trial will be a SAD study of E-WE thrombin IV solution. When developing new 
drugs for clinical indications, it is necessary to collect data on the safety, tolerability, and PD 
(as a surrogate for PK) in order to support further development of the compound as a useful 
clinical candidate and allow recommendations of dose levels and dose intervals in phase 2 
and subsequent studies.  
8.3.2 Dose Selection 
E-WE thrombin appeared well tolerated in a panel of standard animal toxicology studies. The 
proposed clinical starting dose was selected in accordance with the Food and Drug 
Administration (FDA) Guidance “Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers” (July 2005) as this is the first 
study in humans[5]. On the basis of No Observed Adverse Effect Levels (NOAEL) noted in 


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the toxicity studies, the NOAEL dose in rats and cynomolgus monkeys was determined to be 
300 mcg/kg and 50 mcg/kg, respectively. Based on body surface area scaling for cynomolgus 
monkeys (the more biologically relevant species), the human equivalent dose (HED) of the 
cynomolgus monkey NOAEL was determined to be 16.1 mcg/kg. The HED NOAEL value 
derived from the toxicity studies was then compared to the pharmacologically active dose 
generated from efficacy studies that were performed in baboons. A pharmacologically active 
dose for IV administration of E-WE thrombin was determined to be 1.25 mcg/kg and was 
defined as the lowest dose that reduced platelet-rich thrombosis formation in a well-
established baboon model of thrombosis, with a concomitant temporal (up to 30 minutes 
long) ~1.2-fold increase in the aPTT. Scaling based upon bodyweight generated an HED of 
0.7 mcg/kg. Based upon these calculations, the proposed clinical starting dose of E-WE 
thrombin in humans is 0.5 mcg/kg and represents a 32-fold safety margin over the 16.1 
mcg/kg HED NOAEL found in cynomolgus monkeys. This dose is anticipated to have 
minimal, if any biological effect. The maximum proposed dose of E-WE thrombin in this 
study of 4.0 mcg/kg represents a > 4-fold safety margin over the HED NOAEL investigated 
in the safety studies, and will also be based on the available clinical safety data of each dose 
cohort.  
Therefore, the present first in human dose escalation study will initiate single doses at 
0.5 mcg/kg and may escalate doses up to 4.0 mcg/kg depending on the safety and dose 
tolerance parameters observed at each dose level during the study. Dosing will not exceed 
4.0 mcg/kg without a protocol amendment. 
8.3.3 Rationale for PD Markers 
The presumed half-life of active circulating E-WE thrombin in solution is very short 
(seconds to minutes) due to rapid binding to cell surface thrombin receptors. Active enzyme 
is not measurable in plasma using our enzyme capture assay at predicted human therapeutic 
doses. The Sponsor proposes to use a PD biomarker (circulating APC-PCI complexes) to 
assess the magnitude and duration of action, and as a surrogate for drug exposure. 
8.4 
Risk/Benefit 
The safety monitoring practices employed by this protocol (i.e., physical examination, vital 
signs, 12-lead ECG, hematology, serum chemistry, urinalysis, coagulation monitoring, 
immunogenicity, injection site reation, and AE questioning) are adequate to protect the 
subjects’ safety and should detect all TEAEs. 
The approximate volume of blood planned for collection from each subject over the course of 
the study (see Section 11.4), presents no undue risk to the subjects nor does the possibility of 
additional blood drawn in the event an indwelling cannula (for wasting to ensure clean 
sample) is utilized and the possibility of additional blood drawn for recheck of safety labs if 
deemed necessary by the PI or designee. 
There will be no direct health benefit for trial participants from receipt of study drug. An 
indirect health benefit to the healthy subjects enrolled in this trial is the free medical tests 
received at screening and during the study. 
 
 


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9. STUDY OBJECTIVES AND ENDPOINTS 
9.1 
Study Objectives 
The primary objective of the study is to assess the safety and tolerability of single IV bolus 
doses of E-WE thrombin when administered to healthy adult subjects. 
The secondary objective is to assess the PD of single IV bolus doses of E-WE thrombin when 
administered to healthy adult subjects. The APC-PCI will be used as a surrogate biomarker 
for drug exposure. 
9.2 
Study Endpoints 
The primary endpoints of the study will be the number and severity of TEAEs following 
single IV bolus doses of E-WE thrombin and placebo. 
The secondary endpoints are the PD (i.e., APC-PCI) of E-WE thrombin following single IV 
bolus doses. PD will act as a surrogate for PK of E-WE thrombin. 
 
 


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10. INVESTIGATIONAL PLAN 
10.1 Overall Study Design and Plan  
This is a randomized, double-blind, placebo-controlled, SAD study conducted at one study 
center in the US.  
Four (4) cohorts of either 6 subjects (Cohort 1 [4 active and 2 placebo]) or 5 subjects 
(Cohorts 2, 3, and 4 [4 active and 1 placebo]) are planned for evaluation.  
In each cohort, subjects will receive a single IV bolus of E-WE thrombin or placebo. 
Subjects will participate in only 1 cohort. 
Cohort 1 will contain a sentinel group of 2 subjects (1 placebo and 1 active) who will be 
dosed at least 28 days before the remaining group of subjects. The remaining subjects in 
Cohort 1, and subjects in each of Cohorts 2, 3, and 4 will be dosed in 2 groups separated by 
at least 14 days (2 subjects in each group [Cohort 1] or 2 subjects in the first group and 
3 subjects in the second group [Cohorts 2-4]). The placebo will be randomized to either 
group.  
Dose escalation to the next dose level (i.e., next cohort) will be determined as per 
Section 10.4.1.4. See Section 10.4.1.2 for dose levels in each cohort. Subjects will participate 
in only one cohort. An attempt will be made to have at least 30% of the total subjects of a 
race/ethnicity minority group. An attempt will be made to include at least 2 females per 
cohort. 
Safety (i.e., physical examinations, vital signs, ECGs, clinical laboratory tests [including 
coagulation], thrombin time, immunogenicity, injection site reaction, and AEs) will be 
assessed throughout the study.  
Blood samples will be collected for PD assessment (i.e., APC-PCI) of E-WE thrombin at 
scheduled time points listed in the Study Events Flow Chart (Section 6) predose and for 
24 hours postdose.  
If ADA are found at the time of follow-up on Day 14 and/or Day 28, the check-in sample of 
ADA will be evaluated. 
10.1.1 Confinement, Return Visits, and Follow-Up 
Subjects will be housed on Day -1, at the time indicated by the CRU, until after the 24-hour 
blood draw and/or study procedures as indicated in the Study Events Flow Chart (Section 6). 
At all times, a subject may be required to remain at the CRU for longer at the discretion of 
the PI or designee. 
Subjects (including those who terminate early) will return on Days 14 and 28 for follow-up 
procedures (coagulation sample collection, thrombin time measurement, and immunogenicity 
sample collection) and to determine if any AE has occurred since the last study visit). 
Subjects who terminate the study early will be asked to continue aPTT and thrombin time 
monitoring as scheduled until Day 28. 


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Any subjects for whom aPTT and/or thrombin time did not reach ± 10% of the baseline value 
or within the normal range by Day 14, will return every 7 days (±2 days) until aPTT and 
thrombin time reach ±10% of the baseline value or within the normal range and for a FU visit 
(i.e., follow-up procedures and AE evaluation listed on Day 28 will be repeated) 7 days (± 2 
days) after it was reached. 
10.1.2 Study Duration 
The total planned duration of subject participation is approximately 56 days from screening 
to last follow-up. 
10.2 Study Conduct 
See the Study Events Flow Chart for a summary of the schedule of study participation and 
procedures in Section 6. 
10.2.1 Screening 
Screening will begin within 28 days prior to dosing. Informed consent will be obtained at 
screening (see Section 13.1.3). Subjects will have to meet all eligibility criteria before being 
enrolled in the study (see Section 10.3). Subjects will be informed of the study restrictions 
(see Section 10.3.5). 
The following will be recorded at screening: medical history and demographic data, 
including name, sex, age, race, ethnicity, body weight (kg), height (cm), BMI (kg/m2), and 
history of tobacco use.  
Screening procedures are listed in the Study Events Flow Chart Section 6. 
10.2.2 Check-in Procedures (Day -1) 
At check-in (Day -1), subjects will enter the CRU, and those subjects who satisfy all of the 
inclusion criteria and none of the exclusion criteria will qualify and be eligible for 
randomization. A check-in questionnaire will be reviewed for each subject to ensure that 
subjects remain eligible for the study since screening. 
Immunogenicity samples will be collected at check-in. 
Check-in procedures are listed in the Study Events Flow Chart Section 6. 
10.2.3 Treatment Period (Day 1 to Day 2) 
10.2.3.1 Single-dose Administration (Day 1) and Study Procedures (Days 1 to 2) 
On the morning of Day 1, predose evaluations will be obtained. 
Subjects will receive a single IV bolus of E-WE thrombin or placebo on the morning of 
Day 1. See Section 10.4.1 and Section 10.4.3 for planned dose levels and details. 


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Safety and tolerability will be monitored throughout the treatment period as listed in the 
Study Events Flow Chart (Section 6). 
Blood samples for PD assessment (see Section 11.3) will be collected at the time points as 
listed in the Study Events Flow Chart (Section 6). 
10.2.3.2 Meal Schedule 
Water will be allowed ad libitum at all times. Other fluids may be given as part of meals and 
snacks but will be restricted at all other times throughout the confinement period. 
Standard meals and snacks will be provided at the appropriate times during confinement. 
When confined in the CRU, subjects will be required to fast from all food and drink except 
water between meals and snacks. 
Each meal and/or snack served at the CRU will be standardized and will be similar in caloric 
content and composition. The same menu and meal schedule will be administered uniformly 
for all subjects for all cohorts. 
Subjects will be required to fast for at least 8 hours before the serum chemistry tests; 
however, in case of dropouts or rechecks, subjects may not have fasted for 8 hours before the 
serum chemistry sample is taken. 
10.2.4 Follow-up Visits (Day 14 and 28)  
Subjects (including those who terminate early) will return on Days 14 and 28 for follow-up 
procedures (coagulation sample collection, thrombin time measurement, and immunogencity 
sample collection) and to determine if any AE has occurred since the last study visit. If 
thrombin time and/or aPTT are found to be elevated beyond normal range (unless it is still 
within ± 10% of individual’s baseline value at check-in) at Day 14, both tests will be 
repeated. If aPTT and/or thrombin time are elevated beyond the normal range in the retest, a 
mixing study will be performed. The mixing study will be performed on Day 14 by mixing 
the subjects’ plasma 1:1 with normal human pooled plasma and thrombin time evaluated. If 
the thrombin time does not correct, the presence of ADA and cross-reacting 
prothrombin/thrombin antibodies will be presumed and will be directly assessed before dose 
escalation decision. The applicable subject will remain at the CRU until these test results are 
obtained. 
Subjects who terminate the study early will be asked to continue aPTT and thrombin time 
monitoring as scheduled until Day 28. 
Any subjects for whom aPTT and/or thrombin time did not reach ± 10% of the baseline value 
or within the normal range by Day 14, will return every 7 days (±2 days) until aPTT and 
thrombin time reach ±10% of the baseline value or within the normal range and for a FU visit 
(i.e., follow-up procedures and AE evaluation listed on Day 28 will be repeated) 7 days (± 2 
days) after it was reached. 


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Should any subjects withdraw or be withdrawn from the study, all the early termination 
evaluations should be performed if possible, including samples for PD assessments if 
applicable. 
Immunogenicity samples will be collected at the follow-up visits. The follow-up procedures 
are listed in the Study Events Flow Chart Section 6. 
10.2.5 Scheduled End of Study 
The end of the study is scheduled after completion of the evaluations in the forth cohort or 
after dose-limiting clinical safety endpoints have been reached to preclude further increases 
of dose/cohorts.  
10.3 Selection of Study Population 
10.3.1 Number of Subjects 
The study is planned to enroll up to 21 subjects in 4 cohorts [i.e., dose levels] with 6 subjects 
in Cohort 1 [4 subjects randomized to receive the active drug and 2 subjects to receive the 
placebo] and 5 subjects in Cohorts 2, 3, and 4 [4 subjects randomized to receive the active 
drug and 1 subject to receive the placebo]. In each cohort, an attempt will be made to have at 
least 30% of the subjects be of a race/ethnicity minority group. An attempt will be made to 
include at least 2 females in each cohort. 
Cohort 1 will contain a sentinel group of 2 subjects (1 placebo and 1 active). The sentinel 
group will be dosed at least 28 days before the remaining subjects in Cohort 1. The 
remaining subjects in the cohort will be dosed after evaluation of the sentinel subjects’ 
Day 28 safety data and will be dosed in 2 groups separated by at least 14 days (2 subjects in 
the first group and 2 subjects in the second group). The placebo will be randomized to either 
group. 
The Cohorts 2, 3, and 4 will be dosed in 2 groups separated by at least 14 days (2 subjects in 
the first group and 3 subjects in the second group). The placebo will be randomized to either 
group.  
Additional subjects (up to 6 subjects per cohort) may be enrolled if it is deemed appropriate 
by the PI and the Sponsor to repeat a dose level or to study an intermediate dose level (lower 
than those planned) in a new cohort of subjects. 
10.3.2 Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in 
the study: 
1. Healthy, adult, male and/or female (females of non-childbearing potential only), 18 to 
55 years of age, inclusive, at screening. 
2. Continuous non-smoker, who has not used nicotine-containing products for at least 
3 months prior to dosing, based on subject self-reporting. 


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3. Body mass index (BMI) ≥ 18 and < 29 (kg/m2) at screening and weight between 50 and 
125 kg (inclusive) at screening. 
4. Medically healthy with no clinically significant medical history, physical examination, 
laboratory profiles, vital signs or ECGs, as deemed by the PI or designee. 
5. A female must be of non-childbearing potential and must have undergone one of the 
following sterilization procedures at least 6 months prior to dosing: 
a. hysteroscopic sterilization; 
b. bilateral tubal ligation or bilateral salpingectomy; 
c. hysterectomy; 
d. bilateral oophorectomy. 
or be postmenopausal with amenorrhea for at least 1 year prior to dosing and 
follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal status. 
6. A non-vasectomized, male subject must agree to use a condom with spermicide or abstain 
from sexual intercourse during the study until 90 days beyond the dose of study drug. (No 
restrictions are required for a vasectomized male provided his vasectomy has been 
performed 4 months or more prior to dosing of study drug. A male who has been 
vasectomized less than 4 months prior to dosing must follow the same restrictions as a 
non-vasectomized male). 
7. If male, must agree to not donate sperm from dosing until 90 days after dosing. 
8. Understands the study procedures in the informed consent form (ICF), and be willing and 
able to comply with the protocol. 
10.3.3 Exclusion Criteria 
Subjects will be excluded from the study if there is evidence of any of the following criteria 
at screening or check-in, as appropriate.  
1. Subject is mentally or legally incapacitated or has significant emotional problems at the 
time of the screening visit or expected during the conduct of the study. 
2. History or presence of clinically significant medical or psychiatric condition or disease in 
the opinion of the PI or designee. 
3. History of any illness that, in the opinion of the PI or designee, might confound the 
results of the study or poses an additional risk to the subject by their participation in the 
study. 
4. History or presence of alcoholism or drug abuse within the past 2 years prior to dosing. 
5. Consumes 3 units or more of alcohol per day (e.g., 1 unit is equivalent to 240 mL of 
wine, 1 bottle of beer [12 oz.], or 1 shot of liquor [1 oz.]). 
6. History or presence of hypersensitivity or idiosyncratic reaction to the study drug and 
excipients or related compounds. 


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7. History or presence of a disease or disorder, acquired or inherited, that is active, or could 
be reasonably expected to become active during the study, including but not limited to: 
• Hypersensitivity to ß-lactam / penicillin derivatives; 
• Bleeding and blood coagulation disorders, including stroke, hemophilias, 
thrombophilias, or heparin-induced thrombocytopenia; 
• Ischemic disorders, including stroke, heart attack, coronary artery disease; 
• Gastrointestinal disorders, including gastrointestinal bleeds, gallstones, ulcers, 
diseases or dysfunction of the liver and excluding appendectomy and/or 
cholecystectomy; 
• Genitourinary disorders, including renal disease;  
• Cardiovascular disorders, including aneurysms, vasculitis;  
• All conditions that are associated with taking medications for pain;  
• Infection of any organ or system within 30 days of dosing; 
• Malignant and cancerous neoplasms of any organ or system; 
• Psychiatric and behavioral disorders; 
• A clinically significant hematological disorder of any type; 
• Inflammation and inflammatory diseases of any organ system. 
8. Females of childbearing potential. 
9. Females who are pregnant or who are lactating.  
10. Positive urine drug or alcohol results at screening or check-in.  
11. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B 
surface antigen (HBsAg), or hepatitis C antibodies (HCV). 
12. Supine blood pressure is less than 90/50 mmHg or greater than 140/90 mmHg at 
screening. 
13. Supine heart rate is lower than 40 bpm or higher than 99 bpm at screening. 
14. QTcF interval > 450 msec for males or > 460 msec for females, or history of prolonged 
QT syndrome at screening. 
15. Estimated creatinine clearance < 90 mL/minutes at screening using the Cockcroft-Gault 
estimation.  


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16.  Unable to refrain from or anticipates the use of: 
• Any drug, including prescription and non-prescription medications, herbal remedies, 
or vitamin supplements beginning approximately 14 days prior to dosing and 
throughout the study.  
• Any oral or injectable anticoagulant (e.g., warfarin, heparin, low molecular weight 
heparin, etc.), coagulants (aprotinin, tranexamic acid, epsilon‐aminocaproic acid, and 
aminomethylbenzoic acid), anti-platelet (e.g., clopidogrel), nonsteroidal anti-
inflammatory drugs (NSAIDs) and/or acetylsalicylic acid (ASA) beginning 
approximately 10 days prior to dosing and throughout the study.  
• Any drugs known to be significant inducers of cytochrome P-450 enzymes and/or 
P-glycoprotein, including St. John’s Wort, for 28 days prior to dosing and throughout 
the study.  
Appropriate sources (e.g., Flockhart TableTM) will be consulted to confirm lack of PK/PD 
interaction with study medication. Acetaminophen (up to 2 g per 24 hour period) or any 
other treatment of an AE, drug related or not, and considered appropriate and allowable 
by the PI or designee may be permitted after dosing. 
17. Has been on a diet incompatible with the on-study diet, in the opinion of the PI or 
designee, within the 30 days prior to dosing and throughout the study. 
18. Has participated in strenuous exercise or physical activity within 72 hours prior to 
Day -1, unless deemed acceptable by the PI or designee.  
19. Donation of blood or significant blood loss within 56 days prior to dosing. 
20. Plasma donation within 7 days prior to dosing. 
21. Has been hospitalized within 2 months of Day -1. 
22. Participation in another clinical study within 30 days prior to dosing. The 30-day window 
will be derived from the date of the last blood collection or dosing, whichever is later, in 
the previous study to Day 1 of the current study. 
23. Surgery within the past 90 days prior to dosing which in the opinion of the PI or designee 
is clinically relevant. 
24. Presence of any scars, or tattoos which may obscure the injection site, as deemed by PI or 
designee. 
25. Any condition or circumstance, in the opinion of the PI or designee, which may make the 
subject unlikely to complete the study or comply with study procedures and 
requirements, or may pose a risk to the subject's safety. 


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10.3.4 Early Termination of Subjects from the Study 
Subject participation in this trial may be discontinued for any of the following reasons: 
1. Occurrence of any medical condition or circumstance that exposes the subject to 
substantial risk and/or does not allow the subject to adhere to the requirements of the 
protocol. 
2. Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, or 
other medical condition that indicates to the PI or designee that continued participation is 
not in the best interest of the subject. 
3. Subject's decision to withdraw. 
4. Requirement of prohibited concomitant medication. 
5. Subject failure to comply with protocol requirements or study related procedures. 
6. Termination of the study by the Sponsor, FDA, Celerion, or other regulatory authorities. 
7. Pregnancy. 
The clinical report will include reason(s) for subject withdrawals as well as details relevant to 
the subject withdrawal. If a subject is withdrawn from the trial prior to study completion, the 
subject will undergo all procedures scheduled for subjects who terminate early (see 
Section 6) as the situation allows (see Section 10.2.4). Any subject withdrawn due to an AE 
(whether serious or non-serious) or clinically significant abnormal laboratory test values will 
be evaluated by the PI or designee or a monitoring physician and will be treated and/or 
followed up until the symptoms or values return to normal or acceptable levels, as judged by 
the PI or designee. 
Subjects withdrawn may be replaced at the Sponsor’s discretion. 
10.3.5 Study Restrictions 
10.3.5.1 Prohibitions and Concomitant Therapy 
Consumption of foods and beverages containing the following substances will be prohibited 
as indicated: 
• Xanthines/caffeine:  24 hours before dosing and throughout the period of sample 
collection (small amounts of caffeine derived from normal foodstuffs e.g., 
250 mL/8 oz. decaffeinated coffee or other decaffeinated beverage, per day, with the 
exception of espresso; 45 g/1.5 oz. chocolate bar, per day, would not be considered a 
deviation to this restriction);  
• Alcohol:  48 hours before dosing and throughout the period of sample collection; 
Concomitant therapies will be prohibited as listed in the exclusion criteria in Section 10.3.3. 
Acetaminophen (up to 2 g per 24 hour period) or any other treatment of an AE, drug related 
or not, and considered appropriate and allowable by the PI or designee may be permitted 
after dosing. 


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If deviations occur, the PI or designee will decide on a case-by-case basis whether the subject 
may continue participation in the study based on the time the study medication was 
administered and its pharmacology. 
All medications taken by subjects during the course of the study will be recorded. 
10.3.5.2 Activity 
Subjects will remain ambulatory or seated upright for the first 4 hours following study 
medication administration, except when they are supine or semi-reclined for study 
procedures.  
However, should AEs occur at any time, subjects may be placed in an appropriate position. 
Subjects will be instructed to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time within 72 hours prior to Day -1. 
10.4 Treatments 
10.4.1 Treatments Administered 
A separate dosing manual will detail the preparation and treatment administration to be 
followed for this study. 
10.4.1.1 Drug Administration 
E-WE thrombin will be supplied as sterile, non-pyrogenic, preservative-free liquid for IV 
administration. 
E-WE thrombin will be supplied as 0.1 mg/mL for IV use and given as a single IV bolus, 
according to the planned dose (mcg/kg) for each cohort, as noted below in Table 1. 
Matching placebo will be supplied as sterile formulation buffer for injection via IV route. 
Drug and placebo will be administered into or distal to the antecubital vein. 
An unblinded pharmacist will be responsible for providing E-WE thrombin or placebo to the 
blinded study personnel for administration as per the randomization scheme.  
After evaluation of the sentinel subjects’ safety data up to Day 28 by the PI (and SRC if 
applicable, refer to Section 10.4.1.4), the remaing group subjects inCohort 1 will be dosed in 
two groups separated by at least 14 days (2 subjects in the first group and 2 subjects in the 
second group). 
Subjects dosed on the same day will be dosed with an interval of at least 1 hour between 
subjects. 
All doses will be administered as an IV bolus into a peripheral vein. The time of injection for 
each dose level and the estimated volumes are outlined below: 


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Table 1: 
Dosing Duration 
Dose Level 
Manual Push Time 
Cohort 1: 0.5 mcg/kg 
~ 15 seconds 
Cohort 2: 1.0 mcg/kg 
~ 15 seconds  
Cohort 3: 2.0 mcg/kg 
~ 30 seconds 
Cohort 4: 4.0 mcg/kg 
~ 1 minute 
 
Dosing will be done while subjects are supine in bed.  
The subject weight recorded at check-in will be used to calculate the study drug dose. 
The time at which the manual push is started and stopped must be recorded. 
10.4.1.2 Planned Dose Levels 
The planned dose levels are as follows: 
Cohort 1:  0.5 mcg/kg E-WE thrombin or matching placebo (IV bolus) 
Cohort 2:  1.0 mcg/kg E-WE thrombin or matching placebo (IV bolus) 
Cohort 3:  2.0 mcg/kg E-WE thrombin or matching placebo (IV bolus) 
Cohort 4:  4.0 mcg/kg E-WE thrombin or matching placebo (IV bolus) 
Note: The planned dose levels described above may be revised up or down or a dose level 
may be repeated based upon data from a previous dose level, however, doses will not exceed 
4.0 mcg/kg without a protocol amendment.  
For Cohort 1 there will be a sentinel group comprised of 2 subjects dosed at least 28 days 
before the remaining group of subjects; subjects will be randomized in a 1:1 ratio to active 
and placebo. The remaining subjects in the cohort will be dosed after evaluation of the 
sentinel subjects’ Day 28 safety data and will be dosed in 2 groups separated by at least 
14 days (2 subjects in the first group and 2 subjects in the second group). The placebo will be 
randomized to either group. 
The Cohorts 2, 3, and 4 will be dosed in 2 groups separated by at least 14 days (2 subjects in 
the first group and 3 subjects in the second group). The placebo will be randomized to either 
group. 
Thrombin time and aPTT at Day 14 will be tested to evaluate whether or not subjects may be 
generating neutralizing antibodies to thrombin/prothrombin. If the thrombin time and aPTTs 
are normal, the next cohort may be dosed if the rest of the safety data is deemed acceptable 
by the PI or SRC, as applicable. Confirmation of safety data from the previous cohorts will 
include for Cohort 1, 6 subjects (4 active and 2 placebo) and for Cohorts 2, 3, and 4, 5 
subjects (4 active and 1 placebo). 


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If thrombin time and/or aPTT are found to be elevated beyond normal range (unless it is still 
within ± 10% of individual’s baseline value at check-in) at Day 14, both tests will be 
repeated. If aPTT and/or thrombin time are elevated beyond normal range in the retest, a 
mixing study will be performed. The mixing study will be performed by mixing the subjects’ 
plasma 1:1 with normal human pooled plasma. aPTT and thrombin time will be evaluated. If 
the aPTT and/or thrombin time do not correct to normal range, the presence of ADA and 
cross-reacting prothrombin/thrombin antibodies will be presumed, and will be directly 
assessed before a dose escalation decision. 
Any subjects for whom aPTT and/or thrombin time did not reach ± 10% of the baseline value 
or within the normal range by Day 14, will return every 7 days (±2 days) until aPTT and 
thrombin time reach ±10% of the baseline value or within the normal range. 
10.4.1.3 Additional Dose Levels 
Repeat of any cohort or the addition of interim dose levels (lower than those planned) may be 
added, as determined by the SRC, depending on the safety results from the prior cohort(s).  
Dosing will not exceed 4.0 mcg/kg without a protocol amendment. 
Additional cohorts (up to 6 subjects per cohort) may be enrolled as determined by the SRC, 
to repeat a dose level or to study an interim dose level (lower than those planned) in a new 
cohort of subjects. 
The IRB should be immediately notified of this revised approach. 
10.4.1.4 Dose Escalation and Stopping Rules 
Dose escalation to the next dose level (i.e., next cohort) will not take place until after the PI 
has reviewed the safety data. If any findings in the safety data are of concern, then the SRC 
comprised of but not limited to, the Sponsor, medical monitor, and the PI will convene to 
determine if adequate safety and tolerability from the previous cohort has been demonstrated 
to permit proceeding to the next cohort. The SRC review of all pertinent blinded 
safety/tolerability data must comprise of physical examinations, ECGs, vital signs, clinical 
laboratory tests [including coagulation], thrombin time, injection site reaction, and AEs 
available for all subjects who have completed up to Day 14 procedures. 
Data from all subjects in the cohort will be used and reviewed for a dose escalation decision 
and a minimum of 4 subjects must complete the study (up to Day 14) before proceeding to 
the next higher dosing cohort. 
Together they will make one of the following determinations: 
1. 
To continue with the study as planned. 
2. 
To continue with the study and add additional safety evaluations. 
3. 
To continue with the study and repeat a cohort.  


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4. 
To continue with the study by adjusting to an intermediate dose between the current 
dose and the previous lower dose (i.e., add an additional cohort) or to repeat a 
cohort, if: 
a. At least 1 subject has a SAE or visit to the emergency room deemed to be 
possibly study drug related (see Section 11.1.8.4).  
b. At least 25% of subjects in a cohort experience a grade ≥ 2 AE deemed to 
be possibly related to the study drug. 
5. 
To stop the study. The study will be terminated if the following number of subjects 
meet any of the following criteria and the subjects were determined to have received 
active drug after unblinding: 
I. 
≥ 1 subject that receive drug in a cohort experience: 
a. Life-threatening hypersensitivity reactions (e.g., anaphylaxis, respiratory 
symptoms, hypotension etc.). 
b. Any grade thromboembolic event possibly related to the study drug. 
c. Any grade bleeding possibly related to the study drug. 
d. Presence of antibodies against human thrombin or prothrombin. 
e. Presence of ADA. 
II. 
≥ 2 subjects that receive drug in a cohort: 
a. Has a drug possibly or probably related SAE (see Section 11.1.8.4).  
b. Experiences a drug related grade ≥ 3 toxicity (see Section 11.1.8.3).  
Cohorts will be staggered to allow sufficient time for adequate review of safety and 
tolerability from the prior cohort. 
Safety aPTT, PT, and thrombin time data from a cohort will be needed for a dose escalation 
decision. If aPTT and thrombin time are elevated at Day 14, a mixing study will be 
performed. If the mixing study does not normalize the aPTT and/or thrombin time, dose 
escalation will be postponed until ADA data is available. If either ADA assay are confirmed 
to be positive, the study will be stopped according to the dose escalation and stopping rules 
outlined above. APC-PCI complex level data will not be needed for a dose escalation 
decision. 
When applicable, a written statement fully documenting the reasons for study termination 
will be provided to the IRB. 
10.4.2 Identity of Investigational Products 
Investigational materials will be provided by the Sponsor as in Table 2. 


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Table 2: 
Product Descriptions 
 
Product 
Description 
Test 
E-WE thrombin (0.1 mg/mL) 
Placebo 
Placebo for E-WE thrombin (16.2 mM sodium citrate, 
3.8 mM citric acid, 150 mM sodium chloride, 0.1% 
polysorbate 80, at pH 6) 
10.4.3 Method of Assigning Subjects to Treatment Groups 
Each subject will be assigned a unique identification number upon screening. Subjects who 
complete the study screening assessments and meet all the eligibility criteria will be assigned 
a unique randomization identification number prior to the dosing, different from the 
screening number, and will receive the corresponding product according to a randomization 
scheme generated at Celerion.  
In Cohort 1, the sentinel group will consist of 2 subjects who will be randomized to receive 
E-WE thrombin or placebo (1 active and 1 placebo). The remaining 4 subjects in the cohort 
will be randomized to receive E-WE thrombin or placebo (3 active and 1 placebo). 
In Cohorts 2-4, subjects will be randomized to receive a single IV bolus of E-WE thrombin 
or placebo in a 4:1. Subjects will participate in only one cohort. 
The remaining subjects in Cohort 1 (non-sentinel subjects) will be dosed at least 28 days 
after the Cohort 1 sentinel group. The remaining subjects in Cohort 1 and subjects in Cohorts 
2, 3, and 4 will be dosed in 2 groups separated by at least14 days (2 subjects in each group 
[Cohort 1] or 2 subjects in the first group and 3 subjects in the second group [Cohorts 2-4]). 
The placebo will be randomized to either group. 
Subjects in the first enrollment cohort will be numbered 1001 – 1006; subjects in the second 
enrollment cohort will be numbered 2001 - 2005, etc. 
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (e.g., Subject No. 1101 will replace Subject No. 1001). 
10.4.4 Blinding 
This is a double-blind, placebo-controlled study. 
10.4.4.1 Maintenance of Randomization 
A computerized randomization scheme will be created by a Celerion statistician and it shall 
be considered blinded as per the following:  the randomization is available only to the clinic 
pharmacy staff preparing the drug who will not be involved in any other aspect of the study 
including administration of the drug. It will not be made available to the Sponsor, 


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bioanalytical laboratory, subjects, or members of the staff responsible for the monitoring and 
evaluation of safety assessments. 
10.4.4.2 Procedures for Breaking the Blind Prior to Study Completion 
One set of sealed envelopes containing the randomization code will be supplied to the PI or 
designee at the start of the study. 
Breaking of the blind is expressly forbidden except in the event of a medical emergency (e.g., 
SAEs and other AEs ≥ grade 3 that are considered possibly related to the study treatment) 
where the identity of the drug must be known in order to properly treat the subject, or in the 
event of a safety interim analysis at the request of the Sponsor. 
In the event of a medical emergency, it is requested that the PI or designee make every effort 
to contact the Study Monitor or designee prior to breaking the blind. If breaking the blind is 
required because of a medical emergency, the treatment identity would be revealed by the PI 
or designee, for that subject only. In the event that the emergency is one, in which it appears 
that the other subjects may be at imminent risk, the blind may be broken for all subjects 
dosed at that dose level. The unblinding will be properly documented in the study file. 
In all cases where the code is broken, the PI or designee should record the date and reason for 
code breaking. 
At the end of the study, envelopes will be retained or destroyed according to site procedures 
unless specified otherwise by the Sponsor. 
10.4.4.3  Interim Analysis 
Safety: 
If there are safety concerns, all available blinded safety data will be reviewed by the SRC 
prior to dose escalation.  
At the Sponsor’s request, unblinded safety tables, figures, and data listings may be presented 
to the sponsor’s medical expert and head of regulatory for the purposes of planning the next 
initial Phase 2 studies prior to database lock. These interim analyses will be performed on 
data that will be edit-checked and monitored. 
A safety programmer and a biostatistician at Celerion who are not involved with the present 
study will be unblinded to prepare the required unblinded safety tables, figures, and data 
listings. All the personnel related to the present study will remain blinded. 
10.4.4.4 Revealing of Randomization 
In the absence of a medical emergency, the blinded randomization for this study will not be 
revealed until all data are entered in the database, edits checks are performed, queries closed, 
case report forms (CRFs) signed by the PI, and the database is officially locked.  


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CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
10.4.5 Treatment Compliance  
A qualified designee will be responsible for administering and monitoring the timed dose. 
Before and after IV bolus injection, the qualified designee will visually inspect the syringe to 
ensure that the subject has received the entire dose. In the case of an incomplete dosing (e.g., 
large droplet of study medication on the surface of the skin) as deemed by the PI (or 
designee) and/or Sponsor, the subject may be withdrawn. Subjects withdrawn for incomplete 
dosing will be asked to remain at the CRU after drug administration and be monitored 
through Day 28 or 7 days (± 2 days) after aPTT and thrombin time values have returned 
within ± 10% of the baseline value or the normal range (whichever occurs later),similarly to 
other study participants.  
 


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CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
11. STUDY PROCEDURES 
11.1 Safety Assessments 
The Study Events Flow Chart (Section 6) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. 
Additional evaluations/testing may be deemed necessary by the PI or designee and/or the 
Sponsor for reasons related to subject safety. 
For this study, the primary assessment is the safety and tolerability. Safety will be determined 
by evaluating vital signs, ECGs, clinical laboratory parameters, including but not limited to, 
hematology, clinical chemistry profile, coagulation, and urinalysis, immunogenicity, 
injection site reaction, and AEs as outlined in the Study Events Flow Chart (Section 6).  
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures. 
11.1.1 Body Height and Weight 
Body height (cm) and body weight (kg) will be measured as outlined in the Study Events 
Flow Chart (Section 6). BMI will be calculated at screening. 
11.1.2 Physical Examination and Medical History 
A full physical examination will be performed as per Study Events Flow Chart (Section 6) 
and will include, at a minimum, assessment of the following systems: skin, head, ears, eyes, 
nose and throat, respiratory system, cardiovascular system, gastrointestinal system, 
neurological condition, blood and lymphatic systems, and the musculoskeletal system. 
Symptom-driven physical examination may be performed at other times, if deemed necessary 
by the PI or designee. 
11.1.3 Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure, and heart rate, 
will be measured as outlined in the Study Events Flow Chart (Section 6). Additional vital 
signs may be taken at any other times, if deemed necessary. 
Vital sign measurements will be performed with subjects in a supine position, except when 
they are standing or semi-reclined because of study procedures and/or AEs (e.g., nausea, 
dizziness) or if deemed necessary by the PI or designee. 
Vital signs will be measured within 24 hours prior to dosing for the predose time point. 
When scheduled postdose, vital signs will be performed within approximately 10 minutes of 
the scheduled time point.  


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CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
11.1.3.1 Safety 12-Lead ECGs 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart 
(Section 6). Additional ECGs may be taken at any other times, if deemed necessary by the PI 
or designee. 
ECGs will be taken following resting in the supine position. All ECG tracings will be 
reviewed by the PI or designee. 
ECGs will be measured within 24 hours prior to dosing for the predose time point. When 
scheduled postdose, ECGs will be performed within approximately 20 minutes of the 
scheduled time point. 


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CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
11.1.4 Clinical Laboratory Tests 
All tests listed below will be performed as per Study Events Flow Chart (Section 6). In 
addition, laboratory safety tests may be performed at various unscheduled time points, if 
deemed necessary by the PI or designee. 
Hematology 
 
Serum Chemistry* 
• Hemoglobin 
• Hematocrit  
• Total and differential 
leukocyte count 
• Red blood cell count 
• Platelet count 
 
Coagulation 
• PT/INR 
• aPTT 
• Fibrinogen 
• Thrombin time 
 
 
• Blood Urea Nitrogen 
• Bilirubin (total and direct) 
• Alkaline phosphatase 
• Aspartate aminotransferase 
• Alanine aminotransferase 
• Lactate dehydrogenase 
• Albumin 
• Sodium 
• Potassium 
• Bicarbonate 
• Chloride 
• Glucose (fasting) 
• Creatinine** 
Urinalysis 
 
Additional Tests 
• pH 
• Specific gravity 
• Protein*** 
• Glucose 
• Ketones 
• Bilirubin 
• Blood*** 
• Nitrite*** 
• Urobilinogen 
• Leukocyte esterase*** 
 
• HIV test 
• HBsAg 
• HCV 
• Urine drug screen 
 Opiates 
 Amphetamines 
 Cocaine 
 Cannabinoids  
• Urine alcohol screen 
• Serum pregnancy test  
(for females only) 
• FSH (for postmenopausal females only) 
* 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of dropouts or 
rechecks, subjects may not have fasted for 8 hours before the serum chemistry sample is taken.  
** 
At screening, creatinine clearance will be calculated using the Cockcroft-Gault formula. 
*** If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for 
red blood cells, white blood cells, bacteria, casts, and epithelial cells) will be performed. 
11.1.5 Check-In Questionnaire 
A check-in questionnaire will be reviewed for each subject to ensure that they remain eligible 
for the study. The questions will be based on the inclusion and exclusion criteria and study 
restrictions. 


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CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
11.1.6 
Injection Site Reaction Assessment 
The monitoring of AEs will pay special attention to potential injection site reactions. 
Therefore, at specified time points, inspection of administration and surrounding area will be 
performed. Any abnormal findings will be reported as AEs. Injection and needle puncture 
site reactions for drug administration will be evaluated as outlined in the Study Events Flow 
Chart (Section 6). Prior to dosing, the injection site will be examined. When scheduled 
postdose, injection site examinations will be performed within approximately 20 minutes of 
the scheduled time point. Reactions will be rated according to the FDA Guidance for 
Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventative Vaccine Clinical Trials (Sep 2007), [6] as follows: 
Local Reaction 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Pain 
Does not interfere 
with activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or interferes with 
activity 
Any use of narcotic 
pain reliever or 
prevents daily 
activity 
Tenderness 
Mild discomfort to 
touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
Erythema/Redness* 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Induration/Swelling** 
2.5 – 5 cm and 
does not interfere 
with activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or prevents 
daily activity 
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be 
recorded as a continuous variable. 
** Induration/swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 
11.1.7 
Immunogenicity 
Blood samples for immunogenicity assessment will be performed as per Study Events Flow 
Chart (Section 6).  
11.1.7.1 Blood Sampling and Processing for Immunogenicity 
Blood samples for immunogenicity assessment (i.e., E-WE thrombin and wild type [WT] 
thrombin) will be performed as per Study Events Flow Chart (Section 6).  
For the determination of E-WE thrombin ADA, blood samples will be collected in 2 blood 
collection tubes of 4.5 mL each, containing 3.2% sodium citrate, and processed into three 
plasma aliquots of at least 0.5 mL each.  


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CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
For the determination of WT thrombin ADA, whole blood samples will be collected in a 
5 mL blood collection tube, without anticoagulant, and processed to 3 serum aliquots of 
0.5 mL each.  
Samples will be shipped to the analytical laboratory for analysis at the end of the study, 
unless ADA or cross reacting antibodies are suspected from thrombin time elevation at 
Day 14 or Day 28.  
Instruction for blood sampling, collection, processing, and sample shipment will be provided 
separately. 
11.1.7.2 Analytical Method 
Assessment of ADA will be performed by Haemtech Biopharma Services, Inc. refer to 
Section 3. 
11.1.8 Adverse Events 
11.1.8.1 Adverse Event Definition 
An AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. 
A suspected adverse reaction means any AE for which there is a reasonable possibility that 
the drug caused the AE. Reasonable possibility means there is evidence to suggest a causal 
relationship between the drug and the AE.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) 
product [7]. 
11.1.8.2 Monitoring 
Subjects will be monitored throughout confinement for adverse reactions to the study drug 
and/or procedures. Subjects will be asked how they are feeling and encouraged to report AEs 
during confinement and at each follow-up visit.  
AEs (whether serious or non-serious) and clinically significant abnormal laboratory test 
value(s) will be evaluated by the PI or designee and treated and/or followed up until the 
symptoms or value(s) return to normal, or acceptable levels, as judged by the PI or designee. 
Treatment of SAEs will be performed by a physician, either at Celerion or at a nearby 
hospital emergency room. Where appropriate, medical test(s) and/or examination(s) will be 
performed to document resolution of event(s). Outcome may be classified as resolved, 
improved, unchanged, worse, fatal, or unknown (lost to follow-up). 


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CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
11.1.8.3 Reporting 
All AEs that occurred during this clinical trial will be recorded. AEs will be coded using the 
most current version of MedDRA® available at Celerion. 
The PI or designee will review each event and assess its relationship to drug treatment 
(unrelated, unlikely, possibly, probably, or likely,). Each sign or symptom reported will be 
graded on the FDA (Center for Biologics Evaluation and Research) toxicity grading scale for 
healthy volunteers 4-point severity scale (Grade 1, 2, 3 and 4) [8]. The date and time of 
onset, time relationship to drug dosing, duration, and outcome of each event will be noted.  
Relationship of AE: 
The relationship of each AE to the study drug will be assessed using the following 
definitions: 
Unrelated 
 The adverse event must clearly be caused by the participants 
clinical state, or the study procedure/conditions 
 Definitely not related to drug 
 Temporal sequence of an adverse event onset relative to 
administration of drug not reasonable 
 Another obvious cause of an adverse event 
Unlikely 
 Time sequence is unreasonable 
 There is another more likely cause for an adverse event 
Possibly 
 Corresponds to what is known about the drug 
 Time sequence is reasonable 
 Could have been due to another equally, likely cause 
Probably 
 Is a known effect of the drug 
 Time sequence from taking drug is reasonable 
 Ceases on stopping the drug 
 Cannot be reasonably explained by the known characteristics of 
the participants clinical state 
Likely 
 Is a known effect of the drug (e.g. listed in IB) 
 Time sequence from taking drug is reasonable 
 Event stops upon stopping drug, event returns upon restarting 
drug 
Severity of AE: 
Severity rating used during the study will be based on the toxicity grading scale tables 
present in the FDA (Center for Biologics Evaluation and Research) toxicity grading scale for 
healthy volunteers 4-point severity scale (Grade 1, 2, 3 and 4) [8]. 


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CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
The following definitions for rating severity will be used for AEs not identified in the 
guidance: 
Mild (Grade 1) 
 
The AE does not interfere with daily activity. 
Moderate (Grade 2) 
 
The AE interferes with daily activity, but no medical 
intervention is required. 
Severe (Grade 3)  
 
The AE prevents daily activity and requires medical 
intervention. 
Potentially Life-
threatening (Grade 4) 
Emergency room visit or hospitalization is required. 
11.1.8.4 Serious Adverse Events 
If any AEs are serious, as defined by the FDA Code of Federal Regulations (CFR), 
Chapter 21, special procedures will be followed. All SAEs will be reported to the Sponsor 
via fax or e-mail within one working day of becoming aware of the event, whether or not the 
serious events are deemed drug-related. All serious event reporting will adhere to 
21 CFR 312.32 for Investigational New Drugs (IND) and to the Guidance for Industry and 
Investigators: Safety Reporting Requirements for INDs and BA/BE, dated December 2012 
[7].The IRB will be notified of the Alert Reports as per FDA regulations. 
A SAE is any AE or suspected adverse reaction that in the view of either the PI (or designee) 
or Sponsor, results in any of the following outcomes:  Death, a life-threatening adverse event, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in the above definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse.  
Life-threatening is defined as an AE or suspected adverse reaction that in the view of the PI 
(or designee) or Sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. 
Unexpected is defined as an AE or suspected adverse reaction that is not listed in the IB or is 
not listed at the specificity or severity that has been observed; or is not consistent with the 


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CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
risk information described in the general investigational plan or elsewhere in the current 
application, as amended. 
If a SAE occurs to a subject on this study, contact the Sponsor personnel listed in Section 3. 
11.2 Pharmacodynamic Assessment – APC-PCI 
11.2.1 Blood Sampling and Processing 
For all subjects, blood samples for the determination of APC-PCI will be collected in sodium 
heparin blood collection tubes at scheduled time points as delineated in the Study Events 
Flow Chart (Section 6) and processed to plasma.  
The sample times and Hour 0 are in relation to start of IV bolus.  
At the end of the study, platelet poor plasma samples obtained by centrifugation of 
heparinized blood will be shipped to the analytical laboratory for analysis. 
Instruction for blood sampling, collection, processing, and sample shipment will be provided 
separately. 
11.2.2 Analytical Method 
Plasma sample analysis for APC-PCI will be performed by Celerion using qualified 
bioanalytical methods. 
11.3 Pharmacodynamic Assessments – Real-Time aPTT and protein C  
11.3.1 Blood Sampling and Processing 
Blood samples for real-time aPTT and protein C will be analyzed by Aronora on site. 
Samples will be collected in blood collection tubes containing 3.2% sodium citrate at 
scheduled time points as delineated in the Study Events Flow Chart (Section 6) by a Celerion 
employee, and transferred directly to an Aronora employee for sample processing as per their 
internal procedures.  
At the end of the study, platelet poor plasma samples obtained by centrifugation of citrated 
blood will be shipped to the Sponsor for their internal analyses. 
11.3.2 Analytical Method 
Citrated plasma sample analysis for real-time aPTT and protein C will be performed by the 
Sponsor using their internal method.  


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11.4 Blood Volume for Study Assessments 
Table 3: 
Blood Volume during the Study 
Sample Type 
Number of 
Time 
Points 
Approximate 
Volume per 
Time Point * 
(mL) 
Approximate 
Sample Volume 
Over Course of 
Study (mL) 
Screening laboratory safety tests 
(including hematology, serum 
chemistry, serology, and coagulation), 
FSH (for postmenopausal female 
subjects only) and serum pregnancy 
(for female subjects only). 
1 
16 
16 
On-study hematology, serum chemistry 
(this includes serum pregnancy for 
female subjects only when scheduled 
at the same time) 
2 
12.5 
25 
On-study coagulation (aPTT, PT/INR, 
fibrinogen, and, if scheduled at the 
same time, thrombin time)** 
10 
3.5 
35 
Thrombin Time only  
1 
3.5 
3.5 
Blood for plasma immunogenicity 
(E-WE thrombin plasma ADA) 
(Celerion) 
3 
9 
27 
Blood for serum immunogenicity (WT 
thrombin serum ADA) (Celerion) 
3 
5 
15 
Real-time aPTT: Citrated (3.2%) blood 
for aPTT (Aronora)  
8 
2.7 
21.6 
Real-time protein C: Citrated (3.2%) 
blood for protein C (Aronora)  
4 
1.8 
7.2 
Blood for APC-PCI (Celerion) 
8 
4 
32 
Total Blood Volume (mL)→ 
182.3*** 
* Represents the largest collection tube that may be used for this (a smaller tube may be used). 
** If by Day 14 aPTT and/or thrombin time values have not returned within ± 10% of the baseline value or the 
normal range, sampling will continue every 7 days (± 2 days) until the ± 10% of baseline value or to the 
normal range is reached or a maximum of ~500 mL of blood is collected from the subject. Subjects who 
terminate the study early will also be asked to return every 7 days (± 2 days) for aPTT and thrombin time 
monitoring until values return within ± 10% of baseline value or the normal range. 
*** If additional safety or PD analysis is necessary or if larger collection tubes are required to obtain sufficient 
plasma/serum for analysis, additional blood may be obtained (up to a maximum of 50 mL). 


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12. DATA ANALYSIS 
Data will be handled and processed according to Celerion Standard Operating Procedures, 
which are written based on the principles of GCP. 
12.1 Statistical Analysis 
Detailed methodology for summary and statistical analyses of the data collected in this trial 
will be documented in a Statistical Analysis Plan (SAP). The SAP will be prepared by 
Celerion and agreed upon with the Sponsor. This document may modify the plans outlined in 
the protocol; however, any major modifications of the primary endpoints definition and/or its 
analysis will also be reflected in a protocol amendment. Additional statistical analyses other 
than those described in this section may be performed if deemed appropriate and included in 
the SAP.  
12.1.1 Sample Size Calculation 
The sample size chosen for this study was selected without statistical considerations. It has 
been determined adequate to meet the study objectives. Cohort 1 with 6 subjects (4 active 
and 2 placebo) and Cohorts 2, 3, and 4 with 5 subjects (4 active and 1 placebo) are sufficient 
to characterize the single-dose safety, tolerability, and PD profile. 
12.1.2 Subjects to Analyze 
Safety population:  All subjects who received the study drug (active or placebo) will be 
included in the safety summary. 
PD population:  All subjects receiving the study drug (active or placebo) and having any 
measurable PD data will be included in the PD data set. The Sponsor will assess the real-time 
aPTT on-site, and also evaluate protein C. 
12.1.3 Safety Analysis 
The following analyses will be performed; however no formal inferential statistics will be 
done on safety assessments. 
The placebo subjects from all cohorts will be pooled into a single placebo group for all 
summaries and presentations. 
Descriptive statistics will be calculated for quantitative safety data and frequency counts will 
be compiled for classification of qualitative safety data, as appropriate. 
Adverse Events: 
AEs will be coded using the most current version of MedDRA® available at Celerion.  
A by-subject AE data listing, including verbatim term, preferred term, treatment, severity, 
and relationship to drug, will be provided. 


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The number of subjects experiencing TEAEs and number of TEAEs will be summarized by 
dose level using frequency counts. 
Injection site reaction will be assessed. 
Medical History and Physical Examination: 
Medical history will be listed by subject.  
Changes in physical examinations will be described in the text of the final report. 
Clinical Laboratory Results, Electrocardiograms, and Vital Signs Measurements: 
All clinical laboratory results, 12-lead ECGs, vital signs measurements, and their change 
from baseline, will be summarized by dose level and time point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical laboratory 
results.  
Thrombin time will be assessed. 
Concomitant Medications: 
Concomitant medications will be listed by subject. 
Immunogenicity: 
ADA detection will be reported and summarized descriptively. 
12.2 Pharmacodynamics 
12.2.1 Pharmacodynamic Parameters 
APC-PCI values will be listed and presented graphically.  
12.2.2 Statistical Methods for Pharmacodynamic Analyses 
The placebo subjects from all cohorts will be pooled into a single placebo group for all 
summaries and presentations. 
Individual, mean, and median data APC-PCI values, will be presented graphically for all 
treatments. 
Additional analyses may be performed as deemed necessary upon review of the data. 
12.3 Assessment of Pharmacokinetics 
Pharmacokinetics will not be assessed in this study. 
 


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13. STUDY ADMINISTRATION 
13.1 Ethics 
13.1.1 Institutional Review Board 
This protocol will be reviewed by the Advarra IRB, and the study will not start until the IRB 
has approved the protocol or a modification thereof. The IRB is constituted and operates in 
accordance with the principles and requirements described in the US Code of Federal 
Regulations (21 CFR Part 56). The IRB is compliant to International Council on 
Harmonisation (ICH) guidelines, and may be reached at: 
Advarra IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, Maryland 21046, USA 
Tel.:  +1 410 884-2900 
13.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, 21 CFR Parts 50, 56, and 312, the ethical principles set forth in the Declaration 
of Helsinki, GCP, and the ICH harmonized tripartite guideline regarding GCP (E6 
Consolidated Guidance, April 1996). 
13.1.3 Subject Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign and 
date an ICF summarizing the discussion at screening, and will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care. 
Subjects will be given a copy of their signed ICF. 
13.2 Termination of the Study 
The Sponsor reserves the right to discontinue this study and Celerion reserves the right to 
terminate the study in the interest of subject welfare, at any time. 
13.3 Data Quality Assurance 
Standard operating procedures are available for all activities performed at Celerion relevant 
to the quality of this study. Designated personnel of Celerion will be responsible for 
implementing and maintaining quality assurance (QA) and quality control systems to ensure 
that the trial is conducted, and that data are generated, documented and reported in 
compliance with the study protocol, GCP and GLP requirements as well as applicable 
regulatory requirements and local laws, rules and regulations relating to the conduct of the 
clinical study. 


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The Clinical Study Report will be audited by the QA department and the QA audit certificate 
will be included in the study report. 
All clinical data will undergo a 100% quality control check prior to clinical database lock. 
Edit checks are then performed for appropriate databases as a validation routine using SAS® 
to check for missing data, data inconsistencies, data ranges etc. Corrections are made prior to 
statistical database lock. 
13.4 Direct Access to Source Data/Documents 
The PI must maintain, at all times, the primary records (i.e., source documents) of each 
subject’s data. Examples of source documents are laboratory reports, drug inventory, study 
drug label records, and CRFs that are used as the source. 
Celerion will ensure that the Sponsor, IRB and inspection by domestic and foreign regulatory 
authorities will have direct access to all trial-related sites, source data/documents, and reports 
for the purpose of monitoring, auditing (ICH[E6] 5.1.2 & 6.10) and inspection. In the event 
that other trial-related monitoring should be done by other parties, they will be required to 
sign a confidentiality agreement prior to any monitoring and auditing. 
13.5 Study Supplies 
The Sponsor will supply sufficient quantities of E-WE thrombin and the placebo to allow 
completion of this study. The lot numbers, manufacture dates, and expiration dates (if 
available) of the drugs supplied will be recorded in the final report. 
The investigational product(s) will be shipped to a designee at the study site and must be 
stored in a pharmacy or locked and secured in a storage facility with controlled temperature. 
Humidity in the room will be monitored. The room is accessible only to those individuals 
authorized by the PI. 
Records will be made of the receipt and dispensing of the study drugs supplied. At the 
conclusion of the study, any unused study drugs (including placebo) as well as original 
containers (even if empty), will be retained by Celerion, returned to the Sponsor or designee, 
or destroyed, as per Sponsor instructions. If no supplies remain, this fact will be documented 
in the pharmacy product accountability records. 
13.6 Data Handling and Record Keeping 
Celerion CRFs will be used. CRFs are printed directly from the ClinQuick® database. Each 
CRF is reviewed and signed off by the PI. 
ClinQuick® is a fully integrated, study management and data capture system designed and 
built by Celerion for use in phase 1 clinical research centers. ClinQuick® will be used for all 
data that can be captured electronically via barcode or electronic acquisition (e.g., vital signs, 
meal times, blood draw times, etc.). Electronic changes will be traceable through computer 
capture. 


E-WE Thrombin 
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Sponsor Project No.:  EWE-17-01 
SAD Study Protocol 
Celerion Project No.:  CA19169 
Aronora Inc. 
US PIND No.:  PTS #PS003017; CRMTS #10353 
 
CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
Other data (e.g., medical history, inclusion/exclusion criteria, etc.) will be entered into 
ClinQuick® by remote data entry or via double data entry by 2 different associates using an 
automated verification system within ClinQuick®. AEs and concomitant medications will be 
entered into ClinQuick® by single data entry. 
Visual and computerized methods of data validation will be applied in order to ensure 
accurate, consistent, and reliable data for the subsequent statistical analysis. 
These procedures aim to detect out-of-range values, contradictory data, abnormal evolutions 
over time, and possible undetected protocol violations (eligibility criteria, time and 
medication compliance, etc.). 
All raw data generated in connection with this study, together with the original copy of the 
final report, will be retained by Celerion until at least 5 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 5 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the Sponsor. It is the responsibility of the Sponsor to 
inform the PI/Institution as to when these documents no longer need to be retained. 
13.7 Report Format 
According to the ICH Harmonized Tripartite Guideline (Organization of the Common 
Technical Document for the Registration of Pharmaceuticals for Human Use M4 and the ICH 
M2 Expert Working Group), the final report will be written according to the ICH E3 
Guideline (Structure and Content of Clinical Study Reports). 
13.8 Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study progresses 
will be discussed between Sponsor and the PI or designee. All revisions and/or amendments 
to the protocol in writing must be approved by the Sponsor, the PI or designee, and the IRB 
before implementation. 
13.9 Publication Policy 
All unpublished information given to Celerion by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor. 
The data generated by this study are considered confidential information and the property of 
the Sponsor. This confidential information may be published only in collaboration with 
participating personnel from the Sponsor or upon Sponsor’s written consent to publish the 
article. 
 
 


E-WE Thrombin 
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Sponsor Project No.:  EWE-17-01 
SAD Study Protocol 
Celerion Project No.:  CA19169 
Aronora Inc. 
US PIND No.:  PTS #PS003017; CRMTS #10353 
 
CA19169 (EWE-17-01) Final Protocol Amendment 2 14May2018 
14. REFERENCES 
1. Aronora, Inc.:  E-WE thrombin, AB002. Investigators Brochure. Version Number 1; 29 
March 2017. 
2. Berny MA., et al., Thrombin mutant W215A/E217A acts as a platelet GPIb antagonist. 
Arterioscler Thromb Vasc Biol, 2008. 28(2): p. 329-34. 
3. Berny-Lang MA., et al., Thrombin mutant W215A/E217A treatment improves 
neurological outcome and reduces cerebral infarct size in a mouse model of ischemic 
stroke. Stroke, 2011. 42(6): p. 1736-41. 
4. Gruber, A., et al., Relative antithrombotic and antihemostatic effects of protein C 
activator versus low-molecular-weight heparin in primates. Blood, 2007. 109(9): p. 3733-
40. 
5. FDA Guidance for Industry: Estimating the maximum safe starting dose in initial clinical 
trials for therapeutics in adult healthy volunteers. July 2005. Available online:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/ucm078932.pdf   
6. FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. September 2007. Available 
online:  
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator
yInformation/Guidances/Vaccines/ucm091977.pdf 
7. FDA Guidance for Industry and Investigators: Safety Reporting Requirements for INDs 
and BA/BE, dated December 2012. Available online at:  
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM227351.pdf 
8. FDA (CBER) Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. September 2007. 
Available online at: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator
yInformation/Guidances/Vaccines/ucm091977.pdf 

SAP_000.pdf: 
Statistical Analysis Plan 
 
A Phase 1, Single Ascending Dose, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Safety, Tolerability, and Pharmacodynamics of E-WE Thrombin as an 
Intravenous Bolus in Healthy Adult Subjects 
Protocol No: CA19169 
Sponsor Project No.:  EWE-17-01 
US PIND No.:  PTS #PS003017; CRMTS #10353; IND No. 018154 
Final Protocol Date: 19 February 2018 
Amendment 1 Date: 27 March 2018 
Amendment 2 Date: 14 May2018  
Compound Name: E-WE thrombin 
 
 
Celerion Project CA19169 
Final Version 1.0 
Date: 25 July 2018 
 
Aronora, Inc. 
4640 SW Macadam Avenue, Suite 200A 
Portland, Oregon 97239, USA 
 
Celerion 
100 Alexis-Nihon Boulevard 
Suite 360, Montreal 
QC, H4M 2N8, Canada  
 
 


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 2 of 78 
Statistical Analysis Plan Signature Page 
Compound Name: E-WE thrombin 
Protocol: CA19169 
Study Title: A Phase 1, Single Ascending Dose, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of 
E-WE Thrombin as an Intravenous Bolus in Healthy Adult Subjects 
Issue Date: 25 July 2018 
 
 
Signature:_____________________________________ 
Date:_______________ 
Angela Mirzac 
Biostatistician II, Data Management and Biometrics 
Celerion 
100 Alexis-Nihon Boulevard, Suite 360 
Montreal, Quebec, H4M 2N8, Canada  
Signature:_____________________________________ 
Date:_______________ 
Mary Lor, BSc, GrDip 
Senior Scientist II, Clinical Pharmacology Sciences 
Celerion 
100 Alexis Nihon Blvd., Suite 360 
Montreal, Quebec, H4M 2N8, Canada 
 
Signature:_____________________________________ 
Date:_______________ 
Norah Verbout, PhD 
Senior Scientist & Project Manager 
Aronora, Inc. Portland, OR 97239, USA 


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 3 of 78 
Table of Contents 
1. 
INTRODUCTION ..............................................................................................................4 
2. 
OBJECTIVES AND ENDPOINTS ....................................................................................4 
2.1 
Objectives ..................................................................................................................4 
2.2 
Endpoints ..................................................................................................................4 
3. 
STUDY DESIGN ...............................................................................................................4 
4. 
ANALYSIS POPULATIONS ............................................................................................6 
4.1 
Analysis Populations .................................................................................................6 
4.2 
Preliminary Data and Interim Analysis .....................................................................6 
5. 
TREATMENT DESCRIPTIONS .......................................................................................6 
6. 
PHARMACODYNAMIC ANALYSIS ..............................................................................7 
6.1 
APC-PCI ...................................................................................................................7 
6.2 
Real-Time aPTT ........................................................................................................8 
6.3 
Protein C ...................................................................................................................8 
6.4 
Data Summarization and Presentation ......................................................................8 
7. 
IMMUNOGENICITY ........................................................................................................8 
8. 
SAFETY .............................................................................................................................9 
8.1 
Subject Discontinuation ............................................................................................9 
8.2 
Demographics ...........................................................................................................9 
8.3 
Adverse Events..........................................................................................................9 
8.4 
Clinical Laboratory Tests (Serum Chemistry, Hematology, Coagulation,  
Urinalysis) ...............................................................................................................10 
8.5 
Vital Signs ...............................................................................................................12 
8.6 
Electrocardiogram ...................................................................................................12 
8.7 
Concomitant Medications .......................................................................................13 
8.8 
Physical Examination ..............................................................................................13 
8.9 
Injection Site ...........................................................................................................13 
9. 
SUMMARY OF CHANGES FROM PROTOCOL-PLANNED ANALYSIS ................13 
10. SUMMARY TABLES AND FIGURES ..........................................................................13 
10.1 In-text Summary Tables and Figures ......................................................................13 
10.2 Section 14 Summary Tables and Figures ................................................................14 
10.3 Section 16 Data Listings .........................................................................................18 
11. TABLE AND FIGURE SHELLS .....................................................................................21 
11.1 In-text Summary Tables Shells ...............................................................................22 
11.2 Section 14 Summary Tables Shells .........................................................................28 
12. LISTING SHELLS ...........................................................................................................52 
 


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E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 4 of 78 
1. INTRODUCTION 
The following statistical analysis plan (SAP) provides the framework for the 
summarization of the data from this study. The SAP may change due to unforeseen 
circumstances. Any changes made from the planned analysis within protocol, after 
the unblinding, or locking of the database will be documented in the clinical study 
report (CSR). The section referred to as Table Shells within this SAP describes the 
traceability of the tables, figures, and listings (TFLs) back to the data. Note that the 
header for this page will be the one used for the main body of the CSR.  
Any additional exploratory analyses not addressed within this SAP and/or driven by 
the data, or requested by Aronora, Inc., will be considered out of scope and must be 
described in the CSR.  
2. OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
The primary objective of the study is to assess the safety and tolerability of single 
intravenous (IV) bolus doses of E-WE thrombin when administered to healthy adult 
subjects. 
The secondary objective is to assess the pharmacodynamics (PD) of single IV bolus 
doses of E-WE thrombin when administered to healthy adult subjects. The activated 
protein C/protein C inhibitor complex (APC-PCI) will be used as a surrogate 
biomarker for drug exposure. 
2.2 
Endpoints 
The primary endpoints of the study will be the number and severity of treatment-
emergent adverse events (TEAEs) following single IV bolus doses of E-WE thrombin 
and placebo. In addition, physical examinations, vital signs, electrocardiograms 
(ECGs), clinical laboratory tests (including coagulation), thrombin time, 
immunogenicity, and injection site reaction will be assessed throughout the study. 
The secondary endpoints are the PD (i.e., APC-PCI) of E-WE thrombin following 
single IV bolus doses. PD will act as a surrogate for pharmacokinetics (PK) of E-WE 
thrombin. 
3. STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, single ascending dose (SAD) 
study conducted at one study center in the United States (US).  
Four (4) cohorts of either 6 subjects (Cohort 1 [4 active and 2 placebo]) or 5 subjects 
(Cohorts 2, 3, and 4 [4 active and 1 placebo]) are planned for evaluation.  


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 5 of 78 
In each cohort, subjects will receive a single IV bolus of E-WE thrombin or placebo. 
Subjects will participate in only 1 cohort. 
Cohort 1 will contain a sentinel group of 2 subjects (1 placebo and 1 active) who will 
be dosed at least 28 days before the remaining group of subjects. The remaining 
subjects in Cohort 1, and subjects in each of Cohorts 2, 3, and 4 will be dosed in 
2 groups separated by at least 14 days (2 subjects in each group [Cohort 1] or 
2 subjects in the first group and 3 subjects in the second group [Cohorts 2-4]). The 
placebo will be randomized to one of the groups.  
Dose escalation to the next dose level (i.e., next cohort) will not take place until after 
the Principal Investigator (PI) has reviewed the safety data. If any findings in the 
safety data are of concern, then the Safety Review Committee (SRC) comprised of 
but not limited to, the Sponsor, medical monitor, and the PI will convene to determine 
if adequate safety and tolerability from the previous cohort has been demonstrated to 
permit proceeding to the next cohort. Data from all subjects in the cohort will be used 
and reviewed for a dose escalation decision and a minimum of 4 subjects must 
complete the study (up to Day 14) before proceeding to the next higher dosing cohort. 
Subjects will participate in only one cohort. An attempt will be made to have at least 
30% of the total subjects of a race/ethnicity minority group. An attempt will be made 
to include at least 2 females per cohort. 
Safety (i.e., physical examinations, vital signs, ECGs, clinical laboratory tests 
[including coagulation], thrombin time, immunogenicity, injection site reaction, and 
AEs) will be assessed throughout the study.  
Blood samples will be collected for PD assessment (i.e., APC-PCI) of E-WE 
thrombin.  
Blood samples will be also collected for the ADA evaluation. 
Subjects will be housed on Day -1, at the time indicated by the clinical research unit 
(CRU), until after the 24-hour blood draw and/or study procedures. At all times, a 
subject may be required to remain at the CRU for longer at the discretion of the PI or 
designee. 
Subjects (including those who terminate early) will return on Days 14 and 28 for 
follow-up (FU) procedures (coagulation sample collection, thrombin time 
measurement, and immunogenicity sample collection) and to determine if any AE has 
occurred since the last study visit). Subjects who terminate the study early will be 
asked to continue aPTT and thrombin time monitoring as scheduled until Day 28. 
Any subjects for whom aPTT and/or thrombin time did not reach ± 10% of the 
baseline value or within the normal range by Day 14, will return every 7 days 
(±2 days) until aPTT and thrombin time reach ±10% of the baseline value or within 


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 6 of 78 
the normal range and for a FU visit (i.e., FU procedures and AE evaluation listed on 
Day 28 will be repeated) 7 days (± 2 days) after it was reached. 
The total planned duration of subject participation is approximately 56 days from 
screening to last FU. 
4. ANALYSIS POPULATIONS 
4.1 
Analysis Populations 
Safety population:  All subjects who received the study drug (active or placebo) will 
be included in the safety summary. 
PD population:  All subjects receiving the study drug (active or placebo) and having 
any measurable PD data will be included in the PD data set. The Sponsor will assess 
the real time aPTT on-site. The protein C samples will be processed by Celerion 
associates and then shipped to Aronora for later analysis.  
4.2 
Preliminary Data and Interim Analysis 
If there are safety concerns, all available blinded safety/tolerability data (i.e., physical 
examinations, ECGs, vital signs, clinical laboratory tests [including coagulation], 
thrombin time, injection site reaction, and AEs available for all subjects who have 
completed up to Day 14 procedures) will be reviewed by the SRC prior to dose 
escalation.  
At the Sponsor’s request, unblinded safety tables, figures, and data listings may be 
presented to the sponsor’s medical expert and head of regulatory for the purposes of 
planning the next initial Phase 2 studies prior to database lock. These interim analyses 
will be performed on data that will be edit-checked and monitored. 
A safety programmer and a biostatistician at Celerion who are not involved with the 
present study will be unblinded to prepare the required unblinded safety tables, 
figures, and data listings. All the personnel related to the present study will remain 
blinded. 
5. TREATMENT DESCRIPTIONS 
E-WE thrombin will be supplied as sterile, non-pyrogenic, preservative-free liquid for 
IV administration. E-WE thrombin will be supplied as 0.1 mg/mL for IV use and 
given as a single IV bolus, according to the planned dose (mcg/kg) for each cohort, as 
noted Table 5.1. Matching placebo will be supplied as sterile formulation buffer for 
injection via IV route. 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 7 of 78 
 
 
Table 5.1 Dosing Duration 
Dose Level 
Manual Push Time 
Cohort 1: 0.5 mcg/kg 
~ 15 seconds 
Cohort 2: 1.0 mcg/kg 
~ 15 seconds 
Cohort 3: 2.0 mcg/kg 
~ 30 seconds 
Cohort 4: 4.0 mcg/kg 
~ 1 minute 
 
Dose levels will be used in the presentation of tables, figures, and listings. Dose 
levels will be described as proposed in Table 5.2 below: 
Table 5.2 Description of Dose Levels 
 
Dose Level 
Abbreviated Description  
0.5 mcg/kg 
0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg 
1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg 
2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg 
4.0 mcg/kg E-WE thrombin (IV bolus) 
Pooled Placebo 
Placebo Solution (IV bolus) 
Note: The planned dose levels described above may be revised up or down or a dose 
level may be repeated based upon data from a previous dose level, however, doses 
will not exceed 4.0 mcg/kg without a protocol amendment. 
6. PHARMACODYNAMIC ANALYSIS 
There will be 5 dose levels consisting of 4 active drug and 1 pooled placebo. The 
placebo subjects from all dose levels will be pooled into a single placebo group for all 
summaries and presentations. 
Individual, mean, and median data will be presented graphically for all dose levels as 
well as pooled placebo group.  
Additional analyses may be performed as deemed necessary upon review of the data. 
6.1 
APC-PCI 
APC-PCI values will be listed and presented graphically. 
Plasma for APC-PCI will be collected at predose, 0.083, 0.25, 0.5, 1, 2, 4, and 24 hours 
postdose. The sample times and Hour 0 are in relation to start of IV bolus. 


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 8 of 78 
Sample analysis for APC-PCI will be performed by Celerion (Lincoln, NE). 
6.2 
Real-Time aPTT  
Blood samples for real-time aPTT will be analyzed by Aronora on site. Samples will 
be collected in blood collection tubes containing 3.2% sodium citrate by a Celerion 
employee and transferred directly to an Aronora employee for sample processing as 
per their internal procedures.  
At the end of the study, platelet poor plasma samples obtained by centrifugation of 
citrated blood will be shipped to the Sponsor for their internal analyses. 
Blood samples for the assessment of real-time aPTT will be collected at predose, 
0.083, 0.25, 0.5, 1, 2, 4, and 24 hours postdose. 
Data for real-time aPTT will not be analyzed by Celerion. 
6.3 
Protein C 
Blood sample for the assessment of protein C will be collected at the following 
timepoints: predose, 1, 2, and 24 postdose. The protein C samples will be processed 
by Celerion associates and then shipped to Aronora for their internal analyses. 
Data for protein C will not be analyzed by Celerion. 
6.4 
Data Summarization and Presentation 
All PD markers will be tabulated by dose level and a pooled placebo group. Summary 
statistics, including the number of observations (n), arithmetic mean (mean), standard 
deviation (SD), coefficient of variation (%CV), minimum, median, and maximum 
will be computed.  
The level of precision will be presented as follows: n will be presented without 
decimal, mean, SD, minimum, median, and maximum will be presented to 1 decimal 
place. All percentages will be presented to 1 decimal place. 
7. IMMUNOGENICITY 
Plasma and serum samples for immunogenicity testing will be collected on Days -1, 
14, and 28. If ADA are detected on Days 14 and 28, the check-in sample on Day -1 
will be also evaluated. ADA detection will be reported and summarized.  
Assessment of ADA will be performed by Haemtech Biopharma Services, Inc. 
For samples with a positive confirmatory assay, titers of ADA will be presented with 
the same level of precision as received from the bioanalytical laboratory. A table will 
be provided for ADA positive duration for each dose level, where duration is defined 


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 9 of 78 
as the time interval between the first postdose and last postdose occurrence of 
positive ADA. 
8. SAFETY  
No inferential statistics will be performed on the safety endpoints. 
All Case Report Form (CRF) data will be listed by subject and chronologically by 
assessment time points. This will include rechecks, unscheduled assessments, and 
early termination results.  
Applicable continuous variables will be summarized using the number of 
observations (n), mean, SD, minimum, median, and maximum. Frequency counts will 
be reported for categorical data, when appropriate. The placebo subjects from all 
cohorts will be pooled into a single group for summarization.   
The level of precision will be presented as follows: minimum/maximum in the same 
precision as in the database, mean/median in one more precision level than 
minimum/maximum, SD in one more precision level than mean/median, and n will be 
presented as an integer. 
For laboratory, ECGs, and vital signs, where individual data points are missing 
because of dropouts or other reasons, the data will be summarized based on reduced 
denominators. 
8.1 
Subject Discontinuation 
Subject disposition will be listed and summarized by number of subjects dosed, 
completed, and discontinued the study with discontinuation reasons by dose level, 
pooled placebo, and for overall the study. 
8.2 
Demographics 
Demographic data will be listed and summarized. Descriptive statistics will be 
calculated for continuous variables (age, weight, height, and body mass index [BMI]) 
by dose level, pooled placebo, and for overall the study. Frequency counts will be 
provided for categorical variables (race, ethnicity, and sex) by dose level, pooled 
placebo, and for overall the study. Age will be derived from date of birth to date of 
first dosing. 
8.3 
Adverse Events 
All AEs occurring during this clinical trial will be coded using the MedDRA®, 
Version 21.0 or a later version if available. All AEs captured in the database will be 
listed in by-subject data listings including verbatim term, coded term, dose level, 
placebo, severity, relationship to study drug, and action; however, only treatment-


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Statistical Analysis Plan, 25 July 2018 
Page 10 of 78 
emergent AEs (TEAEs) will be summarized. Any non-drug procedure performed due 
to an AE will be listed by subject. 
A TEAE is defined as an AE that is starting or worsening at the time of or after the 
study drug dose administration. If an AE increases in severity, that AE will be given a 
resolution date and time and a new record will be initiated with the new severity. If 
the severity of an AE remains the same or decreases, the AE will be kept open 
through to resolution and the maximum severity will be recorded. If the onset time of 
an AE is missing and the onset date is the same as the treatment dosing date or does 
not fall on a dosing date, the AE will be considered treatment-emergent. If the onset 
date of an AE is missing, then the AE will be considered treatment-emergent. 
TEAEs will be tabulated by system organ class (SOC) and preferred term. Summary 
tables will include number of subjects reporting the TEAE and corresponding 
percentage by dose level, pooled placebo, and overall the study. The number of 
TEAEs will be summarized in a similar way. Percentages will be based on the total 
number of subjects dosed or total number of TEAEs, respectively, for each dose level, 
pooled placebo, or overall the study, as appropriate. In addition, the number of 
TEAEs will be summarized by severity and relationship to study drug. 
If present, serious adverse events (SAEs) will be listed, displayed in a table, and a 
narrative included in the study CSR. 
8.4 
Clinical Laboratory Tests (Serum Chemistry, Hematology, Coagulation, 
 
Urinalysis) 
Clinical laboratory reference ranges will be listed by laboratory group, test, sex, and 
age category, where appropriate. 
Serum chemistry, hematology, coagulation, and urinalysis will be performed at the 
following time points: 
Table 8.1 Laboratory Data Time Points 
Test 
Period 
Day  
Hour 
Serum Chemistry/ 
Hematology/  
Urinalysis 
Screen 
 
 
1 
-1 
Check-in 
 
2* 
24 
Coagulation 
Screen 
 
 
 
1 
Predose, 0.083, 0.25, 0.5, 1, 
2, 4 
 
2* 
24 
 
14 
FU 
 
28 
FU 
*Prior to discharge from CRU or at early termination from the study. 
FU = Follow-up 
Out-of-normal range flags (1st flag) will be recorded as follows:  


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Statistical Analysis Plan, 25 July 2018 
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• for numerical results: high (H) and low (L);  
• for categorical results: did-not-match (*).  
If a value fails the reference range, it will automatically be compared to a computer 
clinically significant (CS) range (2nd flag).  
• If the value falls within the computer CS range, it will be noted as “N” for not 
clinical significant.  
• If the value fails the CS range, it will be flagged with a “Y” which prompts 
the PI to determine how the out-of-range value should be followed using 4 PI 
flags (3rd flag):  
o "N", not clinically significant,  
o "R", requesting a recheck,  
o "^", checking at the next scheduled visit,  
o "Y", clinically significant.  
To distinguish the PI flags from the computer CS range flags, the PI flags “N” and 
“Y” will be presented as “-“ and “+” in the data listing, respectively. 
In addition, a derived flag (a 4th flag) based on a search of the PI comments for a 
comment of “CS” or “Clinically Significant” will be used. The derived flag will be 
populated with “+” if the positive clinically significant determination is found in the 
comments for cases when the PI flag is populated with a “^” or a “R”. 
Out-of-range values and corresponding recheck results will be listed. Out-of-range 
values are considered to be values that are out-of- normal range as defined by the 
clinical laboratory. Results that are indicated as CS by the PI (either in the PI flag or 
in PI comments) will be also listed in a separate table.  
For all safety values that are numeric, descriptive statistics will be presented for each 
laboratory test by dose level, pooled placebo, and time point. Change from baseline 
will be summarized in a similar way. In addition, for the activated partial 
thromboplastin time (aPTT) (coagulation test), the fold change from baseline will be 
calculated and summarized in a similar way. The following formula will be used for 
the calculation: postdose/baseline. Baseline is defined as the result closest and prior to 
the dose on Day 1 (i.e., Day 1 for Coagulation and Day -1 for the rest of tests) which 
may include unscheduled or recheck results, whichever is later. Postdose unscheduled 
events or rechecks will not be included in summaries. Similarly early termination 
results will not be included in summaries.  


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Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
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For each laboratory test, a shift table will be developed to compare the frequency of 
the results at baseline (above normal, normal, or below normal) with the respective 
postdose results. For urinalysis tests, the categories are normal and outside normal. 
8.5 
Vital Signs 
Single measurements of systolic and diastolic blood pressure, heart rate, body 
temperature, and respiratory rate will be obtained in supine position at the following 
time points: 
Table 8.2 Vital Signs Data Time Points 
Measurement 
Period 
Day 
Hour 
Blood Pressure /  
Heart Rate/  
Respiratory Rate / 
Body Temperature 
Screen 
 
 
1 
1  
Predose, 0.25, 0.5, 1, 2, 4  
2* 
24 
*Prior to discharge from CRU or at early termination from the study. 
Vital signs tests will be summarized by dose level, pooled placebo, and time point. 
Change from baseline will be summarized in a similar way. Baseline is defined as the 
result closest and prior to the dose on Day 1, which may include unscheduled or 
recheck results, whichever is later. Postdose unscheduled events or rechecks will not 
be included in summaries. Similarly early termination results will not be included in 
summaries. 
8.6 
Electrocardiogram 
Single 12-lead ECGs (i.e., HR, PR, QRS, QT, and QTcF [i.e., QT corrected for heart 
rate using Fridericia’s correction]) will be measured at the following time points: 
Table 8.3 12-Lead Electrocardiogram Data Time Points 
Parameter 
Period 
Day 
Hour 
HR, PR, QRS, QT, 
QTcF 
Screen 
 
 
1 
1 
Predose  
 
2* 
24 
*Prior to discharge from CRU or at early termination from the study. 
ECGs will be summarized by dose level, pooled placebo, and time point. Change 
from baseline will be summarized in a similar way. Baseline is defined as the result 
closest and prior to the dose on Day 1, which may include unscheduled or recheck 
results, whichever is later. Postdose unscheduled events or rechecks will not be 
included in summaries. Similarly early termination results will not be included in 
summaries.  
The QTcF values that are > 450 ms and increase from baseline > 30 ms, will be 
flagged in the data listings. 


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E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 13 of 78 
8.7 
Concomitant Medications 
All concomitant medications recorded during the study will be coded with the WHO 
Dictionary Version 01-Mar-2018 or a later version if available and listed. 
8.8 
Physical Examination 
Full physical examination will be performed at screening. A symptom-driven 
physical examination will be performed at check-in and FU or may be performed at 
other scheduled times, at the PI’s or designee’s discretion. Abnormal findings will be 
reported as medical history or adverse events. All data found in the CRF will be 
listed. 
8.9 
Injection Site 
Injection and needle puncture site reactions for drug administration will be evaluated 
at the following time points: 
Table 8.4 Injection Site Reaction 
Parameter 
Period 
Day 
Hour 
Site Reaction 
Screen 
 
 
1 
1 
Predose, 1  
 
2* 
24 
*Prior to discharge from CRU or at early termination from the study. 
Abnormal findings will be reported as adverse events. 
9. SUMMARY OF CHANGES FROM PROTOCOL-PLANNED ANALYSIS 
The analyses described in this SAP are aligned with those analyses described in the 
protocol.  
10. SUMMARY TABLES AND FIGURES 
Summary tables and figures are numbered following the International Conference on 
Harmonization (ICH) structure but may be renumbered as appropriate during the 
compilation of the tables and figures for the CSR. Note that summary tables and 
figures will be generated using SAS® Version 9.3 or higher. 
10.1 
In-text Summary Tables and Figures 
The following is a list of table and figure titles that will be included in the text of the 
CSR. Tables and figures will be numbered appropriately during compilation of the 
CSR. 
Section 10: 
Table 10-1 
Subject Disposition Summary (Safety Population) 


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Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 14 of 78 
Section 11: 
Table 11-1 
Demographic Summary (Safety Population) 
Pharmacodynamics 
Table 11-2 
Summary of APC-PCI Pharmacodynamics Following Administration 
of a Single IV Dose of 0.5, 1.0, 2.0, and 4.0 mcg/kg E-WE Thrombin  
Figure 11-1 
Mean Plots of APC-PCI Pharmacodynamics Following Administration 
of a Single IV Dose of 0.5, 1.0, 2.0, and 4.0 mcg/kg E-WE Thrombin 
Immunogenicity 
Table 11-3 
Summary of Anti- E-WE Thrombin Plasma ADA Following 
Administration of a Single IV Dose of 0.5, 1.0, 2.0, and 4.0 mcg/kg E-
WE Thrombin 
Table 11-4 
Summary of Anti-WT Thrombin Serum ADA Following 
Administration of a Single IV Dose of 0.5, 1.0, 2.0, and 4.0 mcg/kg E-
WE Thrombin 
Section 12: 
Table 12-1 
Adverse Event Frequency by Dose Level - Number of Subjects 
Reporting the Event (% of Subjects Dosed) (Safety Population) 
10.2 
Section 14 Summary Tables and Figures 
The following is a list of table and figure titles that will be included in Section 14 of 
the CSR. Table and figure titles may be renumbered as appropriate during the 
compilation of the CSR. 
14.1 
Demographic Data Summary Tables 
Table 14.1.1 Subject Disposition Summary (Safety Population) 
Table 14.1.2 Demographic Summary (Safety Population) 
14.2 
Pharmacodynamic/Immunogenicity Data Summary Tables and Figures  
Pharmacodynamic Tables 
14.2.1 Plasma APC-PCI Tables 
Table 14.2.1.1 Plasma APC-PCI Levels (<units>) Following a Single IV 
Dose of 0.5 mcg/kg E-WE Thrombin (Pharmacodynamic 
Population) 


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 15 of 78 
Table 14.2.1.2 Plasma APC-PCI Levels (<units>) Following a Single IV 
Dose of 1.0 mcg/kg E-WE Thrombin (Pharmacodynamic 
Population) 
Table 14.2.1.3 Plasma APC-PCI Levels (<units>) Following a Single IV 
Dose of 2.0 mcg/kg E-WE Thrombin (Pharmacodynamic 
Population) 
Table 14.2.1.4 Plasma APC-PCI Levels (<units>) Following a Single IV 
Dose of 4.0 mcg/kg E-WE Thrombin (Pharmacodynamic 
Population) 
Table 14.2.1.5 Plasma APC-PCI Levels (<units>) Following Placebo 
Administrations of E-WE Thrombin (Pharmacodynamic 
Population) 
 
Immunogenicity Tables 
14.2.2 Anti-E-WE and Anti-WT Thrombin Antibody 
Table 14.2.2.1 
Plasma E-WE Thrombin ADA Detection Summary by 
Collection Time and Dose Level Following 
Administration of a Single IV Dose of 0.5, 1.0, 2.0, or 4.0 
mcg/kg E-WE Thrombin - Number of Subjects (% Total 
Subjects) 
Table 14.2.2.2 
Serum Anti-WT Thrombin ADA Detection Summary by 
Collection Time and Dose Level Following 
Administration of a Single IV Dose of 0.5, 1.0, 2.0, or 4.0 
mcg/kg  E-WE Thrombin - Number of Subjects (% Total 
Subjects) 
Table 14.2.2.3 
Summary of Titers for Plasma Anti-E-WE Thrombin 
Antibody 
Table 14.2.2.4 
Summary of Titers for Serum Anti-WT Thrombin 
Antibody 
Table 14.2.2.5 
Plasma Anti-E-WE Thrombin Antibody Duration by Dose 
Level Following Administration of a Single IV Dose of 
0.5, 1.0, 2.0, or 4.0 mcg/kg E-WE Thrombin 
Table 14.2.2.6 
Serum Anti-WT Thrombin Antibody Duration by Dose 
Level Following Administration of a Single IV Dose of 
0.5, 1.0, 2.0, or 4.0 mcg/kg E-WE Thrombin 
Pharmacodynamic Figures 
14.2.3 Plasma APC-PCI Figures 
Figure 14.2.3.1 Mean Plasma APC-PCI Levels Versus Time Profiles 
Following a Single IV Dose of 0.5, 1.0, 2.0, 4.0 mcg/kg, or 


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 16 of 78 
Placebo  E-WE Thrombin (Linear Scale) (Pharmacodynamic 
Population) 
Figure 14.2.3.2 Median Plasma APC-PCI Levels Versus Time Profiles 
Following a Single IV Dose of 0.5, 1.0, 2.0, 4.0 mcg/kg, and 
Placebo E-WE Thrombin (Linear Scale) (Pharmacodynamic 
Population) 
 
14.2.4 Immunogenicity Figures 
Figure 14.2.4.1 Summary of Titers for Plasma Anti-E-WE Thrombin 
Antibody by Treatment – Line Plot (Mean ± SD) for 
Confirmatory Test Results 
Figure 14.2.4.2 Summary of Titers for Plasma Anti-E-WE Thrombin 
Antibody by Treatment – Line Plot (Mean) for Confirmatory 
Test Results 
Figure 14.2.4.3 Summary of Titers for Serum Anti-WT Thrombin Antibody 
by Treatment – Line Plot (Mean ± SD) for Confirmatory Test 
Results 
Figure 14.2.4.4 Summary of Titers for Serum Anti-WT Thrombin Antibody 
by Treatment – Line Plot (Mean) for Confirmatory Test 
Results 
 
14.3 
Safety Data Summary Tables  
14.3.1 
Displays of Adverse Events 
Table 14.3.1.1 Treatment-Emergent Adverse Event Frequency by Dose 
Level – Number of Subjects Reporting the Event (% of 
Subject Dosed) (Safety Population) 
Table 14.3.1.2 Treatment-Emergent Adverse Event Frequency by Dose 
Level – Number of Adverse Events (% of Total Adverse 
Events) (Safety Population) 
Table 14.3.1.3 Treatment-Emergent Adverse Event Frequency by Dose 
Level, Severity, and Relationship to Study Drug – Number of 
Adverse Events (Safety Population)  
14.3.2 
Listings of Deaths, other Serious and Significant Adverse Events 
Table 14.3.2.1 Serious Adverse Events (Safety Population) 
14.3.3 
Narratives of Deaths, other Serious and Certain other 
Significant Adverse Events 


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E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 17 of 78 
14.3.4 
Abnormal Laboratory Value Listing (each patient) 
Table 14.3.4.1 Out-of-Range Values and Recheck Results – Serum 
Chemistry (Safety Population) 
Table 14.3.4.2 Out-of-Range Values and Recheck Results – Hematology 
(Safety Population) 
Table 14.3.4.3 Out-of-Range Values and Recheck Results – Coagulation 
(Safety Population) 
Table 14.3.4.4 Out-of-Range Values and Recheck Results – Urinalysis 
(Safety Population) 
Table 14.3.4.5 Clinically Significant Laboratory and Corresponding Results 
(Safety Population) 
14.3.5 
Displays of Other Laboratory, Vital Signs, Electrocardiogram, 
Physical Examination, and Other Safety Data 
Table 14.3.5.1 Clinical Laboratory Summary – Serum Chemistry (Safety 
Population) 
Table 14.3.5.2 Clinical Laboratory Change from Baseline – Serum 
Chemistry (Safety Population) 
Table 14.3.5.3 Clinical Laboratory Shift from Baseline – Serum Chemistry 
(Safety Population) 
Table 14.3.5.4 Clinical Laboratory Summary – Hematology (Safety 
Population) 
Table 14.3.5.5 Clinical Laboratory Change from Baseline – Hematology 
(Safety Population) 
Table 14.3.5.6 Clinical Laboratory Shift from Baseline – Hematology 
(Safety Population) 
Table 14.3.5.7 Clinical Laboratory Summary – Coagulation (Safety 
Population) 
Table 14.3.5.8 Clinical Laboratory Change from Baseline – Coagulation 
(Safety Population) 
Table 14.3.5.9 Clinical Laboratory Fold Change from Baseline – Activated 
Partial Thromboplastin Time (Safety Population) 
Table 14.3.5.10 Clinical Laboratory Shift from Baseline – Coagulation 
(Safety Population) 
Table 14.3.5.11 Clinical Laboratory Summary - Urinalysis (Safety 
Population) 
Table 14.3.5.12 Clinical Laboratory Change from Baseline – Urinalysis 
(Safety Population) 
Table 14.3.5.13 Clinical Laboratory Shift from Baseline – Urinalysis (Safety 
Population) 


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 18 of 78 
Table 14.3.5.14 Vital Sign Summary (Safety Population) 
Table 14.3.5.15 Vital Sign Change from Baseline (Safety Population) 
Table 14.3.5.16 12-Lead Electrocardiogram Summary (Safety Population) 
Table 14.3.5.17 12-Lead Electrocardiogram Change from Baseline (Safety 
Population) 
10.3 
Section 16 Data Listings 
Note: Hepatitis and HIV results that are provided by the clinical laboratory will not 
be presented in subject data listings and will not be included in any database transfer.  
Data listings are numbered following the ICH structure but may be renumbered as 
appropriate during the compilation of the TFLs for the CSR. The following is a list of 
appendix numbers and titles that will be included as data listings: 
16.1 
Study Information 
Appendix 16.1.9 
Statistical Methods 
Appendix 16.1.10.1 
Clinical Laboratory Reference Ranges 
16.2 
Subject Data Listings 
16.2.1 
Subject Discontinuation 
Appendix 16.2.1 
Subject Discontinuation (Safety Population) 
16.2.2 
Protocol Deviations 
Appendix 16.2.2 
Protocol Deviations 
16.2.3 
Subjects Excluded from Pharmacodynamic Analysis 
Appendix 16.2.3 
Subjects Excluded from 
Pharmacodynamic/Immunogenicity Analysis 
Note: Appendices 16.2.2 and 16.2.3 are generated in MS Word for inclusion 
in the study report. 
16.2.4 
Demographic Data 
Appendix 16.2.4.1 
Demographics (Safety Population) 
Appendix 16.2.4.2 
Physical Examination (Safety Population)  
Appendix 16.2.4.3 
Medical and Surgical History (Safety Population) 
Appendix 16.2.4.4 
Substance Use (Safety Population) 
  


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 19 of 78 
16.2.5 
Compliance and/or Drug Concentration Data 
Appendix 16.2.5.1.1 Inclusion Criteria   
Appendix 16.2.5.1.2 Exclusion Criteria 
Appendix 16.2.5.2 
Subject Eligibility (Safety Population) 
Appendix 16.2.5.3.1 Check-in and Return Criteria 
Appendix 16.2.5.3.2 Check-in Criteria and Responses (Safety Population) 
Appendix 16.2.5.4.1 Test Compound Description 
Appendix 16.2.5.4.2 Test Compound Administration Times (Safety 
Population) 
Appendix 16.2.5.5 
Blood Draw Times (Safety Population) 
Appendix 16.2.5.6 
Meal Times (Safety Population) 
Appendix 16.2.5.7 
Prior and Concomitant Medications (Safety Population) 
16.2.6 
Individual Efficacy/Pharmacokinetic/Pharmacodynamic 
Response Data 
Appendix 16.2.6.1 
Individual Plasma APC-PCI Levels Versus Time 
Following Administration of a Single IV Dose of 0.5, 
1.0, 2.0, 4.0 mcg/kg, or Placebo (Linear Scale) for 
<Subject #> 
Appendix 16.2.6.2 
Plasma Anti-E-WE Thrombin Antibodies 
16.2.7 
Adverse Events Listings 
Appendix 16.2.7.1.1 Adverse Events (I of II) (Safety Population) 
Appendix 16.2.7.1.2 Adverse Events (II of II) (Safety Population) 
Appendix 16.2.7.2 
Adverse Event Related Procedure (Safety Population) 
Appendix 16.2.7.3 
Adverse Event Preferred Term Classification (Safety 
Population) 
16.2.8 
Listings of Individual Laboratory Measurements and Other 
Safety Observations 
Appendix 16.2.8.1.1 Clinical Laboratory Report - Serum Chemistry (Safety 
Population)  
Appendix 16.2.8.1.2 Clinical Laboratory Report - Hematology (Safety 
Population) 
Appendix 16.2.8.1.3 Clinical Laboratory Report - Coagulation (Safety 
Population) 
Appendix 16.2.8.1.4 Clinical Laboratory Report - Urinalysis (Safety 
Population) 


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 20 of 78 
Appendix 16.2.8.1.5 Clinical Laboratory Report - Urine Drug Screening 
(Safety Population) 
Appendix 16.2.8.1.6 Clinical Laboratory Report - Comments (Safety 
Population) 
Appendix 16.2.8.2 
Vital Signs (Safety Population) 
Appendix 16.2.8.3 
12-Lead Electrocardiogram (Safety Population) 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 21 of 78 
11. TABLE AND FIGURE SHELLS  
The following table shells provide a framework for the display of data from this 
study. The shells may change due to unforeseen circumstances. These shells may not 
be reflective of every aspect of this study, but are intended to show the general layout 
of the tables that will be presented and included in the final CSR. Unless otherwise 
noted, all tables will be presented in Times New Roman font size 8. These tables will 
be generated off of the Celerion ADaM Version 2.1. 
 


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 22 of 78 
11.1 
In-text Summary Tables Shells 
Table 10-1  
Subject Disposition Summary (Safety Population) 
 
 
Dose Level 
Pooled 
Placebo 
Overall 
Disposition 
0.5 mcg/kg 
1.0 mcg/kg 
2.0 mcg/kg 
4.0 mcg/kg 
Dosed 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Completed 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Discontinued 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
 
<Reason1> 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
 
<Reason2> 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Pooled Placebo: Placebo Solution (IV bolus) 
<AE = Adverse event> 
Source: Table 14.1.1 
Program:  /CAXXXXX/sas_prg/stsas/intext/t_disp.sas  DDMMMYYYY  HH:MM 
 
 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
 
 
 
 
 
 
 
     Page 23 of 78 
Table 11-1  
Demographic Summary (Safety Population) 
 
Trait 
Category/ 
Statistics 
Dose Level 
Pooled 
Placebo 
 
0.5 mcg/kg 
1.0 mcg/kg 
2.0 mcg/kg 
4.0 mcg/kg 
Overall 
Sex 
Female 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Race 
Asian 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
 
Black or African American 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
 
White 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Ethnicity 
Hispanic or Latino 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
 
Not Hispanic or Latino 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Age* (yrs) 
n 
XX 
XX 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
Minimum 
XX 
XX 
XX 
XX 
XX 
XX 
 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Maximum 
XX 
XX 
XX 
XX 
XX 
XX 
Weight (kg) 
n 
XX 
XX 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
Minimum 
XX 
XX 
XX 
XX 
XX 
XX 
 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Maximum 
XX 
XX 
XX 
XX 
XX 
XX 
0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Pooled Placebo: Placebo Solution (IV bolus)  
*Age is calculated at the time of first dosing. 
BMI = Body mass index 
Source: Table 14.1.2 
Program:  /CAXXXXX/sas_prg/stsas/intexttest/t_dem.sas  DDMMMYYYY  HH:MM 


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
 
 
 
 
 
 
 
     Page 24 of 78 
Programmer Notes:  
• This is just a mock table shell. Please use the race categories listed in the CRF. 
• Height (cm) and BMI (kg/m²) will be also summarized in this table. 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 25 of 78 
In-text Table 11-2 will be in the following format. 
 
Table 11-2  
Summary of APC-PCI Following Administration of a Single IV Dose   
 
 
 
 
of 0.5,  1.0, 2.0, and 4.0 mcg/kg E-WE Thrombin 
 
 
Hour 
 0.5 mcg/kg 
(N=X) 
1.0 mcg/kg 
(N=X) 
2.0 mcg/kg 
(N=X) 
4.0 mcg/kg 
(N=X) 
Placebo 
(N=X) 
XX 
X ± X 
X ± X 
X ± X 
X ± X 
X ± X 
XX 
X ± X 
X ± X 
X ± X 
X ± X 
X ± X 
XX 
X ± X 
X ± X 
X ± X 
X ± X 
X ± X 
XX 
X ± X 
X ± X 
X ± X 
X ± X 
X ± X 
N is the total number of subjects dosed at each dose level. 
Source: Table XXX 
 
Treatments:  
• 
0.5 mcg/kg E-WE thrombin (IV bolus) 
• 
1.0 mcg/kg E-WE thrombin (IV bolus)  
• 
2.0 mcg/kg E-WE thrombin (IV bolus)  
• 
4.0 mcg/kg E-WE thrombin (IV bolus) 
• 
Pooled Placebo (IV bolus) 
 
Programmer’s note:  
 
• 
Arithmetic mean ± SD will be presented.  
• 
Table 11-2 the source table will be 14.2.1.1 through 14.2.1.5. 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 26 of 78 
In-text Tables 11-3 and 11-4 will be in the following format. 
 
 
Table 11-3  
Summary of Anti- E-WE Thrombin Plasma ADA Following Administration  
 
 
 
 
of a Single IV Dose of 0.5, 1.0, 2.0, and 4.0 mcg/kg E-WE Thrombin 
 
 
0.5 mcg/kg (n=x) 
1.0 mcg/kg (n=x) 
2.0 mcg/kg (n=x) 
4.0 mcg/kg (n=x) 
Placebo (n=x) 
Predose (Day -1) 
 
 
 
 
 
ADA Test Result 
Number 
Negative/Positive  
X/X 
X/X 
X/X 
X/X 
X/X 
Confirmatory E-
WE Thrombin 
Positive       
X 
X 
X 
X 
X 
Neutralizing 
Positive 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Day 14  
 
 
 
 
 
ADA Test Result 
Number 
Negative/Positive  
X/X 
X/X 
X/X 
X/X 
X/X 
Confirmatory E-
WE Thrombin 
Positive       
X 
X 
X 
X 
X 
Neutralizing 
Positive 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Day 28  
 
 
 
 
 
ADA Test Result 
Number 
Negative/Positive  
X/X 
X/X 
X/X 
X/X 
X/X 
Confirmatory E-
WE Thrombin 
Positive       
X 
X 
X 
X 
X 
Neutralizing 
Positive 
X 
X 
X 
X 
X 
  
Presentation of Data: 
• 
The following outcomes will be presented as number of subjects (% of the population): confirmatory positive will be a 
percentage of the total subject in the dose level  
• 
Number of subjects will be presented as an integer (no decimals) 
• 
4 dose levels will be presented instead on the same table 
• 
Internal Table template: Table ITPar1 
 
Programmer’s note:  
• 
Table 11-3 the source table will be 14.2.2.1. 
• 
Table 11-4 the source table will be 14.2.2.2. 
• 
ADA collection times: Predose, Day 14 and Day 28 postdose. 
 
 
 
 
 
Program:  /CAXXXXX/sas_prg/pksas/intext-pk-tables.sas    
DDMMMYYYY  HH:MM 
Program:  /CAXXXXX/sas_prg/pksas/adam_intext_pkparam.sas   DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol Number CA19169 
Celerion, Clinical Study Report No. CA19169 
 
Statistical Analysis Plan, 25 July 2018 
Page 27 of 78 
Table 12-1  
Treatment-Emergent Adverse Event Frequency by Cohort - Number of 
Subjects Reporting the Event (% of Subjects Dosed) (Safety Population) 
 
 
Dose Level 
Pooled 
Placebo 
Overall 
Adverse Event* 
0.5 mcg/kg 
1.0 mcg/kg 
2.0 mcg/kg 
4.0 mcg/kg 
Number of Subjects With TEAEs 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Number of Subjects Without TEAEs 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
System Organ Class 1 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
 
Preferred Term 1 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
 
Preferred Term 2 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
System Organ Class 2 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
 
Preferred Term 1 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
 
Preferred Term 2 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Pooled Placebo: Placebo Solution (IV bolus) 
*Adverse events are classified according to MedDRA Version 21.0. 
TEAEs = Treatment-emergent adverse events 
If a subject has 2 or more clinical adverse events, the subject is counted only once within a category. The same subject may appear in different 
categories. 
Source: Table 14.3.1.1 
Program:  /CAXXXXX/sas_prg/stsas/intext/t_ae.sas  DDMMMYYYY  HH:MM 
 
 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 28 of 78 
11.2 
Section 14 Summary Tables Shells 
 
                                                                                        Part 1 of X 
 
                             Table 14.1.1  Subject Disposition Summary (Safety Population) 
 
                                                                               Dose Level 
                                                              ---------------------------------------------     Pooled 
                                    Disposition               0.5 mcg/kg  1.0 mcg/kg  2.0 mcg/kg  4.0 mcg/kg    Placebo   Overall       
                                    --------------------------------------------------------------------------------------------- 
                                    Dosed                       X (XX%)     X (XX%)     X (XX%)     X (XX%)     X (XX%)   X (XX%) 
                                    Completed                   X (XX%)     X (XX%)     X (XX%)     X (XX%)     X (XX%)   X (XX%) 
                                    Discontinued                X (XX%)     X (XX%)     X (XX%)     X (XX%)     X (XX%)   X (XX%) 
                                      <Reason 1>                X (XX%)     X (XX%)     X (XX%)     X (XX%)     X (XX%)   X (XX%) 
                                      <Reason 2>                X (XX%)     X (XX%)     X (XX%)     X (XX%)     X (XX%)   X (XX%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Pooled Placebo: Placebo Solution (IV bolus)  
 
Program:  /CAXXXXX/sas_prg/stsas/tab PROGRAMNAME.sas  DDMMMYYYY  HH:MM     
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 29 of 78 
                                                                                                                                 Page 1 of X 
 
Table 14.1.2  Demographic Summary (Safety Population) 
 
                                                                                      Dose Level 
                                           Category/                 ---------------------------------------------   Pooled 
                         Trait             Statistics                0.5 mcg/kg  1.0 mcg/kg  2.0 mcg/kg  4.0 mcg/kg  Placebo    Overall                
                         --------------------------------------------------------------------------------------------------------------- 
                         Sex                Female                     X ( XX%)   X ( XX%)   X ( XX%)   X ( XX%)     X (XX%)    X (XX%) 
 
                         Race               Asian                      X ( XX%)   X ( XX%)   X ( XX%)   X ( XX%)     X (XX%)    X (XX%) 
                                            Black or African           X ( XX%)   X ( XX%)   X ( XX%)   X ( XX%)     X (XX%)    X (XX%) 
                                            American 
                                            White                      X ( XX%)   X ( XX%)   X ( XX%)   X ( XX%)     X (XX%)    X (XX%) 
 
                         Ethnicity          Hispanic or Latino         X ( XX%)   X ( XX%)   X ( XX%)   X ( XX%)     X (XX%)    X (XX%) 
                                            Not Hispanic or Latino     X ( XX%)   X ( XX%)   X ( XX%)   X ( XX%)     X (XX%)    X (XX%) 
 
                         Age* (yrs)         n                                X          X          X          X            X         X 
                                            Mean                          XX.X       XX.X       XX.X       XX.X         XX.X      XX.X 
                                            SD                            X.XX       X.XX       X.XX       X.XX         X.XX      X.XX 
                                            Minimum                         XX         XX         XX         XX           XX        XX 
                                            Median                        XX.X       XX.X       XX.X       XX.X         XX.X      XX.X 
                                            Maximum                         XX         XX         XX         XX           XX        XX 
 
                         Weight (kg)        n                                X          X          X          X            X         X 
                                            Mean                          XX.X       XX.X       XX.X       XX.X         XX.X      XX.X 
                                            SD                            X.XX       X.XX       X.XX       X.XX         X.XX      X.XX 
                                            Minimum                         XX         XX         XX         XX           XX        XX 
                                            Median                        XX.X       XX.X       XX.X       XX.X         XX.X      XX.X 
                                            Maximum                         XX         XX         XX         XX           XX        XX 
 
Programmer Note:  This is just a mock table shell. Please use the race categories listed in the CRF. 
                  Please also include Height (cm) and BMI (kg/m2). 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Pooled Placebo: Placebo Solution (IV bolus)  
        *Age is calculated at the time of first dosing. 
 
Program:  /CAXXXXX/sas_prg/stsas/tab PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 30 of 78 
Tables 14.2.1.1 through 14.2.1.5 will be in the following format: 
 
Table 14.2.1.1 
Plasma APC-PCI Levels (<units>) Following a Single IV Dose of 0.5 mcg/kg E-WE Thrombin 
(Pharmacodynamic Population) 
 
                 Subject              ------------------ Sample Times (hr) ------------- 
                 Number               Predose      Hour X     Hour X   Hour X    Hour X              
                 ----------------------------------------------------------------------- 
                 XXX                    XXX        XXX        XXX       XXX      XXX 
                 XXX                    XXX        XXX        XXX       XXX      XXX 
                 XXX                    XXX        XXX        XXX       XXX      XXX 
                 XXX                    XXX        XXX        XXX       XXX      XXX 
                 XXX                    XXX        XXX        XXX       XXX      XXX 
                 XXX                    XXX        XXX        XXX       XXX      XXX 
                 ----------------------------------------------------------------------- 
                 n                         X         X          X         X        X   
                 Mean                   X.XX      X.XX       X.XX      X.XX     X.XX   
                 SD                     X.XX      X.XX       X.XX      X.XX     X.XX   
                 CV(%)                  X.XX      X.XX       X.XX      X.XX     X.XX 
                 Minimum                X.XX      X.XX       X.XX      X.XX     X.XX 
                 Median                 X.XX      X.XX       X.XX      X.XX     X.XX 
                 Maximum                X.XX      X.XX       X.XX      X.XX     X.XX 
                 ------------------------------------------------------------------------- 
                 . = Value missing or not reportable. 
 
 
 
 
 
 
Programmer Notes: 
• 
PD time points for the 3 PD markers are presented in Sections 6.1 through 6.3 of the SAP  
• 
Verify Section 6.4 for presentation of descriptive statistics. 
 
Program:  /AAXXXXX/ECR/sas prg/pksas/PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 31 of 78 
 Tables 14.2.2.1 and 14.2.2.2 will be in the following format. 
 
 
                                                                                                                        Page 1 of X 
 
Table 14.2.2.1 
Plasma Anti-E-WE Thrombin Antibody Detection Following Administration of a Single IV Dose of 0.5, 
1.0, 2.0, or 4.0 mcg/kg E-WE Thrombin Summary by Collection Time and Treatment - Number of Subjects 
(% Total Subjects) 
 
 
                                                  0.5 mcg/kg                                     1.0 mcg/kg 
                                   -----------------------------------------       -------------------------------------- 
                                   Day X     Day X    Day X   Overall*             Day X     Day X    Day X    Overall*  
                                   -------------------------------------------------------------------------------------- 
Test                 Result         N=X       N=X      N=X     N = X               N=X       N=X      N=X      N = X 
------------------------------------------------------------------------------------------------------------------------- 
Initial              Negative      X (X%)    X (X%)   X (X%)   X (X%)              X (X%)    X (X%)   X (X%)   X (X%) 
                     Positive      X (X%)    X (X%)   X (X%)   X (X%)              X (X%)    X (X%)   X (X%)   X (X%) 
Confirmatory         Negative      X (X%)    X (X%)   X (X%)   X (X%)              X (X%)    X (X%)   X (X%)   X (X%)     
                     Positive      X (X%)    X (X%)   X (X%)   X (X%)              X (X%)    X (X%)   X (X%)   X (X%) 
Neutralizing         Negative      X (X%)    X (X%)   X (X%)   X (X%)              X (X%)    X (X%)   X (X%)   X (X%)     
                     Positive      X (X%)    X (X%)   X (X%)   X (X%)              X (X%)    X (X%)   X (X%)   X (X%) 
------------------------------------------------------------------------------------------------------------------------- 
 
N is the total number of subjects dosed at each dose level. 
 
Programmer Note: 
• 
Immunogenicity sampling times: Day -1, Day 14, and Day 28 
• 
Treatments:  
• 
0.5 mcg/kg E-WE thrombin (IV bolus) 
• 
1.0 mcg/kg E-WE thrombin (IV bolus)  
• 
2.0 mcg/kg E-WE thrombin (IV bolus)  
• 
4.0 mcg/kg E-WE thrombin (IV bolus)  
• 
Pooled Placebo: Placebo Solution (IV bolus) 
 
 
Note:  * if the response of a subject is positive at least once postdose, it will be counted as “positive”; otherwise will be 
considered as  
   “negative”. 
Only screening positives will be reassayed for confirmatory analysis. 
 
 
Program:  /AAXXXXX/ECR/sas_prg/pksas PROGRAMNAME.sas  DDMMMYYYY  HH:MM      
 
 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 32 of 78 
 
 
Tables 14.2.2.3 through 14.2.2.4 will be in the following format: 
 
 
 
 
 
Table 14.2.2.3 
Summary of Titers for Plasma Anti-E-WE Thrombin Antibody 
 
 
 
                         
Subject       0.5 mcg/mL        1.0 mcg/mL    
                                   ------------------------------------------------------------ 
     X               XX                 XX        
                                   ------------------------------------------------------------ 
                                        n                X                  X 
 Mean             XX.X               XX.X 
 SD               X.XX               X.XX 
                                        Minimum          XX                 XX 
 Median          XX.X                XX.X 
 Maximum          XX                 XX  
                                   ------------------------------------------------------------ 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Pooled Placebo: Placebo Solution (IV bolus)  
 
 
Programmer note: if the screening result is negative, confirmatory and titer assays will not be performed. If confirmatory result is 
negative, but the screening was positive, the titer assay will not be performed. 
 
 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 33 of 78 
Tables 14.2.2.5 and 14.2.2.6 will be in the following format. 
 
 
Page 1 of X 
 
Table 14.2.2.5 Anti-E-WE Thrombin Antibody +Duration by Dose Level Following Administration of a Single IV Dose of 0.5, 1.0, 2.0, or 
4.0 mcg/kg E-WE Thrombin  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
         
 
 
 
 
 
                        
E-WE Thrombin    Subject       Duration*  
                                   ----------------------------------------- 
0.5 mcg/kg       X             X Days 
 
 
 
     X             X Days   
 
1.0 mcg/kg       X             X Days                              
 
 
 
 
 X             x Days                
                                   ----------------------------------------- 
 
 
 
 
 
 
Programmer note:  
• 
Treatments:  
• 0.5 mcg/kg E-WE thrombin (IV bolus) 
• 1.0 mcg/kg E-WE thrombin (IV bolus)  
• 2.0 mcg/kg E-WE thrombin (IV bolus)  
• 4.0 mcg/kg E-WE thrombin (IV bolus)  
• Pooled Placebo: Placebo Solution (IV bolus)  
 
 
Note:  * duration is defined as the time interval between the first postdose and last postdose occurrence 
of positive ADA.  If positive ADA is only on Day 28 the duration will be N/A. 
 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 34 of 78 
Note: Figures of 14.2.3 and In-text Figure 11-1 will be in the following format.   
 
 
Figure 14.2.3.1 
 
 
Mean <Matrix Analyte> Concentrations Versus Time 
(Linear Scale) 
 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 35 of 78 
Figure 14.2.3.2 
 
 
Median <Matrix Analyte> Concentrations Versus Time 
(Linear Scale) 
 
 
 
 
 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 36 of 78 
Notes for Generating the Actual Mean Figure: 
 
• 
Legend will be <> and <>  
• 
Y axis label will be <Matrix> <Analyte> Concentration (<unit>) 
• 
X axis label will be “Hours From Dosing” 
• 
Mean plots will have 4 dose levels and placebos overlayed.  
• 
Please generate figures in color. Please use the same color and symbol for each treatment throughout. 
 
 
 
 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 37 of 78 
Note: Figures of 14.2.4.1 and 14.2.4.3 will be in the following format.   
 
 
Figure 14.2.4.1 Summary of Titers for Plasma Anti-E-WE Thrombin Antibody by Treatment – Line Plot (Mean ± SD) for Confirmatory Test Results 
 
                    
  
 
Programmer Note: If data for neutralizing test are available, please present similar figure. Plots to be generated in SAS. 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 38 of 78 
Note: Figures of 14.2.4.2 and 14.2.4.4 will be in the following format.   
 
 
Figure 14.2.4.2 Summary of Titers for Plasma Anti-E-WE Thrombin Antibody by Treatment – Line Plot (Mean) for Confirmatory Test Results 
 
 
 
 
 
Programmer Note: If data for neutralizing test are available, please present similar figure. Plot to be generated in SAS. 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 39 of 78 
 
Page 1 of X 
 
Table 14.3.1.1 Treatment-Emergent Adverse Event Frequency by Cohort - Number of Subjects Reporting the Event  
(% of Subjects Dosed) (Safety Population) 
 
                                                                          
                                                                       Dose Level 
                                                    ----------------------------------------------   Pooled 
     Adverse Event*                                 0.5 mcg/kg  1.0 mcg/kg  2.0 mcg/kg  4.0 mcg/kg   Placebo     Overall 
     --------------------------------------------------------------------------------------------------------------------- 
     Number of Subjects Dosed                        XX ( XX%)  XX ( XX%)   XX ( XX%)   XX (XXX%)    XX ( XX%)   XX (XXX%) 
     Number of Subjects With TEAEs^                   X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
     Number of Subjects Without TEAEs^               XX ( XX%)  XX ( XX%)   XX ( XX%)   XX (XXX%)    XX ( XX%)   XX (XXX%) 
     --------------------------------------------------------------------------------------------------------------------- 
     Nervous system disorders                         X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
          Dizziness                                   X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
          Headache                                    X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
          Presyncope                                  X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
     Respiratory, thoracic and mediastinal disorders  X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
          Dry throat                                  X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
          Oropharyngeal pain                          X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
          Sinus congestion                            X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
          Sneezing                                    X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
     General disorders and administration site        X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
     conditions 
          Fatigue                                     X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
          Thirst                                      X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
 
 
   
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Pooled Placebo: Placebo Solution (IV bolus)  
 
 
*Adverse events are classified according to MedDRA Version 21.0. ^ = Treatment-emergent adverse events 
        If a subject has 2 or more clinical adverse events, the subject is counted only once within a category. The same subject may appear  
        in different categories. 
 
Program:  /CAXXXXX/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 40 of 78 
Page 1 of X 
 
Table 14.3.1.2  Treatment-Emergent Adverse Event Frequency by Cohort - Number of Adverse Events  
(% of Total Adverse Events) (Safety Population) 
 
                                                           
                                                 
                                                                       Dose Level 
                                                     ----------------------------------------------   Pooled 
     Adverse Event*                                  0.5 mcg/kg  1.0 mcg/kg  2.0 mcg/kg  4.0 mcg/kg   Placebo     Overall 
     --------------------------------------------------------------------------------------------------------------------- 
     Number of TEAEs                                  X (100%)   X (100%)    X (100%)    X (100%)     X ( XX%)    X ( XX%) 
     --------------------------------------------------------------------------------------------------------------------- 
     Nervous system disorders                         X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
          Dizziness                                   X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
          Headache                                    X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
          Presyncope                                  X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
     Respiratory, thoracic and mediastinal disorders  X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
          Dry throat                                  X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
          Oropharyngeal pain                          X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
          Sinus congestion                            X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
          Sneezing                                    X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
     General disorders and administration site        X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
     conditions 
          Fatigue                                     X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
          Thirst                                      X ( XX%)   X ( XX%)    X ( XX%)    X ( XX%)     X ( XX%)    X ( XX%) 
 
  
 
 
  
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Pooled Placebo: Placebo Solution (IV bolus)  
 
 
*Adverse events are classified according to MedDRA Version 21.0. ^ = Treatment-emergent adverse events 
 
Program:  /CAXXXXX/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 41 of 78 
 
                                                                                                                       Page 1 of X 
 
Table 14.3.1.3  Treatment-Emergent Adverse Event Frequency by Cohort, Severity, and Relationship to Study Drug -  
Number of Adverse Events (Safety Population) 
 
 
                       Dose                                       Severity/Intensity                        Relationship to Study Drug 
                       Level/  Number of    Number   ---------------------------------------  --------------------------------------------- 
                       Pooled  Subjects     of                        
 Adverse Event*        Placebo With TEAEs   TEAEs    Grade 1   Grade 2     Grade 3   Grade 4  Unrelated Unlikely Possibly  Probably  Likely 
 ------------------------------------------------------------------------------------------------------------------------------------------ 
 Dizziness               X         X          X         X          X          X          X        X        X        X        X        X 
                         X         X          X         X          X          X          X        X        X        X        X        X 
 Dry eye                 X         X          X         X          X          X          X        X        X        X        X        X  
 Dry mouth               X         X          X         X          X          X          X        X        X        X        X        X 
 Dry throat              X         X          X         X          X          X          X        X        X        X        X        X 
 Ear pain                X         X          X         X          X          X          X        X        X        X        X        X 
                         X         X          X         X          X          X          X        X        X        X        X        X 
 Fatigue                 X         X          X         X          X          X          X        X        X        X        X        X 
 Headache                X         X          X         X          X          X          X        X        X        X        X        X 
 Dizziness               X         X          X         X          X          X          X        X        X        X        X        X 
                         X         X          X         X          X          X          X        X        X        X        X        X 
 Hyperhidrosis           X         X          X         X          X          X          X        X        X        X        X        X 
 Laceration              X         X          X         X          X          X          X        X        X        X        X        X 
 Limb crushing injury    X         X          X         X          X          X          X        X        X        X        X        X 
 Muscle twitching        X         X          X         X          X          X          X        X        X        X        X        X 
 ------------------------------------------------------------------------------------------------------------------------------------------ 
                         X         X          X         X          X          X          X        X        X        X        X        X 
                         X         X          X         X          X          X          X        X        X        X        X        X 
                         X         X          X         X          X          X          X        X        X        X        X        X 
                         X         X          X         X          X          X          X        X        X        X        X        X 
            Pooled Placebo        XX         XX         X          X          X          X        X        X        X        X        X 
                   Overall        XX         XX         X          X          X          X        X        X        X        X        X 
 ------------------------------------------------------------------------------------------------------------------------------------------ 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Pooled Placebo: Placebo Solution (IV bolus)  
  
 
*Adverse events are classified according to MedDRA Version 21.0. ^ = Treatment-emergent adverse events 
        If a subject experience the same adverse event (AE) at more than one level of severity during a treatment, each AE is counted  
        separately. If a subject experience the same AE at more than one level of drug relationship during a treatment, each AE is  
        counted separately. 
        Severity/Intensity: Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially life-threatening 
 
Program:  /CAXXXXX/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 


  
Statistical Analysis Plan, 25 July 2018 
Page 42 of 78 
 
                                                                                                                                 Page 1 of X 
 
Table 14.3.2.1 Serious Adverse Events (Safety Population) 
 
 
                                       Onset                                                                       
Dose Level/   Subject  Adverse     ---------------                 Severity/                       Relationship to     
Placebo       Number   Event       Date       Time    Frequency    Intensity   Serious  Outcome    Study Drug         Action  
------------------------------------------------------------------------------------------------------------------------------ 
XXX <units>     X      XXXXXXXXXXX DDMMMYYYY  XX:XX   XXXXXXXXX    XXXX        XXXX     Resolved   XXXXXXXX           XXXXXXXXX    
 
 
 
Programmer Note: If no SAE, then table will contain the statement: “There were no serious adverse events recorded during the study.” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
 
Program:  /AAXXXXX/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 43 of 78 
Tables 14.3.4.1 to 14.3.4.4 will have the following format: 
Page 1 of X 
                
                               Table 14.3.4.1  Out-of-Range Values and Recheck Results - Serum Chemistry (Safety Population) 
  
                                                                        Parameter1  Parameter2   Parameter3  Parameter4   Parameter5  
 Dose Level/  Subject Age#/  Study                                        <Range>     <Range>      <Range>      <Range>     <Range>   
 Placebo      Number  Sex    Period   Day   Hour    Date       Time       (Unit)      (Unit)       (Unit)      (Unit)       (Unit)   
 ----------------------------------------------------------------------------------------------------------------------------------- 
 XXX <units>    X     XX/X   Screen    .      .     DDMMMYYYY  HH:MM:SS    XX HN                                             XX LN   
                               1      -X   -XX.XX   DDMMMYYYY  HH:MM:SS    XX LY-      XX LN       XX HN         XX LYR+              
                             Recheck                DDMMMYYYY  HH:MM:SS                                          XX              
 
 
Programmer Notes:  Replace Parameter1, 2 etc. with actual lab tests in the study. Sort unscheduled assessment and early termination 
chronologically with other scheduled assessments and rechecks. Recheck should be sorted with the scheduled time point the 
recheck is for. 
 
Clinically significant lab values will be generally captured as AEs, some of which the PI may indicate in Appendix 
16.2.8.1.6 lab comments (as per GPG.03.0028 sections 2.9 and 2.10). Derive an additional flag for PI flag -/+ based on 
comments (i.e. NCS/CS). Present this derived 4th column in all tables, and list only PI-determined out-of-range clinically 
significant lab values in Table 14.3.4.5.  
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
        Placebo: Placebo Solution (IV bolus)  
        #Age is calculated at the time of first dosing. F = Female; M = Male  
        H = Above reference range, L = Below reference range                                                                     
        Computer: N = Not clinically significant, Y = Clinically significant                                                           
        PI Interpretation: - = Not clinically significant, R = Recheck requested, ^ = Will be retested later, + = Clinically significant 
 
Program:  /CAXXXXX/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 44 of 78 
 
Page 1 of X 
 
                           Table 14.3.4.5  Clinically Significant Laboratory and Corresponding Results (Safety Population) 
 
   Dose Level/  Subject  Age#/ Study                                                                                     Reference                    
   Placebo      Number   Sex   Period     Day   Hour  Date       Time      Department       Test           Result        Range         Unit      
   ----------------------------------------------------------------------------------------------------------------------------------------- 
   XXX <units>     X      XX/X    X         X   -X.XX  DDMMMYYYY  HH:MM:SS  Serum Chemistry  Cholesterol    XXX           X – X         mg/dL  
                                           X   XX.XX  DDMMMYYYY  HH:MM:SS  Serum Chemistry  Cholesterol    XXX  HYR+     X – X         mg/dL    
                                           X   XX.XX  DDMMMYYYY  HH:MM:SS  Serum Chemistry  Cholesterol    XXX  HY-      X – X         mg/dL     
                                           X   XX.XX  DDMMMYYYY  HH:MM:SS  Serum Chemistry  Cholesterol    XXX  HN       X – X         mg/dL  
 
 
 
 
 
 
 
 
 
                                                                                                                               
 
 
Programmer Note: All time points for a subject/test with at least one value deemed as CS by the PI will be presented in this table. 
                 If there were no CS values as deemed by PI (i.e., no “CS” or “Clinically Significant” in the PI comment field in the     
                 laboratory dataset), then this table will contain only the statement: “There were no laboratory values deemed clinically  
                 significant by the PI in the study.” 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
        #Age is calculated at the time of first dosing.  
        H = Above reference range                                                                     
         Computer: Y = Clinically significant                                                           
         PI Interpretation: R = Recheck requested, + = Clinically significant  
 
Program:  /CAXXXXX/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 45 of 78 
Tables 14.3.5.1, 14.3.5.4, 14.3.5.7, and 14.3.5.11 will be in the following format: 
                                                                                                              Page 1 of X 
 
Table 14.3.5.1  Clinical Laboratory Summary - Serum Chemistry (Safety Population) 
 
                                                                                              Dose Level 
                                                                                 ------------------------------------                      
    Laboratory Test        Reference                                                <dose  <dose       <dose    <dose     Pooled 
    (unit)                 Range                Time Point          Statistic    level 1> level 2>  level 3> level 4>    Placebo 
    ---------------------------------------------------------------------------------------------------------------------------- 
    XXXXXXXXX (unit)       X.X-XX.X#            Screen              n                  XX       XX        XX       XX       XX 
                                                                    Mean             X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    SD              X.XXX    X.XXX     X.XXX    X.XXX    X.XXX 
                                                                    Minimum          X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    Median            X.X      X.X       X.X      X.X      X.X 
                                                                    Maximum          XX.X     XX.X      XX.X     XX.X     XX.X 
 
                                                Baseline*           n                  XX       XX        XX       XX       XX 
                                                                    Mean             X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    SD              X.XXX    X.XXX     X.XXX    X.XXX    X.XXX 
                                                                    Minimum          X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    Median            X.X      X.X       X.X      X.X      X.X 
                                                                    Maximum          XX.X     XX.X      XX.X     XX.X     XX.X 
 
                                                Day X, Hour X.XX    n                  XX       XX        XX       XX       XX 
                                                                    Mean             X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    SD              X.XXX    X.XXX     X.XXX    X.XXX    X.XXX 
                                                                    Minimum          X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    Median            X.X      X.X       X.X      X.X      X.X 
                                                                    Maximum          XX.X     XX.X      XX.X     XX.X     XX.X 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Pooled Placebo: Placebo Solution (IV bolus) 
       # = Lowest of the lower ranges and highest of the higher ranges are used. Refer to Appendix 16.1.10.1 for the breakdown. 
       * Baseline is defined as the result closest and prior to dose on Day 1. 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 46 of 78 
Tables 14.3.5.2, 14.3.5.5, 14.3.5.8, 14.3.5.9 and 14.3.5.12 will be in the following format: 
                                                                                                              Page 1 of X 
 
Table 14.3.5.2  Clinical Laboratory Change from Baseline - Serum Chemistry (Safety Population) 
 
 
                                                                                           Dose Level 
                                                                               --------------------------------------         
    Laboratory Test        Reference                                               <dose  <dose       <dose    <dose      Pooled 
    (unit)                 Range                Time Point          Statistic    level 1> level 2>  level 3> level 4>    Placebo 
    ---------------------------------------------------------------------------------------------------------------------------- 
    XXXXXXXXX (unit)       X.X-XX.X#            Day X, Hour X.XX    n                  XX       XX        XX       XX       XX 
                                                                    Mean             X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    SD              X.XXX    X.XXX     X.XXX    X.XXX    X.XXX 
                                                                    Minimum          X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    Median            X.X      X.X       X.X      X.X      X.X 
                                                                    Maximum          XX.X     XX.X      XX.X     XX.X     XX.X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Pooled Placebo: Placebo Solution (IV bolus) 
       # = Lowest of the lower ranges and highest of the higher ranges are used. Refer to Appendix 16.1.10.1 for the breakdown. 
        Baseline is defined as the result closest and prior to dose on Day 1. 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 47 of 78 
Tables 14.3.5.3, 14.3.5.6, 14.3.5.10, and 14.3.5.13 will be in the following format: 
Page 1 of X 
 
Table 14.3.5.3  Clinical Laboratory Shift From Baseline - Serum Chemistry (Safety Population)  
 
                            Dose                           
                            Level/                              Baseline* L                      Baseline* N                      Baseline* H 
Laboratory Test  Reference  Pooled                    -------------------------------   -----------------------------   ------------------------------ 
(unit)           Range      Placebo Time Point            L         N          H            L         N          H          L          N          H  
-------------------------------------------------------------------------------------   -----------------------------   ------------------------------ 
XXXXXXX (unit)   X.X-XX.X#  XXX     Day X, Hour X.XX  X (  X%)  XX ( XX%)  X (  X%)     X (  X%)  XX ( XX%)  X (  X%)   X (  X%)   XX ( XX%)  X ( X%) 
                            <units> 
 
 
 
 
Programmer Note:  For Urinalysis tests, the categories will be N = Normal and O = Outside Normal. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Pooled Placebo: Placebo Solution (IV bolus) 
N = Within Normal Range, L = Below Normal Range, H = Above Normal Range 
       # = Lowest of the lower ranges and highest of the higher ranges are used. Refer to Appendix 16.1.10.1 for the breakdown. 
       * Baseline is defined as the result closest and prior to dose on Day 1. 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 48 of 78 
 
                                                                                                                                               Page 1 of X 
 
                                              Table 14.3.5.14  Vital Sign Summary (Safety Population) 
 
 
                                                                                              Dose Level 
                                                                                 --------------------------------------                      
                                                                                   <dose  <dose     <dose    <dose       Pooled 
    Vital Sign (unit)                           Time Point          Statistic    level 1> level 2>  level 3> level 4>    Placebo 
    ---------------------------------------------------------------------------------------------------------------------------- 
    XXXXXXXXX (unit)                            Screen              n                  XX       XX        XX       XX       XX 
                                                                    Mean             X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    SD              X.XXX    X.XXX     X.XXX    X.XXX    X.XXX 
                                                                    Minimum          X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    Median            X.X      X.X       X.X      X.X      X.X 
                                                                    Maximum          XX.X     XX.X      XX.X     XX.X     XX.X 
 
                                                Baseline*           n                  XX       XX        XX       XX       XX 
                                                                    Mean             X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    SD              X.XXX    X.XXX     X.XXX    X.XXX    X.XXX 
                                                                    Minimum          X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    Median            X.X      X.X       X.X      X.X      X.X 
                                                                    Maximum          XX.X     XX.X      XX.X     XX.X     XX.X 
 
                                                Day X, Hour X.XX    n                  XX       XX        XX       XX       XX 
                                                                    Mean             X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    SD              X.XXX    X.XXX     X.XXX    X.XXX    X.XXX 
                                                                    Minimum          X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    Median            X.X      X.X       X.X      X.X      X.X 
                                                                    Maximum          XX.X     XX.X      XX.X     XX.X     XX.X 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Pooled Placebo: Placebo Solution (IV bolus) 
  
  * Baseline is defined as the result closest and prior to the dose on Day 1. 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 49 of 78 
                                                                                                                                               Page 1 of X 
 
                                              Table 14.3.5.15  Vital Sign Change from Baseline (Safety Population) 
 
 
                                                                                              Dose Level 
                                                                                 --------------------------------------                      
                                                                                   <dose  <dose     <dose    <dose       Pooled 
    Vital Sign (unit)                           Time Point          Statistic    level 1> level 2>  level 3> level 4>    Placebo 
    ---------------------------------------------------------------------------------------------------------------------------- 
    XXXXXXXXX (unit)                            Day X, Hour X.XX    n                  XX       XX        XX       XX       XX 
                                                                    Mean             X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    SD              X.XXX    X.XXX     X.XXX    X.XXX    X.XXX 
                                                                    Minimum          X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    Median            X.X      X.X       X.X      X.X      X.X 
                                                                    Maximum          XX.X     XX.X      XX.X     XX.X     XX.X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Pooled Placebo: Placebo Solution (IV bolus) 
  
    Baseline is defined as the result closest and prior to the dose on Day 1. 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 


  
Statistical Analysis Plan, 25 July 2018 
Page 50 of 78 
                                                                                                                                               Page 1 of X 
 
                                    Table 14.3.5.16  12-Lead Electrocardiogram Summary (Safety Population) 
 
                                                                                                          
                                                                                              Dose Level 
                                                                                 --------------------------------------                      
                                                                                   <dose  <dose     <dose    <dose       Pooled 
    Measurement (unit)                          Time Point          Statistic    level 1> level 2>  level 3> level 4>    Placebo 
    ---------------------------------------------------------------------------------------------------------------------------- 
    XXXXXXXXX (unit)                            Screen              n                  XX       XX        XX       XX       XX 
                                                                    Mean             X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    SD              X.XXX    X.XXX     X.XXX    X.XXX    X.XXX 
                                                                    Minimum          X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    Median            X.X      X.X       X.X      X.X      X.X 
                                                                    Maximum          XX.X     XX.X      XX.X     XX.X     XX.X 
 
                                                Baseline*           n                  XX       XX        XX       XX       XX 
                                                                    Mean             X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    SD              X.XXX    X.XXX     X.XXX    X.XXX    X.XXX 
                                                                    Minimum          X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    Median            X.X      X.X       X.X      X.X      X.X 
                                                                    Maximum          XX.X     XX.X      XX.X     XX.X     XX.X 
 
                                                Day X, Hour X.XX    n                  XX       XX        XX       XX       XX 
                                                                    Mean             X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    SD              X.XXX    X.XXX     X.XXX    X.XXX    X.XXX 
                                                                    Minimum          X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    Median            X.X      X.X       X.X      X.X      X.X 
                                                                    Maximum          XX.X     XX.X      XX.X     XX.X     XX.X 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Pooled Placebo: Placebo Solution (IV bolus) 
 
  * Baseline is defined as the result closest and prior to the dose on Day 1. 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 51 of 78 
                                                                                                                                               Page 1 of X 
 
                                    Table 14.3.5.17  12-Lead Electrocardiogram Change From Baseline (Safety Population) 
 
                                                                                                          
                                                                                              Dose Level 
                                                                                 --------------------------------------                      
                                                                                   <dose  <dose     <dose    <dose       Pooled 
    Measurement (unit)                          Time Point          Statistic    level 1> level 2>  level 3> level 4>    Placebo 
    ---------------------------------------------------------------------------------------------------------------------------- 
    XXXXXXXXX (unit)                            Day X, Hour X.XX    n                  XX       XX        XX       XX       XX 
                                                                    Mean             X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    SD              X.XXX    X.XXX     X.XXX    X.XXX    X.XXX 
                                                                    Minimum          X.XX     X.XX      X.XX     X.XX     X.XX 
                                                                    Median            X.X      X.X       X.X      X.X      X.X 
                                                                    Maximum          XX.X     XX.X      XX.X     XX.X     XX.X 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Pooled Placebo: Placebo Solution (IV bolus) 
 
    Baseline is defined as the result closest and prior to the dose on Day 1. 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 52 of 78 
12. LISTING SHELLS 
The following listing shells provide a framework for the display of data from this 
study. The shells may change due to unforeseen circumstances. These shells may not 
be reflective of every aspect of this study, but are intended to show the general layout 
of the listings that will be presented and included in the final CSR. These listings will 
be generated off of the Celerion SDTM Tabulation Model 1.4 mapped in accordance 
with SDTM Implementation Guide 3.2. All listings will be presented in Courier New 
size font 9. 


  
Statistical Analysis Plan, 25 July 2018 
Page 53 of 78 
 
 
Page 1 of X 
 
                                   Appendix 16.1.10.1  Clinical Laboratory Reference Ranges  
 
                                                                                           Reference 
        Laboratory Group           Test Name                     Sex         Age Category  Range           Unit      
        -------------------------------------------------------------------------------------------------------- 
        Serum Chemistry            Test Name                     XXXXXX      XX            XX – XX         units 
                                   Test Name                     XXXXXX      XX            XX – XX         units 
                                   Test Name                     XXXXXX      XX            XX – XX         units 
                                   Test Name                     XXXXXX      XX            XX – XX         units 
                                   Test Name                     XXXXXX      XX            XX – XX         units 
                                   Test Name                     XXXXXX      XX            XX – XX         units 
                                                                                                                     
        Hematology                 Test Name                     XXXXXX      XX            XX – XX         units 
                                   Test Name                     XXXXXX      XX            XX – XX         units 
                                   Test Name                     XXXXXX      XX            XX – XX         units 
                                   Test Name                     XXXXXX      XX            XX – XX         units 
                                   Test Name                     XXXXXX      XX            XX – XX         units 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
<similar for remaining Laboratory Groups and Test Names> 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 54 of 78 
 
                                                                                                                                 Page 1 of X 
 
                                    Appendix 16.2.1  Subject Discontinuation (Safety Population) 
  
                                         Dose Level/  Subject    Study                   Completed  
                                         Placebo      Number     Period    Date          Study?     Reason for Discontinuation  Specify 
                                         ----------------------------------------------------------------------------------------------- 
                                         XXX <units>       X     Post      DDMMMYYYY     Yes    
                                                           X     Post      DDMMMYYYY     Yes    
                                                           X     Post      DDMMMYYYY     Yes    
                                                           X     Post      DDMMMYYYY     Yes    
                                                           X     Post      DDMMMYYYY     No         Personal Reason              XXXXXXXX 
                                                           X     Post      DDMMMYYYY     Yes    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 55 of 78 
                                                                                                                                 Page 1 of X 
 
                                              Appendix 16.2.4.1  Demographics (Safety Population) 
                                                                                                                                
                                                                                                              Body Mass   Informed                    
       Dose Level/  Subject    Date of      Age*                                         Height    Weight      Index      Consent 
       Placebo      Number     Birth       (yrs)    Sex       Race        Ethnicity      (cm)      (kg)       (kg/m2)       Date 
       --------------------------------------------------------------------------------------------------------------------------- 
       XXX <units>    X        DDMMMYYYY     XX     AAAAAA    AAAAAAAA    AAAAAAAAAA      XXX      XX.XX       XX.XX     DDMMMYYYY 
                      X        DDMMMYYYY     XX     AAAAAA    AAAAAAAA    AAAAAAAAAA      XXX      XX.XX       XX.XX     DDMMMYYYY 
                      X        DDMMMYYYY     XX     AAAAAA    AAAAAAAA    AAAAAAAAAA      XXX      XX.XX       XX.XX     DDMMMYYYY 
                      X        DDMMMYYYY     XX     AAAAAA    AAAAAAAA    AAAAAAAAAA      XXX      XX.XX       XX.XX     DDMMMYYYY 
                      X        DDMMMYYYY     XX     AAAAAA    AAAAAAAA    AAAAAAAAAA      XXX      XX.XX       XX.XX     DDMMMYYYY 
                      X        DDMMMYYYY     XX     AAAAAA    AAAAAAAA    AAAAAAAAAA      XXX      XX.XX       XX.XX     DDMMMYYYY 
                      X        DDMMMYYYY     XX     AAAAAA    AAAAAAAA    AAAAAAAAAA      XXX      XX.XX       XX.XX     DDMMMYYYY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
       *Age is calculated from the date of first dosing. 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 56 of 78 
Page 1 of X 
 
 
Appendix 16.2.4.2  Physical Examination (Safety Population) 
 
  
    Dose Level/  Subject  Study                                Was PE                                                          
    Placebo      Number   Period   Day   Hour    Date        Performed?     Comment 
  ------------------------------------------------------------------------------------ 
    XXX <units>    X      Screen    .      .     DDMMMYYYY      XXX         
                   X        X      –X   -XX.X    DDMMMYYYY      XXX         
                                    X    XX.X    DDMMMYYYY      XXX         
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
        PE = Physical Examination 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 57 of 78 
 
                                                                                                                                 Page 1 of X 
 
 
                                      Appendix 16.2.4.3  Medical and Surgical History (Safety Population) 
  
                   Date 
  Dose Level/  Subject    Any     Study                                             ----------------------                                         
  Placebo      Number   History?  Period  Body System                Category       Start         End          Condition or Event                            
-------------------------------------------------------------------------------------------------------------------------------------- 
  XXX <units>     X       XXX     Screen  XXXXXX  XXXXX XXXXXXX      Medical        DDMMMYYYY     Ongoing      XXXXXXX XXXXXX XXXXXXXX                       
                                          XXXXXXXXX                  Surgical       DDMMMYYYY     DDMMMYYYY    
                  X       XXX     Screen  XXXXXXXX XXXXX XXXXXX      Medical        DDMMMYYYY     DDMMMYYYY            
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 58 of 78 
 
                                                                                                                                 Page 1 of X 
 
                                                    Appendix 16.2.4.4  Substance Use (Safety Population) 
 
                                                                     Date 
           Dose Level/  Subject   Study                         ----------------------                                                            
           Placebo      Number    Period    Substance           Start       End            Description 
           ------------------------------------------------------------------------------------------------------- 
           XXX <units>    X       Screen    XXXXXXXX XXX        DDMMMYYYY   DDMMMYYYY      XXXXXXXXXX XXXXXX XXXX  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 59 of 78 
 
                                                                                                                                 Page 1 of X 
 
                                                  Appendix 16.2.5.1.1  Inclusion Criteria  
  
  
   X.  < >.  
   X.  < >.                                  
   X.  < >.                                                                                         
   X.  < >.             
   X.  < >.            
   X.  < >.             
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 60 of 78 
 
                                                                                                                                 Page 1 of X 
 
                                                  Appendix 16.2.5.1.2  Exclusion Criteria  
  
  
   X.  < >.  
   X.  < >.                                  
   X.  < >.                                                                                         
   X.  < >.            
   X.  < >.             
   X.  < >.             
   X.  < >.             
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 61 of 78 
 
                                                                                                                               Page 1 of X 
 
                                           Appendix 16.2.5.2  Subject Eligibility (Safety Population) 
  
                                 
             Dose Level/  Subject  Study                       Did subject meet 
             Placebo      Number   Period    Date         all eligibility criteria?    Criterion Not Met*      Specify  
             ----------------------------------------------------------------------------------------------------------------------- 
             XXX <units>    X      Screen    DDMMMYYYY              Yes         
                            X      Screen    DDMMMYYYY              Yes  
                            X      Screen    DDMMMYYYY              No                  EXCLUSION X             XXXXXXXXXXXXXXX XXXX        
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
        *Please refer to Appendices 16.2.5.1.1 and 16.2.5.1.2 for specific inclusion and exclusion criteria. 
                                                                      
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
                                                               
 
 


  
Statistical Analysis Plan, 25 July 2018 
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                                                                                                                                 Page 1 of X 
 
Appendix 16.2.5.3.1  Check-in and Return Criteria  
  
  
    
   X.  Did the Subject report any study restriction violations since the last study visit?                                             
   X.  IF YES TO ANY QUESTION, WAS SUBJECT APPROVED FOR STUDY?                                                                             
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan, 25 July 2018 
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                                                                                                                              Page 1 of X 
 
Appendix 16.2.5.3.2  Check-in Criteria and Return Responses (Safety Population) 
  
 
                                                                          Check-in Criteria 
         Dose Level/ Subject  Study                                       ------------------                                                          
         Placebo     Number   Period  Day   Hour  Date       Time           1          2      Specify                                                 
         ---------------------------------------------------------------------------------------------------------------------------------- 
         XXX <units>    X      X      -X   -XX.X  DDMMMYYYY  HH:MM:SS       No         NA     Will only be present and populated if there is  
                                       X    XX.X  DDMMMYYYY  HH:MM:SS       No         NA       a comment present in the study database. 
                                       X    XX.X  DDMMMYYYY  HH:MM:SS       No         NA      
                        X      X      -X   -XX.X  DDMMMYYYY  HH:MM:SS       No         NA                                                            
                                       X    XX.X  DDMMMYYYY  HH:MM:SS       No         NA        
                                       X    XX.X  DDMMMYYYY  HH:MM:SS       No         NA      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
           
                                             
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
  Please refer to Appendix 16.2.5.3.1 for the Check-in criteria. 
        NA = Not applicable  
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
                                                                 
 
 


  
Statistical Analysis Plan, 25 July 2018 
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                                                                                                                                 Page 1 of X 
 
                                        Appendix 16.2.5.4.1  Test Compound Description  
  
                         Compound                                         Form             Route    
                         -------------------------------------------------------------------------- 
                         XXXXXXXXXXXXXX                                    < >             XXXX     
 
                         XXXXXXXXXXXXXX                                    < >             XXXX     
                                                                                                                                                 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan, 25 July 2018 
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                                                                                                                                 Page 1 of X 
 
                               Appendix 16.2.5.4.2  Test Compound Administration Times (Safety Population) 
  
                                                          Start 
  Dose Level/  Subject   Study                       -------------------   End                                                                             
  Placebo      Number    Period   Day   Interval     Date        Time      Time      Compound              Dosage    Comments                
---------------------------------------------------------------------------------------------------------------------------------------- 
  XXX <units>    X        X        X    X.XX – X.XX  DDMMMYYYY   X:XX:XX   X:XX:XX   XXXXXXXXX              < >      XXXXXXXXXXXXXXXXXXX                     
                                   X    X.XX – X.XX  DDMMMYYYY   X:XX:XX   X:XX:XX   XXXXXXXXX              < >       
                                   X    X.XX – X.XX  DDMMMYYYY   X:XX:XX   X:XX:XX   XXXXXXXXX              < >       
  
                                                                                                      
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
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                                                                                                                                 Page 1 of X 
 
                                      Appendix 16.2.5.5  Blood Draw Times (Safety Population) 
  
Dose Level/  Subject  Study                                 Actual                                                                     
Placebo      Number   Period    Day   Hour     Date         Time    Vacutainer ID    Bioassay      Comment                                      
-------------------------------------------------------------------------------------------------------------- 
XXX <units>    X       X         X   -X.XX     DDMMMYYYY   X:XX:XX  XXXXXXXXXXX     XXXXXXXXXXX   XXXXXXXXXXX                                  
                                     XX.XX     DDMMMYYYY   X:XX:XX  XXXXXXXXXXX     XXXXXXXXXXX                                           
                                     XX.XX     DDMMMYYYY   X:XX:XX  XXXXXXXXXXX     XXXXXXXXXXX                                        
                                     XX.XX     DDMMMYYYY  XX:XX:XX  XXXXXXXXXXX     XXXXXXXXXXX   XXXXXXXXXX                                 
                                     XX.XX     DDMMMYYYY  XX:XX:XX  XXXXXXXXXXX     XXXXXXXXXXX                                                 
                                     XX.XX     DDMMMYYYY  XX:XX:XX  XXXXXXXXXXX     XXXXXXXXXXX                             
                                     XX.XX     DDMMMYYYY  XX:XX:XX  XXXXXXXXXXX     XXXXXXXXXXX   XXXXXXXXXXX                     
                                     XX.XX     DDMMMYYYY  XX:XX:XX  XXXXXXXXXXX     XXXXXXXXXXX 
                                     XX.XX     DDMMMYYYY  XX:XX:XX  XXXXXXXXXXX     XXXXXXXXXXX  
                                     XX.XX     DDMMMYYYY   X:XX:XX  XXXXXXXXXXX     XXXXXXXXXXX                                                 
                                     XX.XX     DDMMMYYYY   X:XX:XX  XXXXXXXXXXX     XXXXXXXXXXX 
                                     XX.XX     DDMMMYYYY  XX:XX:XX  XXXXXXXXXXX     XXXXXXXXXXX 
                                 X   XX.XX     DDMMMYYYY   X:XX:XX  XXXXXXXXXXX     XXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
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                                                                                                                                 Page 1 of X 
 
                                        Appendix 16.2.5.6  Meal Times (Safety Population) 
  
 Dose Level/ Subject  Study                           Actual      Start     Stop                                                     
 Placebo     Number   Period   Day  Hour   Event      Date        Time      Time        Comments                                      
 ------------------------------------------------------------------------------------------------------------------------ 
 XXX <units>    X      X       -X  -XX.XX  LUNCH      DDMMMYYYY   XX:XX:XX  XX:XX:XX                                                
                                   -XX.XX  DINNER     DDMMMYYYY   XX:XX:XX  XX:XX:XX                                                
                                   -XX.XX  SNACK      DDMMMYYYY   XX:XX:XX  XX:XX:XX                                                
                                X   XX.XX  BREAKFAST  DDMMMYYYY   XX:XX:XX  XX:XX:XX       
                                    XX.XX  LUNCH      DDMMMYYYY   XX:XX:XX  XX:XX:XX                                                
                                    XX.XX  DINNER     DDMMMYYYY   XX:XX:XX  XX:XX:XX                                                
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
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                                                                                                                                 Page 1 of X 
 
                                           Appendix 16.2.5.7  Prior and Concomitant Medications (Safety Population) 
                                                                                                                                     
                                                               Start               Stop                                              Prior 
Dose Level/ Subject  Any    Medication                    ------------------  -------------------                                    to      
Placebo     Number   Med?   (WHO* Term)    Dosage  Route  Date      Time      Date       Time      Frequency Indication Continuing?  Study? 
-------------------------------------------------------------------------------------------------------------------------------------------- 
XXX <units>  X       No     None                                                                                                  
             X       Yes    ACETAMINOPHEN  620 mg  Oral   DDMMMYYYY HH:MM:SS  DDMMMYYYY  HH:MM:SS  Once      Toothache      No         X 
                       (ACETAMINOPHEN) 
           
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
      *Concomitant medications are coded with World Health Organization (WHO) Drug Dictionary Version 01Mar2018. 
       Med = Medication  
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
 


  
Statistical Analysis Plan, 25 July 2018                                                                                              Page 69 of 78 
 
Individual profiles in Appendix 16.2.6 will be in the following format. 
 
Appendix 16.2.6.1 
 
Individual <Matrix Analyte> Concentrations Versus Time  
for Subject X 
 
 
 


  
Statistical Analysis Plan, 25 July 2018                                                                                              Page 70 of 78 
Notes for Generating the Actual Individual Figure: 
 
• 
Legend will be <> and <>  
• 
Y axis label will be <Matrix> <analyte> Concentration (unit) 
• 
X axis label will be “Hours From Dosing” 
• 
Please generate figures in color. Please use the same color and symbol for 
each treatment throughout.


  
Statistical Analysis Plan, 25 July 2018 
Page 71 of 78 
 
                                                                                                                                 Page 1 of X 
 
                                        Appendix 16.2.7.1.1  Adverse Events (I of II) (Safety Population) 
 
                                                                     Time From                                             
                                                                     Last Dose       Onset             Resolved         Duration  
Dose Level/ Subject                                                  ----------  ----------------   ----------------  ------------- 
Placebo     Number   TE?^   Adverse Event*    Preferred Term         (DD:HH:MM)  Date       Time    Date       Time    (DD:HH:MM) 
----------------------------------------------------------------------------------------------------------------------------------- 
XXX <units>   X             None                                                                                                
              X      Yes    XXXXXXXXXXXXX     XXXXXXXXXX XXXXXXX      XX:XX:XX   DDMMMYYYY  XX:XX   DDMMMYYYY  XX:XX    XX:XX:XX  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
      *Adverse events are classified according to MedDRA Version 21.0. 
      ^TE = Treatment-emergent 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 72 of 78 
 
                                                                                                                                 Page 1 of X 
 
                                       Appendix 16.2.7.1.2  Adverse Events (II of II) (Safety Population) 
 
                                                                                                                  
                                                        Onset                                                         
  Dose Level/  Subject        Adverse             -----------------        Severity/                      Relationship to 
  Placebo      Number   TE?^  Event               Date        Time  Freq*  Intensity  Serious  Outcome    Study Drug 
  ------------------------------------------------------------------------------------------------------------------------ 
  XXX <units>    X            None                                                                                       
                 X      Yes   XXXXXXXXXXXXXXXXXX  DDMMMYYYY   XX:XX Inter.  Grade 1   Not      Resolved   XXXXXXXXXXXXXXXX    
                                                                            Mild      serious 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
      ^TE = Treatment-emergent 
      *Freq represents Frequency:  SI = Single Episode, Inter. = Intermittent, Cont. = Continuous                            
 
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Statistical Analysis Plan, 25 July 2018 
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                                                                                                                                Page 1 of X 
 
 
                                         Appendix 16.2.7.2  Adverse Event Related Procedure (Safety Population) 
 
                                                   Onset                    Procedure                
       Dose Level/ Subject        Adverse      ---------------   ------------------------------------ 
       Placebo     Number   TE?^  Event        Date      Time    Date      Time    Description          
       ---------------------------------------------------------------------------------------------- 
       XXX <units>   X      Yes   DRY LIPS     DDMMMYYYY XX:XX   DDMMMYYYY XX:XX   PETROLEUM JELLY      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
        ^TE = Treatment-emergent 
 
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Statistical Analysis Plan, 25 July 2018 
Page 74 of 78 
 
                                                                                                                                Page 1 of X 
 
                              Appendix 16.2.7.3  Adverse Event Preferred Term Classification (Safety Population) 
 
                                                                                                                   Onset      
 Dose Level/  Subject        Adverse                                                                          ------------------ 
 Placebo      Number   TE?^  Event*                      Preferred Term             System Organ Class        Date       Time  
 ------------------------------------------------------------------------------------------------------------------------------- 
 XXX <units>    X      Yes   XXXXXXX XXXXX XXXX XXXXXX   XXXXXXXXXX XXXXXXX         XXXXXXXXXXXXXXXXXXXXX     DDMMMYYYY  XX:XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
       *Adverse events are classified according to MedDRA Version 21.0. 
       ^TE = Treatment-emergent 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                


  
Statistical Analysis Plan, 25 July 2018 
Page 75 of 78 
Appendices 16.2.8.1.1 to 16.2.8.1.5 will have the following format. 
 
                                                                                                                                 Page 1 of X 
 
                                   Appendix 16.2.8.1.1  Clinical Laboratory Report - Serum Chemistry (Safety Population) 
  
                                                                                                                                                
                                                              Parameter1  Parameter2  Parameter3  Parameter4  Parameter5 Parameter6  
  Dose Level/ Subject   Age#/  Study                           < Range>   < Range>    < Range>     < Range>   < Range>    < Range>        
  Placebo     Number    Sex    Period  Day   Hour   Date        (Unit)     (Unit)      (Unit)       (Unit)     (Unit)     (Unit)      
  ---------------------------------------------------------------------------------------------------------------------------------- 
  XXX <units>   X       XX/X   Screen   .      .    DDMMMYYYY   XX HN        XX          XX           XX         XX HN      XX        
                                X      -X   -XX.X   DDMMMYYYY   XX LYR+      XX LN       XX           XX LY-     XX         XX        
 
 
 
Programmer Note:  Replace Parameter1, 2 etc. with actual lab tests in the study. Sort unscheduled assessment and early term chronologically 
with other scheduled assessments and rechecks.  Recheck should be sorted with the scheduled time point the recheck is 
for.  
Clinically significant lab values generally will be captured as AEs, some of which the PI may indicate in Appendix 
16.2.8.1.6 lab comments (as per GPG.03.0028 sections 2.9 and 2.10). Derive an additional flag for PI flag (+) based on 
positive CS/Clinically Significant comments. Present this derived 4th column in all tables, and also list the PI-
determined out-of-range clinically significant lab values in Table 14.3.4.5. 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
  #Age is calculated from the date of first dosing. F = Female; M = Male 
  H = Above reference range, L = Below reference range                                                                                         
  Computer: N = Not clinically significant, Y = Clinically significant                                                                         
  PI interpretation: - = Not clinically significant, + = Clinically Significant, R = To be rechecked 
                     ^ = Will be retested at a later event                                
 
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Statistical Analysis Plan, 25 July 2018 
Page 76 of 78 
 
                                                                                                                                 Page 1 of X 
 
                                         Appendix 16.2.8.1.5  Clinical Laboratory Report – Comments (Safety Population) 
  
 Dose Level/  Subject Age#/ Study                                                                                                                      
 Placebo      Number  Sex   Period   Day   Hour    Date       Department      Test          Result     Unit      Comment                     
 --------------------------------------------------------------------------------------------------------------------------------------- 
 XXX <units>  XX/X     X     X       -X   -XX.X    DDMMMYYYY  Other Tests     Fibrinogen    XXX        mg/dL     Not significant in the      
                                                                                                                 context of this study.      
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
 #Age is calculated from the date of first dosing. F = Female; M = Male 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 77 of 78 
 
                                                                                                                                Page 1 of X 
 
                                              Appendix 16.2.8.2  Vital Signs (Safety Population) 
  
 
                                                                       Blood Pressure (mmHg)         Respi-    Tempera-                       
 Dose Level/  Subject  Study                                          ----------------------  Pulse  ration    ture     Weight           
 Placebo      Number   Period  Day  Hour     Date       Time    Test     Systolic/Diastolic   (bpm)  (rpm)     (°C)     (kg)   Comment    
 ------------------------------------------------------------------------------------------------------------------------------------------- 
 XXX <units>           Screen   .     .      DDMMMYYYY  X:XX:XX SUPX      XXX/ XX               XX    XX        XX       XX    XXXX                        
                 X       X     -X  -XX.X     DDMMMYYYY  X:XX:XX SUPX      XXX/ XX               XX    XX        XX       XX    XXXXXXXXX 
                                X   XX.X     DDMMMYYYY  X:XX:XX SUPX      XXX/ XX               XX            
 
 
 
 
 
 
Programmer Note: Sort unscheduled assessment and early term chronologically with other scheduled assessments and rechecks.  Recheck should 
be sorted with the scheduled time point the recheck is for. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
        SUPX = X-minute supine; R = Recheck value  
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan, 25 July 2018 
Page 78 of 78 
 
                                                                                                                                 Page 1 of X 
 
                                            Appendix 16.2.8.3  12-Lead Electrocardiogram (Safety Population) 
 
                                                                        Heart                                                                      
  Dose Level/ Subject Study                                                 Rate     PR     QRS    QT    QTcF*                                       
  Placebo     Number  Period  Day   Hour  Date       Time     Result        (bpm)   (ms)   (ms)   (ms)   (ms)    Comments                             
  -------------------------------------------------------------------------------------------------------------------------- 
  XXX <units>  X      Screen   .      .   DDMMMYYYY  X:XX:XX  Normal         XX     XXX     XX    XXX    XXX^#                            
               X       X       X    XX.X  DDMMMYYYY  X:XX:XX  Normal         XX     XXX     XX    XXX    XXX     XXXXXXXXX             
                                    XX.X  DDMMMYYYY  X:XX:XX  Normal         XX     XXX     XX    XXX    XXX     XXXXXXXXX             
 
 
 
 
Programmer Note: Sort unscheduled assessment and early term chronologically with other scheduled assessments and rechecks.  Recheck should 
be sorted with the scheduled timepoint the recheck is for. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  0.5 mcg/kg: 0.5 mcg/kg E-WE thrombin (IV bolus) 
1.0 mcg/kg: 1.0 mcg/kg E-WE thrombin (IV bolus) 
2.0 mcg/kg: 2.0 mcg/kg E-WE thrombin (IV bolus) 
4.0 mcg/kg: 4.0 mcg/kg E-WE thrombin (IV bolus) 
Placebo: Placebo Solution (IV bolus) 
  QTcF* = QT corrected for heart rate using Fridericia’s correction. 
  Abnormal, NCS = Abnormal, Not clinically significant 
  ^ = QTcF is > 450 ms 
  # = QTcF change from baseline is > 30 ms 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM