A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of a Single Dose of E-WE Thrombin, Administered During a Regular Hemodialysis Procedure, in Patients With End-Stage Renal Disease on Chronic Hemodialysis
Phase: PHASE2
Conditions: End Stage Renal Disease, Thrombosis
Sponsor: Aronora, Inc.

 
Page 1 
 
 
 
 
 
 
Clinical Protocol 
 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety 
and Efficacy of a Single Dose of E-WE Thrombin, Administered During a Regular 
Hemodialysis Procedure, in Patients with End-Stage Renal Disease on Chronic 
Hemodialysis 
 
 
 
Celerion Project No.: CA26622 
 
Sponsor Project No.: EWE-19-02 
 
US IND No.: 18154  
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 

CONFIDENTIAL  
CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 2 
1. 
PROTOCOL REVISION HISTORY 
DATE/NAME DESCRIPTION 
22April2020 
by Natacha 
Benrimoh 
Final Protocol, Amendment 2: 
This protocol was amended to update exclusion criterion #9 in order to aid in 
recruitment. Cut--off values for hemoglobin entry levels is not required for this 
study’s population (patients with end-stage renal disease). Removal of this 
criterion will not affect patients safety upon drug administration and will not 
interfere with study endpoints. 
Therefore, the last bullet in Section 11.2 Exclusion Criteria, criterion # 9, 
“Hemoglobin concentration < 10 g/dL at screening or check-in on Day -8” was 
removed. 
In addition, the protocol clarification dated February 12, 2020 was incoporated 
in this amendment. In Section 13.5.1 Blood Sampling and Processing and in 
Section 13.7.1 Protein C Analysis, allowable time deviation window for 
post-dose blood collections were thus added.  
01May2019  
by Joelle 
Batonga 
Final Protocol, Amendment 1: 
This protocol was amended at the Sponsor’s request to add sample timepoints 
for protein C in order to characterize protein C in all hemodialysis sessions. 
Additional samples will be collected at the start and at the end of hemodialysis 
on Days -7, -5, -2, and 3. Thus the total number of time points for protein C 
analysis sample collection will increase from 8 to 16: 
In Section 6 – Study Event Flow Chart, collection of blood samples for protein 
C analysis were added at the start and the end of hemodialysis on Days -7, -5, -2, 
and 3. 
In Section 13.8 - Blood Volume for Study Assessments, Table 3 - Blood 
Volume during the Study, was amended as follows (deleted text in 
strikethrough and added text in bold in a condensed version of the table): 
Sample Type 
Number 
of Time 
Points 
Approximate 
Volume per 
Time Point * 
(mL) 
Approximate 
Sample Volume 
Over Course of 
Study (mL) 
Blood for protein C 
(ships to Aronora) 
816 
2 
1632 
Total Blood Volume (mL)→ 
Up to 
220236*** 
15Mar2019  
by Joelle 
Batonga 
Final Protocol 
 

CONFIDENTIAL  
CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 3 
2. PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety 
and Efficacy of a Single Dose of E-WE Thrombin, Administered During a Regular 
Hemodialysis Procedure, in Patients with End-Stage Renal Disease on Chronic 
Hemodialysis 
 
 
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 
CLINICAL SITE AND PRINCIPAL INVESTIGATOR 
 
 
 
Site Address: 
Orlando Clinical Research Center 
5055 S. Orange Avenue 
Orlando, Florida. 32809-3017, USA 
Tel.: +1 407 240-7878 
 
 
 
 
Signature 
 Date 
 
 
 
 
  
 
Printed Name 
 

CONFIDENTIAL  
CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 4 
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 
Joelle Batonga, MSc 
Senior Pharmacokinetic Scientist I,  
Data Management and Biometrics 
Celerion 
100 Alexis-Nihon Boulevard, Suite 360 
Montreal, Quebec H4M 2N8, Canada 
Tel.: +1 514 744-8745 
Fax: +1 514 744-8700 
E-mail: joelle.batonga@celerion.com 
Bioanalytical Laboratory for 
APC-PCI Samples 
Celerion 
621 Rose Street 
Lincoln, Nebraska 68502, USA 
Tel.: +1 402 476-2811 
Fax: +1 402 939-0428 
Shipment Address for Protein C, 
Total Protein Accumulation and 
Dialysate Samples 
Aronora, Inc.  
4640 SW Macadam Avenue, Suite 200A  
Portland, Oregon 97239, USA  
Tel.: +1 503 964-0250 
Fax: +1 503 389-7330 
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 
Clinical Laboratory 
Orlando Clinical Research Center 
5055 S. Orange Avenue 
Orlando, Florida 32809-3017 
Tel.: +1 407 240-7878 
Fax: +1 407 240-9846 

CONFIDENTIAL  
CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 5 
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 
 

CONFIDENTIAL  
CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 6 
4. TABLE OF CONTENTS 
1. PROTOCOL REVISION HISTORY ......................................................................... 2 
2. PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES ........................ 3 
3. ADDITIONAL KEY CONTACTS FOR THE STUDY ............................................. 4 
4. TABLE OF CONTENTS ........................................................................................... 6 
5. SYNOPSIS ................................................................................................................ 9 
6. STUDY EVENTS FLOW CHART.......................................................................... 13 
7. ABBREVIATIONS ................................................................................................. 16 
8. BACKGROUND AND RATIONALE..................................................................... 19 
8.1 
Introduction .................................................................................................... 19 
8.2 
Background .................................................................................................... 19 
8.2.1 
Nonclinical Studies ........................................................................... 19 
8.2.1.1 
Pharmacokinetics ............................................................. 20 
8.2.1.2 
Pharmacodynamics ........................................................... 20 
8.2.1.3 
Toxicology ....................................................................... 21 
8.2.2 
Clinical Studies ................................................................................ 21 
8.2.2.1 
Safety Data ....................................................................... 22 
8.2.2.2 
Pharmacodynamic Data .................................................... 22 
8.3 
Rationale ........................................................................................................ 24 
8.3.1 
Purpose of the Study Design ............................................................. 24 
8.3.2 
Dose Selection .................................................................................. 26 
8.3.3 
Rationale for Pharmacodynamic Markers ......................................... 26 
8.4 
Risk/Benefit ................................................................................................... 26 
9. STUDY OBJECTIVES AND ENDPOINTS ............................................................ 28 
9.1 
Study Objectives ............................................................................................ 28 
9.2 
Study Endpoints ............................................................................................. 28 
10. INVESTIGATIONAL PLAN .................................................................................. 29 
10.1 Overall Study Design and Plan ....................................................................... 29 
10.1.1 
Confinement, Return Visits, and Follow-Up ..................................... 30 
10.1.2 
Study Duration ................................................................................. 30 
10.2 Study Conduct ................................................................................................ 30 
11. STUDY POPULATION .......................................................................................... 30 
11.1 Inclusion Criteria ............................................................................................ 30 
11.2 Exclusion Criteria ........................................................................................... 31 
11.3 Early Termination of Patients from the Study ................................................. 34 
11.4 Study Restrictions .......................................................................................... 35 

CONFIDENTIAL  
CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
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11.4.1 
Prohibitions and Concomitant Medication ........................................ 35 
11.4.2 
Meals ............................................................................................... 35 
11.4.3 
Activity ............................................................................................ 35 
12. TREATMENTS....................................................................................................... 36 
12.1 Treatments Administered................................................................................ 36 
12.2 Dose Modification .......................................................................................... 37 
12.3 Method of Assigning Patients to Treatment Groups ........................................ 37 
12.4 Blinding ......................................................................................................... 37 
12.4.1 
Maintenance of Randomization ........................................................ 37 
12.4.2 
Procedures for Breaking the Blind Prior to Study Completion .......... 37 
12.4.2.1 Revealing of Randomization ............................................ 38 
12.4.3 
Treatment Compliance...................................................................... 38 
13. STUDY ASSESSMENTS AND PROCEDURES .................................................... 39 
13.1 Screening ....................................................................................................... 39 
13.2 Safety and Tolerability Assessments ............................................................... 39 
13.2.1 
Body Weight .................................................................................... 39 
13.2.2 
Physical Examination ....................................................................... 39 
13.2.3 
Vital Signs ........................................................................................ 40 
13.2.4 
ECG Monitoring ............................................................................... 40 
13.2.5 
Vascular Access Site Reaction Assessment ....................................... 40 
13.2.6 
Bleeding of Access Site .................................................................... 41 
13.2.7 
Clinical Laboratory Tests.................................................................. 42 
13.2.8 
Adverse Events ................................................................................. 43 
13.2.8.1 Adverse Event Definition ................................................. 43 
13.2.8.2 Monitoring ....................................................................... 43 
13.2.8.3 Reporting ......................................................................... 43 
13.2.8.4 Serious Adverse Events .................................................... 45 
13.3 Hemodialysis Procedure and Blood Clots in the Dialyzer Cartridge ................ 45 
13.4 Immunogenicity ............................................................................................. 46 
13.4.1 
Blood Sampling and Processing for Immunogenicity ........................ 46 
13.4.2 
Analytical Method ............................................................................ 46 
13.5 Pharmacodynamic Assessment – APC-PCI .................................................... 46 
13.5.1 
Blood Sampling and Processing ........................................................ 46 
13.5.2 
Analytical Method ............................................................................ 47 
13.6 Pharmacodynamic Assessments – Drug Efficacy and Efficiency of HD.......... 47 
13.7 Internal Analyses ............................................................................................ 47 
13.7.1 
Protein C Analysis ............................................................................ 48 
13.7.2 
Dialysate Analysis ............................................................................ 48 

CONFIDENTIAL  
CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 8 
13.7.3 
Analysis of Protein Accumulation Within the Dialyzer Cartridge ..... 48 
13.8 Blood Volume for Study Assessments ............................................................ 49 
14. STATISTICAL CONSIDERATIONS ..................................................................... 50 
14.1 Sample Size Determination ............................................................................ 50 
14.2 Population for Analyses.................................................................................. 50 
14.3 Statistical Analyses ........................................................................................ 50 
14.3.1 
Safety and Tolerability Analyses ...................................................... 50 
14.3.2 
Immunogenicity Analyses ................................................................ 51 
14.3.3 
Pharmacodynamic Analyses ............................................................. 51 
15. STUDY ADMINISTRATION ................................................................................. 52 
15.1 Ethics ............................................................................................................. 52 
15.1.1 
Institutional Review Board ............................................................... 52 
15.1.2 
Ethical Conduct of the Study ............................................................ 52 
15.1.3 
Subject Information and Consent ...................................................... 52 
15.1.4 
Confidentiality.................................................................................. 52 
15.2 Termination of the Study ................................................................................ 53 
15.3 Data Quality Assurance .................................................................................. 53 
15.4 Direct Access to Source Data/Documents ....................................................... 53 
15.5 Drug Supplies, Packaging and Labeling ......................................................... 53 
15.6 Data Handling and Record Keeping ................................................................ 54 
15.7 Report Format ................................................................................................ 54 
15.8 Protocol Amendments .................................................................................... 54 
15.9 Publication Policy .......................................................................................... 54 
16. REFERENCES ........................................................................................................ 55 
 
LIST OF TABLES 
 
Table 1. Cohort and Treatment Randomization ........................................................... 29 
Table 2. Investigational Products ................................................................................ 36 
Table 3. Blood Volume during the Study .................................................................... 49 
 
LIST OF FIGURES 
 
Figure 1. APC-PCI Complexes after E-WE Thrombin Administration in Healthy 
Subjects......................................................................................................... 23 
Figure 2. Coagulation Parameters after E-WE Thrombin Administration in Healthy 
Subjects......................................................................................................... 24 
 
 

CONFIDENTIAL  
CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 9 
5. SYNOPSIS 
Compound 
E-WE thrombin (AB002) 
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 of clot formation in hemodialyzer circuits during 
hemodialysis (HD)  
Study Phase  
Phase 2 
Study Objectives 
The primary objective of this study is: 
• To assess the safety and tolerability of a single dose of 
E-WE thrombin infused into the dialysis line during a 
4-hour HD procedure in patients with end stage renal 
disease (ESRD). 
The secondary objectives of this study are: 
• To assess the pharmacodynamics (PD) of a single dose of 
E-WE thrombin infused into the dialysis line during a 
4-hour HD procedure in patients with ESRD. Activated 
protein C/protein C inhibitor complex (APC-PCI) will be 
used as a surrogate biomarker for drug exposure. 
• To assess the efficacy of a single dose of E-WE thrombin 
infused into the dialysis line during a 4-hour HD 
procedure in patients with ESRD. Efficacy will be 
assessed by thrombus accumulation within the dialyzer 
cartridge (evaluated by visual inspection) and 
measurement of urea removed by 4 hours of dialysis (ratio 
of volume of fluid completely cleared of urea [Kt/V] and 
urea reduction ratio [URR]). 
Study Design 
This is a phase 2, randomized, double-blind, placebo-controlled, 
single-dose study of E-WE thrombin designed to evaluate the 
safety and efficacy at 2 dose levels administered to patients with 
ESRD during HD conducted at one study center in the United 
States (US).  
Patients will be enrolled in Cohort 1 or Cohort 2; cohorts will be 
dosed sequentially. Dosing of Cohort 2 will commence following 
completion of all study events for all patients in Cohort 1. Within 
each cohort, patients will be randomized to receive active drug or 
matching placebo as summarized below: 
 

CONFIDENTIAL  
CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 10 
Cohort 
Treatment 
Active:Placebo 
Cohort 
Size 
1 
0.5 µg/kg bolus dose administered into the 
dialysis line immediately followed by a 
0.25 µg/kg/hour continuous infusion dose 
into the dialysis line over 4 hours of E-WE 
thrombin or matching placebo, for a total of 
1.5 µg/kg 
2:1 
12:6 
2 
1 µg/kg bolus dose administered into the 
dialysis line immediately followed by a 
0.5 µg/kg/hour continuous infusion dose 
into the dialysis line over 4 hours of E-WE 
thrombin or matching placebo, for a total of 
3 µg/kg 
2:1 
12:6 
This study includes a screening period of 28 days prior to 
checking in to the clinical research unit (CRU) on Day -8. From 
Day -8 (8 days prior to dosing on Day 1) through Day 3, all 
patients will undergo HD 5 times and will be assessed for all 
scheduled procedures and endpoints before and after each HD 
session as per the Study Events Flow Chart (Section 6), using 
only one type of dialyzer cartridge for each patient.  
On Day 1, prior to dosing, patients will undergo baseline 
measurements followed by initiation of a regular HD procedure, 
consistently using only one type of dialyzer cartridge for each 
patient. A single dose of E-WE thrombin or matching placebo 
will be administered into the dialysis line during the HD 
procedure. Patients will continue to undergo HD procedures and 
scheduled assessments from Day 1 through Day 3. 
Study assessments will include adverse events (AEs), including 
HD vascular access site (arteriovenous [AV] fistula or AV graft) 
reactions, physical examinations, vital sign measurements, 
12-lead electrocardiogram (ECGs), clinical laboratory tests, 
coagulation tests, immunogenicity assessments, and PD blood 
sampling for APC-PCI and measurement of urea removed by 
4 hours of dialysis to be performed throughout the study 
according to the Study Events Flow Chart (Section 6). On 
Days -7, -5, -2, 1, and 3, bleeding time from the HD vascular 
access sites on the AV fistula or AV graft (ladder or buttonhole 
technique) will be evaluated immediately at the end of the HD 
session. The dialyzer cartridge will be rinsed, visually inspected 
and graded against a standardized visual assessment scale at the 
end of the HD procedure, and photographed on 4 sides.  
Additionally, plasma and dialysate samples will be collected and 
sent to Sponsor along with the used and rinsed dialyzer cartridges 
for potential internal evaluation of plasma protein C, dialysate 
urea, and total protein accumulation within the dialyzer cartridge. 

CONFIDENTIAL  
CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 11 
All patients who receive the study drug or matching placebo 
(including patients who terminate the study early) will return to 
the CRU on Day 14 (± 2 days) for coagulation tests, 
immunogenicity sample collection, and to determine if any AE 
has occurred since the last study visit. 
Number of Patients 
A total of at least 36 adult male and female (of non-childbearing 
potential) patients will be enrolled; 18 patients are planned for each 
cohort. 
In each cohort, an attempt will be made to enroll at least 50% of 
females and at least 30% of a race/ethnic minority group. An 
attempt will also be made to approximately match key 
characteristics, including sex, average age, and weight between 
cohorts. 
Duration of 
Participation for 
Patients 
The total planned duration of patient participation is 
approximately 50 days from screening to follow-up, with CRU 
confinement from check-in on Day -8 to Day 3. Patients will 
return to the CRU on Day 14 (± 2 days) for follow-up procedures. 
Dosage, Dosage 
Form, Route, and 
Dose Regimen: 
On Day 1, patients in each cohort will receive a single dose of 
E-WE thrombin or matching placebo as a bolus followed by an 
infusion into the dialysis line during a 4-hour HD procedure. 
Cohort 1 will be completed prior to initiation of Cohort 2. 
Planned doses will be as follows: 
Cohort 1: 0.5 µg/kg bolus dose administered into the dialysis line 
immediately followed by a 0.25 µg/kg/hour continuous infusion 
dose into the dialysis line over 4 hours of E-WE thrombin or 
matching placebo, for a total dose of 1.5 µg/kg. 
Cohort 2: 1 µg/kg bolus dose administered into the dialysis line 
immediately followed by a 0.5 µg/kg/hour continuous infusion 
dose into the dialysis line over 4 hours of E-WE thrombin or 
matching placebo, for a total dose of 3 µg/kg. 
Key Assessments 
Safety  
Safety assessments will include number and severity of AEs 
(including HD vascular access site reactions), physical 
examinations, bleeding time from the HD vascular access sites, 
vital sign measurements, 12-lead ECGs, clinical laboratory tests, 
and coagulation tests.  
Number and severity of AE will be tabulated and summary 
statistics for the 12-lead ECGs, vital signs, clinical laboratory and 
coagulation tests may be computed and provided, as deemed 
clinically appropriate.  

CONFIDENTIAL  
CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 12 
Pharmacodynamics: 
Plasma APC-PCI will be measured as a surrogate biomarker of 
drug exposure. Efficacy of antithrombotic activity will be 
evaluated by thrombus accumulation within the dialyzer cartridge 
(evaluated by visual inspection). Efficiency of HD will be 
assessed using blood urea nitrogen (BUN) levels before and after 
dialysis to determine urea removed by 4 hours of dialysis (Kt/V 
and URR) after E-WE thrombin active treatment versus 
pre-treatment and placebo.  
Change from baseline for all PD measurements will be 
summarized by treatment (2 active dose levels and pooled 
placebo) and per timepoints using descriptive statistics.  
Immunogenicity:  
Development of antibodies to E-WE thrombin or wild type (WT) 
thrombin will be monitored using a multi-tiered approach that 
will include screening, confirmatory, and if applicable, antibody 
titer and neutralizing antibody assays. 
 

CONFIDENTIAL  
CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 13 
6. STUDY EVENTS FLOW CHART 
Study Procedures a 
Screening 
b 
(Day -37 
to Day -9) 
Study Days 
FUc 
Evaluation Period 
Days → 
-8 
-7 
-5 
-2 
1 
2 
3 
HD → 
 
HD e 
HD e 
HD e 
HD e 
 
 
HD e 
Hours → 
C-I d 
start 
end 
start end start end 
P 
0 
0.167 0.5 
1 
2 
3 
4 
6 
24 
start 
end 
Administrative 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full Physical 
Examination f 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X h 
 
Abbreviated Physical 
Examination f 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X g 
X h 
X g 
X h 
X g 
X h 
X g 
 
 
 
 
 
 
X h 
 
 
X g 
X h 
 
12-Lead Safety ECG  
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X h 
 
Vital Signs (HR, BP, 
RR, and T)  
X 
X 
X g 
 
X g 
 
X g 
 
X g 
 
 
 
X 
 
 
 
 
 
X g 
 
 
Bleeding Time at 
Access Site 
 
 
 
X i 
 
X i 
 
X i  
 
 
 
 
 
 
 
X i 
 
 
 
X i 
 
Hem, Serum Chem j, 
and UA k 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Coagulation l  
X 
X 
X g 
X h 
X g 
X h 
X g 
X h 
X g 
 
 
 
 
 
 
X h 
 
 
X g 
X h 
X 
Platelet Count  
 
 
X g 
X h 
X g 
X h 
X g 
X h 
X g 
 
 
 
 
 
 
X h 
 
 
X g 
X h 
 
Serum Pregnancy 
Test (♀only) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH (PMP 
♀only)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Saliva Drug Screen 
and Saliva/Breath 
Alcohol Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis 
Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Monitoring 
 
X 
X 

CONFIDENTIAL  
CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 14 
Study Procedures a 
Screening 
b 
(Day -37 
to Day -9) 
Study Days 
FUc 
Evaluation Period 
Days → 
-8 
-7 
-5 
-2 
1 
2 
3 
HD → 
 
HD e 
HD e 
HD e 
HD e 
 
 
HD e 
Hours → 
C-I d 
start 
end 
start end start end 
P 
0 
0.167 0.5 
1 
2 
3 
4 
6 
24 
start 
end 
ConMeds 
Monitoring 
X 
X 
 
Study Drug 
Administration/ 
PD/Immunogenicity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E-WE Thrombin/ 
Matching Placebo 
Administration m 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Blood for E-WE 
Thrombin PD 
(APC-PCI) 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
Blood for Protein C 
 
 
X g 
X h 
X g 
X h 
X g 
X h 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X g 
X h 
 
Plasma and Serum 
Immunogenicity 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood BUN (for 
Kt/V and URR)  
 
 
X g 
X h 
X g 
X h 
X g 
X h 
X g 
 
 
 
 
 
 
X h 
 
 
X g 
X h 
 
Dialysate  
Collection  
 
 
X n  
  
X n 
  
X n 
  
 
 
 
X 
 
 
X 
 
 
 
X n 
 
 
Ultrafiltration 
Recorded 
 
 
 
X h 
 
X h 
 
X h 
 
 
 
 
 
 
 
X h 
 
 
 
X h 
 
Visual Assessment 
Photography and 
Processing of 
Dialyzer Membrane 
 
 
 
X o 
 
X o 
 
X o 
 
 
 
 
 
 
 
X o 
 
 
 
X o 
 
Vascular Access Site 
Reaction Assessment 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X p 
 
 
X 
X p 
 
Confinement in the 
CRU 
 
X 
 
CRU Visits 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

CONFIDENTIAL  
CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 15 
a 
For details on Procedures, refer to Section 13.  
b 
Within 28 days prior to Day -8. 
c 
All patients who receive the study drug or matching placebo (including patients who terminate the study early) will return to the CRU on Day 14 
(± 2 days) for coagulation tests, immunogenicity sample collection, and to determine if any AE has occurred since the last study visit. 
d 
Patients will be admitted to the CRU on Day -8, at the time indicated by the CRU, and will remain confined up to Day 3 or early termination. 
e 
During confinement to the CRU, patients will undergo HD 5 times: on Day -7, -5, -2, Day 1, and Day 3. For each patient, the HD will last 
approximately 4 hours as per patient standard schedule which will be the same throughout the study. 
f 
Symptom-driven physical examination may be performed at other times, at the PI’s or designee’s discretion. 
g 
To be performed within 1 hour prior to the start of HD. 
h 
To be performed at the end of HD.  
i 
The HD vascular access sites (AV fistula or AV graft puncture sites) are to be evaluated immediately after the end of HD and removal of the needles 
from the fistula or graft for bleeding cessation or other reactions. 
j 
Samples for serum chemistry will be obtained following a fast of at least 4 hours, however, in case of dropouts or rechecks, patients may not have fasted 
for 4 hours prior to the serum chemistry sample is taken. 
k 
For anuric patients, UA may not be performed.  
l 
Coagulation parameters include aPTT, PT/INR, fibrinogen, and TT.  
m A single dose of E-WE thrombin or matching placebo will be administered into the dialysis line according to the randomization schedule, upon initiation 
of the HD procedure. The dose will be administered as a bolus dose immediately followed by a continuous infusion over 4 hours. Hour 0 will 
correspond to the beginning of E-WE thrombin bolus administration. 
n 
The dialysate sample will be taken at 30 minutes and at 3 hours after the start of HD. The dialysate will be frozen and sent to Aronora. 
o 
To be performed when the dialyzer cartridge is removed and collected at the end of HD. 
p 
To be performed within approximately 20 minutes after completion of HD. 
 
Abbreviations: ♀ = Females, AE = Adverse events, APC-PCI = activated protein C/protein C inhibitor complex, aPTT = activated partial thromboplastin time, 
BUN = Blood urea nitrogen, BP = Blood pressure, C-I = Check-in, Chem = Chemistry, ConMeds = Concomitant medication, CRU = Clinical research unit, 
ECG = Electrocardiogram, FSH = Follicle-stimulating hormone, FU = Follow-up, Hem = Hematology, HD = Hemodialysis, HIV = Human immunodeficiency 
virus, HR = Heart rate, INR = international normalized ratio, Kt/V = ratio of volume of fluid completely cleared of urea, P = Predose, PD = Pharmacodynamic, 
PI = Principal Investigator, PMP = Postmenopausal, PT = prothrombin time, RR = Respiratory rate, T = Temperature, TT = thrombin time, UA = Urinalysis, 
URR = Urea reduction ratio. 
 
 

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7. ABBREVIATIONS 
µg 
Microgram 
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 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AV 
Arteriovenous 
BMI 
Body mass index 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
°C 
Degrees Celsius 
CFR 
Code of Federal Regulations 
cm 
Centimeter 
CRF 
Case report form 
CRU 
Clinical Research Unit 
CS 
Clinically significant 
ECG 
Electrocardiogram 
ESRD 
End stage renal disease 
FDA 
Food and Drug Administration 
FIH 
First in human 
FSH 
Follicle-stimulating hormone 
FU 
Follow-up  
g 
Gram 
GCP 
Good clinical practice 
GLP 
Good laboratory practice 
HBsAg 
Hepatitis B surface antigen 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 

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HD 
Hemodialysis 
HIT 
Heparin-induced thrombocytopenia 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonization 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram 
Kt/V 
Ratio of volume of fluid completely cleared of urea 
m2 
Meters squared 
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 
PD 
Pharmacodynamic(s) 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PT 
Prothrombin time 
QA 
Quality assurance 
QTcF 
Corrected QT interval using Fridericia’s correction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SRC 
Safety Review Committee 

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TEAE 
Treatment-emergent adverse event 
TT 
Thrombin time 
ULN 
Upper limit of normal 
URR 
Urea reduction ratio 
US 
United States  
USA 
United States of America 
WT 
Wild type 
 

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8. BACKGROUND AND RATIONALE 
8.1 
Introduction 
E-WE thrombin (AB002) is a recombinant antithrombotic protein C activator enzyme analog 
of human alpha thrombin. Intravenously injected E-WE thrombin generates endogenous 
activated protein C (APC) on intravascular cell surfaces and does not change fibrinogen or 
platelet count in healthy adult subjects while at its intended pharmacological doses. Due to 
avid binding of E-WE thrombin to thrombin receptors, predominantly thrombomodulin and 
GPIb on cells, therapeutic doses of the free (unbound) 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. under the product identification number 
AB002 and is intended for single dose administration into the blood circulation through a 
venous access. Proposed indications for E-WE thrombin include arterial thrombosis and 
thromboembolism, including those associated with acute cerebrovascular accidents, acute 
coronary syndrome and other severe acute thrombus formation-associated ischemic events. 
Additional indications may include peri-interventional and extracorporeal organ support-
associated thromboprophylaxis, and temporal antiinflammatory treatment.   
A brief overview of available information regarding AB002 follows below. Details can be 
found in the E-WE thrombin, AB002 Investigator’s Brochure of 25 February 2019 [1]. 
8.2 
Background 
8.2.1 Nonclinical Studies  
The molecular mechanism by which E-WE thrombin exerts its antithrombotic activity has 
been proposed to involve the selective activation of surface receptor-bound endogenous 
protein C under intravascular shear flow. Experimental data suggest that antithrombotic 
treatment with E-WE thrombin could utilize an endogenous targeting system via cell-surface 
associated thrombin receptors including, among others, thrombomodulin and glycoprotein Ib 
[2], 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 are expected to 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 receptor-associated protein C, generating the potent endogenous 
antithrombotic and antiinflammatory enzyme APC. Unlike antithrombin, a direct inhibitor of 
enzymatic coagulation factors, endogenous APC cleaves and inactivates co-localized 
cofactors Va and VIIIa, thereby downregulating prothrombotic but not preventing hemostatic 
thrombin generation. Both endogenous and infused exogenous APC are capable of 
interrupting natural and experimental thrombogenesis, however, without the risk of 
paralyzing hemostasis. In fact, gene silencing or knockdown of factor V and/or VIII results in 
viable, though hemophilic animals. Complete factor VIII deficiency in people or animals 
increases the risk of bleeding and causes a bleeding disorder (hemophilia), but is generally 
compatible with life. Low levels of factor V and factor VIII also increase the risk of bleeding, 

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but to a lesser degree. By contrast, complete factor X, VII or II deficiencies are embryonic-
lethal. Natural endogenous APC has not been shown to completely block factor VIII and 
factor V activity, and even high dose exogenous recombinant APC infusion has not been 
consistently linked to bleeding in animal models or in humans. Furthermore, animal 
experiments and in vitro studies suggest that APC (predominantly protein C receptor bound) 
exerts additional protective effects by upregulating cytoprotective mechanisms and 
promoting antiapoptotic and antiinflammatory signaling through cleavage of transmembrane 
receptors, such as protease activated receptors 1 and 3. 
In both mice and primates, E-WE thrombin administration has antithrombotic effects at very 
low doses that do not have notable antihemostatic activity. The endogenous APC that escapes 
the surface at low E-WE thrombin doses does not increase clotting and bleeding times 
outside the normal range. 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 at its minimum effective 
doses, hemostasis markers (clotting times and bleeding times) remained within the “clinically 
insignificant” range. These data suggest that, in contrast to currently marketed 
antithrombotics, most of which target essential elements of the hemostatic coagulation 
cascade in the fluid phase, E-WE thrombin may preferentially target thrombi without notably 
increasing bleeding after injury. 
8.2.1.1 Pharmacokinetics 
Limited pharmacokinetic (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 plasma E-WE thrombin following high doses of E-WE 
thrombin (> 10 µg/kg). The observed PK profile in these animals closely mirrored the drug 
exposure PD biomarker assays (APC-PCI and activated partial thromboplastin time [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 
some of these reactions are accelerated by heparin. Therefore, it has been technically 
challenging to develop an ultrasensitive assay for the residual or trace free E-WE thrombin 
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 the fluid phase. 
8.2.1.2 Pharmacodynamics 
Injection of E-WE thrombin results in the temporal and selective generation of endogenous 
APC and subsequent escape of some of this endogenous APC into the blood circulation. In 
vitro, in the presence of phospholipid membranes, APC inactivates factor Va and factor 
VIIIa, resulting in a temporal prolongation of the aPTT that is observed at higher doses of 
E-WE thrombin. 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 

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APC is comparable. The rate of APC inhibition by PCI in plasma is significantly accelerated 
in the presence of heparin, and the inactive 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 intravenous 
(IV) bolus of E-WE thrombin (0.75 to 10 µg/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.  
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 or 
reference range 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 cynomolgus monkeys. Administration of E-WE thrombin to 
cynomolgus monkeys (12.5, 25, 50 µg/kg) caused a temporal increase in the concentration of 
APC-PCI complexes, in a dose-dependent manner. In addition, the anticipated minimal to 
modest temporal PD effect of aPTT prolongation occurred in all test article dose groups. 
APTT values were within the reference range 24 hours later. 
8.2.1.3 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 µg/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 µg/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 AEs, apart 
from the temporal aPTT prolongation outside the reference range (the anticipated systemic 
effect at high doses), were observed. Based on these results, the no observed adverse effect 
level (NOAEL) was determined to be 300 µg/kg/dose and 50 µg/kg/dose, for rats and 
cynomolgus monkeys, respectively.  
8.2.2 Clinical Studies 
A first-in-human (FIH) study (Study No. EWE-17-01 [Celerion Project No.: CA19169]) was 
completed in the US on 25 November 2018. This study was a single ascending dose study in 

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healthy adult male and female subjects with the purpose of collecting safety, tolerability, and 
PD information in order to support further development of E-WE thrombin. A total of 
21 male and female subjects were evaluated following IV bolus injection of one of four doses 
of E-WE thrombin (0.5, 1, 2, 4 µg/kg). 
All 21 subjects who entered the study received the study medication or placebo and 
completed the study per protocol. Below is a summary of the preliminary data from this FIH 
study as of 24 of January 2019. 
8.2.2.1 Safety Data 
There were no deaths or serious AEs (SAEs) experienced in Study No. EWE-17-01 [Celerion 
Project No.: CA19169]. No subjects were discontinued due to AEs.  
Overall, 4 of 21 (19%) subjects experienced a total of 8 treatment-emergent AEs (TEAEs) in 
this study, with 3 of 16 (19%) subjects following active treatment and 1 of 5 subjects (20%) 
following placebo. The majority of the events (5) were mild (Grade 1) in severity and 3 were 
moderate (Grade 2). Of the 8 TEAEs reported, only one was suspected to be possibly 
treatment related by the Principal Investigator (PI). 
The most common TEAE was headache, experienced by 2 (13%) active-treatment subjects. 
One case of headache of moderate severity (Grade 2) was deemed to be possibly treatment 
related by the PI and had a reported onset of approximately 10 minutes after dosing, 
resolving 36 hours later. The other case of headache (Grade 1) was deemed to be unrelated to 
treatment by the PI and was reported 17 days after dosing, resolving 24 hours later. Other 
TEAEs reported included back pain, pruritus, papular rash and skin exfoliation in one 
placebo subject and vessel puncture site hemorrhage at the site of IV attempt in one active 
treatment subject.  
Temporal aPTT prolongation was not evaluated as an AE, because it was an expected 
response, indicating a natural response to activation of endogenous protein C and release of 
some APC into systemic circulation.  
A single IV dose of E-WE thrombin up to 4 µg/kg appeared to be safe and generally well 
tolerated by the healthy male and female subjects in this study. 
8.2.2.2 Pharmacodynamic Data 
The APC-PCI was used as a surrogate biomarker for drug exposure.  
Mean plasma APC-PCI concentration results following single IV doses of E-WE thrombin 
are presented in Figure 1. Plasma APC-PCI was detectable in all subjects at the first sampling 
time point of 0.08 hour (5 minutes) post-injection and remained detectable throughout the 
entire sampling interval in all subjects up to 2 hours in the 0.5 µg/kg dose level group and up 
to 4 hours in the 1, 2 and 4 µg/kg dose level groups. Plasma concentrations of APC-PCI 
increased in a temporal and dose-dependent manner. All concentrations returned to baseline 
by 24 hours. Peak mean APC-PCI concentrations occurred at 0.5 hour (30 minutes) in all 
dose level groups. Ascending doses of E-WE thrombin increased the peak and overall 

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APC-PCI concentrations in a dose-proportional manner from the 0.5 to 2 µg/kg dose levels, 
and slightly less than dose-proportional from the 2 to 4 µg/kg. 
Figure 1. 
APC-PCI Complexes after E-WE Thrombin Administration in Healthy 
Subjects 
 
Anticoagulation was verified by a temporal, dose-dependent increase in the aPTT, which 
returned to baseline by 4 hours (in the 0.5 and 1 µg/kg groups) and by 24 hours (in the 2 and 
4 µg/kg groups). Administration of E-WE thrombin did not significantly impact prothrombin 
time (PT), platelets or fibrinogen levels (Figure 2). In the figure, laboratory reference ranges 
are shown with black dashed lines and clinically significant ranges are shown with red 
dashed lines. 
 
 

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Figure 2. 
Coagulation Parameters after E-WE Thrombin Administration in Healthy 
Subjects 
 
8.3 
Rationale 
8.3.1 Purpose of the Study Design 
A FIH study was conducted in healthy subjects and concluded that a single dose of E-WE 
thrombin up to 4 µg/kg, administered as a bolus, was safe and generally well tolerated. This 
study will explore antithrombotic potential and utility of single doses of E-WE thrombin 
administered as a bolus followed by an infusion in the treatment and prevention of thrombus 
formation in an extracorporeal device such as an HD cartridge. 
Thromboembolic disease and bleeding are common comorbidities in patients with chronic 
kidney diseases [5]. In most ESRD patients, heparin is routinely used during outpatient HD 
to reduce clotting in the dialyzer cartridge and to improve HD efficiency. However, 
administration of heparin during HD temporally increases the risk of bleeding. A safe 
alternative for patients with active bleeding, patients with previously documented or acquired 
heparin-induced thrombocytopenia, or that are at high risk for bleeding complications, is 
heparin-free dialysis [6-8] and the majority of HD patients that are admitted to the hospital 
are routinely dialyzed without heparin due to bleeding concerns.  

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In this study design, patients will be confined to the clinic for the majority of the trial and 
will not receive heparin during their HD sessions. While heparin-free HD can increase 
clotting within the dialyzer, resulting in the need for exchange of the dialyzer cartridge 
during HD in 5-7% of the procedures [9], there is no evidence that HD without heparin 
results in increased thromboembolic complications. Indeed, heparin anticoagulation during 
HD is not intended for systemic thromboprophylaxis and a recent retrospective analysis of 
data from the United States Renal Data System and electronic medical records shows that 
heparin-free HD is not associated with increased risk of thromboembolic events in ESRD 
patients [10]. Therefore, the removal of standard of care heparin anticoagulation in either arm 
for the short duration of the study is not expected to be a clinically relevant safety risk, nor 
place the patients at an increased risk for development of thromboembolic complications. 
Additionally, it enables the most rigorous assessment of safety and efficacy for E-WE 
thrombin that would not be possible if heparin anticoagulation during HD was maintained. 
E-WE thrombin is expected to reduce thrombogenesis by downregulating thrombin 
generation in the extracorporeal circuit and hemodialyzer without clinically significant 
impairment of the patient’s hemostasis or promoting thrombosis. Both thromboembolism and 
bleeding are common comorbidities in ESRD patients on HD, and heparin for HD is not well 
tolerated in some patients, as about 4% of ESRD patients develop heparin-induced 
thrombocytopenia (HIT). Severe HIT is a life-threatening acute complication of heparin 
exposure. HIT antibodies have been detected in about 8% of HD patients who receive 
unfractionated heparin, and some of them are at risk of developing a severe HIT event. Thus, 
an intrinsically safe short-term and self-limiting anticoagulant as an alternative to heparin is 
currently an unmet need for this patient population. As such, E-WE thrombin administration 
during HD may be an effective method to protect the hemodialyzer from clot development, 
and stands as a promising, short-acting alternative to other anticoagulants in this population. 
It is therefore of interest to assess E-WE thrombin safety and effectiveness in ESRD patients 
on chronic HD. 
A placebo arm is included in this study design in order to robustly demonstrate the safety and 
efficacy of E-WE thrombin while not placing the patients at unnecessary risk, as mentioned 
above. The primary endpoint in this study is safety, measured as the number or 
frequency/rate of AEs that occur during the comparable observation periods. A heparin-free 
inpatient HD observation period (from Day -8 to Day 1 prior to dosing) is included in the 
trial design to establish a baseline for the heparin-free procedure. Continuation of the 
heparin-free HD procedure during the subsequent trial period and inclusion of a placebo arm 
allows for the determination of whether an AE is drug-related or not and permits accurate 
assessment of the safety of the study drug. The addition of a placebo arm also removes 
potential bias from the interpretation of AEs by the PIs and from the reporting by the 
patients. The secondary endpoint for this study is efficacy of E-WE thrombin on HD which 
may be more clearly observed with a placebo control instead of an active control (e.g., 
heparin). While the placebo arm may be at the same risk of clotting within the dialysis circuit 
as during the pre-dosing period (Days -8 to 1), data cited above suggests that these patients 
will not be at higher risk for either thromboembolic or bleeding complications. Should 
clotting occur within the dialyzer cartridge during a HD session that results in dialyzer 
failure, the dialyzer cartridge will be replaced, and the patient will be closely monitored by 

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the PI. It is important to note that replacement of the dialyzer cartridge during HD is safe for 
the patient and a routine procedure in cases of dialyzer failure.  
8.3.2 Dose Selection 
A FIH study was conducted in healthy subjects and concluded that a single bolus dose of 
E-WE thrombin up to 4 µg/kg was safe and generally well tolerated. Thus the 1.5 and 
3 µg/kg doses were selected for this phase 2 study in order to provide adequate PD and 
efficacy characterization but still allowing a safety margin should the results differ in this 
population compared to healthy subjects. E-WE thrombin will be administered as a 
combination of a small bolus loading dose to induce rapid response but without significant 
systemic anticoagulation, and an infusion over 4 hours to prolong and sustain the duration of 
effect to cover the entire HD procedure. 
8.3.3 Rationale for Pharmacodynamic 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. The active 
enzyme is not measurable in plasma using our enzyme capture assay at predicted human 
therapeutic doses. The Sponsor will use a PD biomarker (circulating APC-PCI complexes) as 
a surrogate for drug exposure. 
8.4 
Risk/Benefit 
ESRD patients are often ill and are prone to a variety of AEs on or off HD, ranging, for 
example, from infections to hypertension to bleeding to thromboembolism to acute ischemic 
cardiovascular emergencies, even if they are apparently stable on chronic HD. 
E-WE thrombin is a purified protein produced by recombinant DNA technology in a 
bacterial (Escherichia coli) cell culture system. All drugs, including heparins or recombinant 
proteins can occasionally and unpredictably evoke acute or chronic allergic reactions. Some 
ESRD patients develop chronic HD- and uremia-related moderate hemorrhagic diathesis or 
hemostasis impairment. The hemostatic safety of E-WE thrombin in the complex conditions 
of ESRD and chronic HD is not yet known. The safety monitoring practices employed by this 
protocol (i.e., AE questioning [including HD vascular access site reaction], physical 
examinations, bleeding time from the HD vascular access sites, vital sign measurements, 
12-lead ECGs, clinical laboratory and coagulation tests) are adequate to protect the patients’ 
safety and should detect all expected and unexpected TEAEs. In addition, the cohorts will be 
dosed in a sequential manner, starting with the lower dose level, Cohort 1.  
There may be a higher risk of clots developing in the hemodialyzer during heparin-free HD. 
Should this occur, the site standard operating procedures will be followed to replace the 
clotted dialyzer and resume HD using a new cartridge under the supervision of the PI. It is 
important to note that replacement of the dialyzer cartridge is a safe procedure for the patient. 
While studies suggest that there is no risk of thromboembolic complications should this 
occur, complete clotting of the dialyzer circuit could result in up to ~228 mL of blood loss, 
and is usually prevented by replacing the dialyzer before complete occlusion. 

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As with all injectable recombinant or natural biologic products, subjects who receive these 
drug products may become immunized against the drug product. Subjects receiving E-WE 
thrombin may thus develop anti-drug antibodies (ADA), which may or may not neutralize the 
drug, or cross-react with and inhibit endogenous thrombin functions. While development of 
immunity and appearance of ADA in the circulation is not an AE as long as the ADA does 
not cross react with endogenous thrombin, the appearance of such antibodies will be 
monitored, as it may affect future tests and uses of the product, including future evaluation of 
repeat drug administration. Development of ADA that cross-react with the host’s 
prothrombin/thrombin is a remote but existing possibility. All subjects will be assessed for 
the presence of antibodies to either E-WE thrombin or wildtype thrombin using validated 
assays. 
There may be direct health benefits for study participants from receipt of study drug, some 
evaluated among the secondary outcome measures. E-WE thrombin has shown 
antithrombotic effects in nonclinical studies. Reduced thrombus accumulation on the dialyzer 
surface may potentially improve the efficiency of HD as well. An indirect health benefit for 
study participants enrolled in this study 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 this study is: 
• To assess the safety and tolerability of a single dose of E-WE thrombin infused into 
the dialysis line during a 4-hour HD procedure in patients with ESRD. 
The secondary objectives of this study are: 
• To assess the PD of a single dose of E-WE thrombin infused into the dialysis line 
during a 4-hour HD procedure in patients with ESRD. APC-PCI will be used as a 
surrogate biomarker for drug exposure. 
• To assess the efficacy of a single dose of E-WE thrombin infused into the dialysis 
line during a 4-hour HD procedure in patients with ESRD. Efficacy will be assessed 
by thrombus accumulation within the dialyzer cartridge (evaluated by visual 
inspection) and measurement of urea removed by 4 hours of dialysis (Kt/V and 
URR). 
9.2 
Study Endpoints 
Primary outcome measures: 
• The safety and tolerability of E-WE thrombin following active treatment will be 
evaluated versus pre-treatment and placebo by number and severity of AEs (including 
HD vascular access site reactions), physical examinations, bleeding time from the HD 
vascular access sites, vital sign measurements, 12-lead ECGs, clinical laboratory 
tests, and coagulation tests. 
Secondary outcome measures: 
• PD of E-WE thrombin will be measured by APC-PCI and plasma APC-PCI will act 
as a surrogate marker for E-WE thrombin drug exposure. 
• Efficacy of antithrombotic activity will be evaluated by thrombus accumulation 
within the dialyzer cartridge (evaluated by visual inspection) after E-WE thrombin 
active treatment versus pre-treatment and placebo. 
• Efficiency of HD will be assessed using BUN levels before and after dialysis to 
determine urea removed by 4 hours of dialysis (Kt/V and URR) after E-WE thrombin 
active treatment versus pre-treatment and placebo. 
Other outcome measures: 
• Development of antibodies to E-WE thrombin or WT thrombin after drug exposure. 
 
 

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10. INVESTIGATIONAL PLAN 
10.1 Overall Study Design and Plan  
This is a phase 2, randomized, double-blind, placebo-controlled, single-dose study of E-WE 
thrombin designed to evaluate the safety and efficacy at 2 dose levels administered to 
patients with ESRD during HD conducted at one study center in the US.  
Patients will be enrolled in Cohort 1 or Cohort 2; cohorts will be dosed sequentially. Dosing 
of Cohort 2 will commence following completion of all study events for all patients in 
Cohort 1. Within each cohort, patients will be randomized to receive active drug or matching 
placebo as summarized below: 
Table 1. 
Cohort and Treatment Randomization 
Cohort 
Treatment 
Active:Placebo Cohort 
Size 
1 
0.5 µg/kg bolus dose administered into the dialysis line 
immediately followed by a 0.25 µg/kg/hour continuous 
infusion dose into the dialysis line over 4 hours of E-WE 
thrombin or matching placebo, for a total dose of 1.5 µg/kg 
2:1 
12:6 
2 
1 µg/kg bolus dose administered into the dialysis line 
immediately followed by a 0.5 µg/kg/hour continuous 
infusion dose into the dialysis line over 4 hours of E-WE 
thrombin or matching placebo, for a total dose of 3 µg/kg 
2:1 
12:6 
 
This study includes a screening period of 28 days prior to checking in to the CRU on Day -8. 
From Day -8 (8 days prior to dosing on Day 1) through Day 3, all patients will undergo HD 
5 times and will be assessed for all scheduled procedures and endpoints before and after each 
HD session as per the Study Events Flow Chart (Section 6), using only one type of dialyzer 
cartridge for each patient.  
On Day 1, prior to dosing, patients will undergo baseline measurements followed by 
initiation of a regular HD procedure, consistently using only one type of dialyzer cartridge 
for each patient. A single dose of E-WE thrombin or matching placebo will be administered 
into the dialysis line during the HD procedure. Patients will continue to undergo HD 
procedures and scheduled assessments from Day 1 through Day 3. 
Study assessments will include AEs, including HD vascular access site (AV fistula or AV 
graft) reactions, physical examinations, vital sign measurements, 12-lead ECGs, clinical 
laboratory tests, coagulation tests, immunogenicity assessments, and PD blood sampling for 
APC-PCI and measurement of urea removed by 4 hours of dialysis to be performed 
throughout the study according to the Study Events Flow Chart (Section 6). On 
Days -7, -5, -2, 1, and 3, bleeding time from the HD vascular access sites on the AV fistula or 
AV graft (ladder or buttonhole technique) will be evaluated immediately at the end of the HD 
session. The dialyzer cartridge will be rinsed, visually inspected and graded against a 

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standardized visual assessment scale at the end of the HD procedure, and photographed on 
4 sides.  
Additionally, plasma and dialysate samples will be collected and sent to Sponsor along with 
the used and rinsed dialyzer cartridges for potential internal evaluation of plasma protein C, 
dialysate urea, and total protein accumulation within the dialyzer cartridge. 
10.1.1 Confinement, Return Visits, and Follow-Up 
Patients will be admitted to the CRU on Day -8, at the time indicated by the CRU, until after 
completion of study procedures on Day 3 as indicated in the Study Events Flow Chart 
(Section 6). At all times, a patient may be required to remain at the CRU for longer at the 
discretion of the PI or designee. 
All patients who receive the study drug or matching placebo (including patients who 
terminate the study early) will return to the CRU on Day 14 (± 2 days) for coagulation tests, 
immunogenicity sample collection, and to determine if any AE has occurred since the last 
study visit. 
10.1.2 Study Duration 
The total planned duration of patient participation is approximately 50 days from screening 
to 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. The end of the study is defined as the date of the last scheduled 
study procedure as outlined in the Study Events Flow Chart (Section 6). 
11. STUDY POPULATION 
11.1 Inclusion Criteria 
Patients must fulfill all of the following inclusion criteria to be eligible for participation in 
the study: 
1. ESRD maintained on stable outpatient HD regimen, using an established (> 3 months) 
and normally functioning, regular flow, uninfected mature AV fistula (or AV graft) and 
skin consistent with standard chronic HD access injuries, and HD stability defined as 
Kt/V ≥ 1.2 within 3 months prior to screening at a healthcare center for > 3 months from 
screening. 
2. On HD regimen at least 3 times per week for a minimum of 3 hours per dialysis session, 
using a complication-free well maintained AV fistula (or AV graft), expected and plan to 
continue this throughout and for at least 3 months beyond the study. 
3. Is capable of understanding the written informed consent, provides signed and witnessed 
written informed consent and agrees to comply with protocol requirements and 
study-related procedures. 

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4. Willing to be confined to the CRU for the duration of the study, able to comply with all 
study-related requirements, and able to adhere to study restrictions and visit schedules. 
5. Male or female, between 18 and 80 years of age (inclusive) at the time of screening.  
6. BMI of ≥ 18 at the time of screening. 
7. Considered by the PI to be clinically stable with respect to underlying ESRD, based on 
the medical evaluation that includes medical and surgical history, and a complete 
physical examination including vital sign measurements, ECGs, and clinical laboratory 
and coagulation test results at screening. Repeat assessments are permitted for any 
laboratory, coagulation, ECG, or vital sign parameter required for enrollment. 
8. Female patients must be of non-childbearing potential and must have undergone one of 
the following sterilization procedures at least 6 months prior to dosing: 
• hysteroscopic sterilization; 
• bilateral tubal ligation or bilateral salpingectomy; 
• hysterectomy; 
• 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 as per PI or designee judgment. 
9. Male patients must either be sterile (vasectomy with history of a negative sperm count 
following the procedure); practice total abstinence from sexual intercourse as the 
preferred lifestyle (periodic abstinence is not acceptable); use a male condom with any 
sexual activity; or agree to use a birth control method considered to be appropriate by the 
Investigator from the time of dosing until 90 days after study drug administration. Male 
patients must agree not to donate sperm for a period of 90 days after study drug 
administration. 
11.2 Exclusion Criteria 
Patients must not be enrolled in the study if they meet any of the following criteria: 
1. Documented history of acute vasoocclusive thrombotic event (acute coronary syndrome, 
stroke or transient ischemic attack, venous thromboembolic event), or vascular access 
fistula or AV graft failure in the past 3 months.  
2. With the exception of unfractionated heparin during HD that is allowed until study 
check-in, concomitant or prior use of anticoagulant/antiplatelet agents (e.g., low 
molecular weight heparins, warfarin, apixaban, bivalirudin, ticagrelor, edoxaban, 
dabigatran, rivaroxaban, clopidogrel, prasugrel, ticlopidine, eptifibatide, tirofiban, 
dipyridamole, diclofenac, and all other non steroidal antiinflammatory drugs) that may 
affect hemostasis for 2 weeks prior to check-in on Day -8 and throughout the study. 

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3. Any clinically significant (CS) concomitant disease or condition (including treatment for 
such conditions) that, in the opinion of the PI, could either interfere with the study drug, 
compromise interpretation of study data, or pose an unacceptable risk to the patient. 
4. Any other CS abnormalities in laboratory test results at screening or Day -8 check-in that 
would, in the opinion of the PI, increase the patient's risk of participation, jeopardize 
complete participation in the study, or compromise interpretation of study data. 
5. Pregnant (positive pregnancy test) at screening or check-in on Day -8. If serum human 
chorionic gonadotropin (hCG) pregnancy test results are indeterminate, follow-up testing 
should be performed to determine eligibility. 
All female patients will not be pregnant and will have a negative pregnancy test at 
screening and check-in on Day -8, with the following exception: females receiving 
dialysis with an indeterminate pregnancy test result or persistently low hCG resulting in a 
false positive pregnancy test may be included in the study at the discretion of the PI. 
Postmenopausal patients with a result outside the postmenopausal range or an 
indeterminate pregnancy test will undergo additional testing with FSH to confirm 
postmenopausal status prior to study enrollment. 
6. Treatment with another investigational drug or participation in a device study within 
30 days (or 5 half-lives, whichever is longer) prior to check-in on Day -8. 
7. Acute illness that is considered by the PI to be CS within 2 weeks of check-in on Day -8. 
8. Surgery within the past 90 days prior to dosing which in the opinion of the PI or designee 
is clinically relevant. 
9. Currently have established underlying inherited or acquired symptomatic bleeding 
disorders and/or are at risk for excessive bleeding per PI judgment or current active 
bleeding (e.g., gastrointestinal, intracranial), aside from minor bleeding from the puncture 
site on the AV fistula or AV graft, which would be expected to occur during the dialysis 
procedure, with the following values: 
• Platelet count < 100,000 cells/mm3 (if < 100,000 cells/mm3 but > 75,000 cells/mm3, 
with permission of PI and medical monitor) at screening or check-in on Day -8  
• INR > 1.4 at screening or check-in on Day -8 
• aPTT up to 1.2 x upper limit of normal (ULN) (if > 1.2 x ULN and up to < 1.5 x 
ULN, with permission of PI and medical monitor) at screening or check-in on Day -8 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 x ULN at 
screening or check-in on Day -8 
• Total bilirubin > 1.2 x ULN at screening or check-in on Day -8 
10. Seated blood pressure < 90/40 mmHg at screening and check-in on Day -8.  
11. Exclusion criteria for ECG at screening and check-in on Day -8: 

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Heart rate 
< 45 and > 110 bpm 
QTcF interval  
> 500 msec 
bpm = beats per minute; msec = milliseconds; QTcF = QT interval corrected using 
Fridericia’s formula 
• Any significant arrhythmia or conduction abnormality, (including but not specific to 
atrioventricular block [2nd degree or higher], Wolff Parkinson White syndrome [unless 
curative radio ablation therapy]), which, in the opinion of the PI and Medical 
Monitor, could interfere with the safety for the individual patient. 
• Non-sustained or sustained ventricular tachycardia (> 2 consecutive ventricular 
ectopic beats at a rate of > 1.7/second). 
12. History of a CS allergy or a known sensitivity or idiosyncratic reaction to any compound 
known to be present in E-WE thrombin, its related compounds, or any compound listed 
as being present in the study formulation. 
13. Hypersensitivity to ß-lactam / penicillin derivatives. 
14. Participate in strenuous exercise from 72 hours prior to check-in on Day -8 and 
throughout the study. 
15. Positive test for drugs of abuse and/or positive alcohol test at screening or check-in on 
Day -8 if not accounted for by a prescription medication. Patients with a positive test 
based on a prescribed medication may be enrolled. 
16. Positive test at screening for hepatitis B surface antigen (HBsAg) or human 
immunodeficiency virus (HIV). If a patient with ESRD has positive test results for 
hepatitis C virus (HCV) but liver function tests are otherwise not clinically significant, 
the patient may be included at the PI’s discretion. 
17. Receiving blood purification therapy other than HD. 
18. Donation of blood or significant blood loss within 56 days prior to dosing. 
19. Plasma donation within 7 days prior to dosing. 
20. Presence of advanced malignant neoplasms of any organ or system that produces illness 
or symptoms that have been treated within 3 months with chemotherapy or whole body 
irradiation, or bone marrow irradiation, and may affect life expectancy in the following 
6 months. 
21. Any other reason that would render the patient unsuitable for study enrollment at the 
discretion of the PI. 

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11.3 Early Termination of Patients from the Study 
Patient participation in this study may be discontinued for any of the following reasons: 
1. Occurrence of any medical condition or circumstance that exposes the patient to 
substantial risk and/or does not allow the patient to adhere to the requirements of the 
protocol. 
2. If the patient clots the hemodialyzer or the dialysis circuit in the pre-treatment 
observation period (from Day -8 to Day 1 prior to dosing) at least twice during one HD 
session, they may be discontinued from the study at the discretion of the PI. If the patient 
repeatedly clots the hemodialyzer or dialysis circuit during each HD session, continuation 
of the patient in the study will be at the PI’s discretion. However, available data obtained 
from such subjects will be included in the analyses. 
3. Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, or 
other medical condition that indicates to the PI that continued participation is not in the 
best interest of the patient. 
4. Patient's decision to withdraw. 
5. Requirement of prohibited concomitant medication. 
6. Patient failure to comply with protocol requirements or study-related procedures. 
7. Termination of the study by the Sponsor, Food and Drug Administration (FDA), 
Celerion, CRU, or other regulatory authorities.  
8. In the case of incomplete dosing (e.g., a large droplet of study medication on the surface 
of the skin) as deemed by the PI (or designee) and/or Sponsor. 
The clinical report will include reason(s) for patient withdrawals as well as details relevant to 
the patient withdrawal.  
If a patient is withdrawn from the trial prior to study completion, the patient will undergo all 
procedures scheduled for early termination as the situation allows (see the Study Events Flow 
Chart (Section 6). Any patient withdrawn due to an AE (whether serious or non-serious) or 
clinically significant abnormal laboratory test values will be evaluated by the PI 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. 

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11.4 Study Restrictions  
11.4.1 Prohibitions and Concomitant Medication 
Consumption of foods and beverages containing the following substances will be prohibited 
as indicated: 
• Xanthines/caffeine: 48 hours prior to dosing and throughout the period of sample 
collection (small amounts of caffeine derived from normal foodstuffs e.g., 
250 mL/8 oz./1 cup 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 prior to dosing and throughout the period of sample collection; 
Concomitant medications will be listed, recorded, and allowed except for those listed as 
prohibited in the exclusion criteria in Section 11.2. It is understood and will be considered 
that treatment with certain drugs or cessation of treatment with certain drugs may have 
adverse effects and could interfere with the evaluation of the primary outcome measures of 
the study. Apart from anticoagulant/antiplatelet agents, no patient will be requested to stop 
taking any medication to be able to participate in the trial. 
Acetaminophen (up to 2 g per 24 hours) or opioids may be administered, for fever or chronic 
pain control, at the discretion of the PI or designee. Administration of opioids for certain 
types of pain management may be allowed. 
If deviations occur, the PI or designee in consultation with the Sponsor if needed will decide 
on a case-by-case basis whether the patient may continue participation in the study. 
11.4.2 Meals 
At the CRU, meals and/or snacks and fluids will be provided at appropriate times following 
check-in and throughout the study as per the clinical site standard procedure. 
11.4.3 Activity 
On Day 1, as dosing will be upon initiation of the HD session, patients will be dosed in the 
same position as required for their HD session. Patients will maintain that position for the 
whole HD session, as per standard HD procedure, except when they are supine or semi-
reclined for other study procedures. At other times, there will be no specific activity 
restrictions. However, should AEs occur at any time, patients may be placed in an 
appropriate position. 
Patients will be instructed to refrain from strenuous exercise which could cause muscle aches 
or injury, including contact sports at any time from 72 hours prior to check-in on Day -8 and 
throughout the study. 
 
 

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12. TREATMENTS 
12.1 Treatments Administered 
A separate pharmacy manual provided by the Sponsor will detail the preparation and 
treatment administration to be followed for this study. 
E-WE thrombin will be supplied as a sterile, non-pyrogenic, preservative-free liquid for 
bolus and infusion. 
E-WE thrombin will be supplied as 0.1 mg/mL, according to the planned dose (µg/kg) for 
each cohort, as noted below in Table 2. 
Matching placebo will be supplied as sterile formulation buffer for bolus and infusion. 
Table 2. 
Investigational Products 
Product 
Description 
Test 
E-WE thrombin (0.1 mg/mL) 
Placebo 
Matching 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) 
An unblinded pharmacist will be responsible for providing E-WE thrombin or matching 
placebo to the blinded study personnel for administration as per the randomization scheme.  
Patients will be enrolled in Cohort 1 or Cohort 2. Within each cohort, patients will be 
randomized to active drug or matching placebo as summarized in Table 1. 
On Day 1, patients in each cohort will receive a single dose of E-WE thrombin or matching 
placebo as a bolus followed by an infusion into the dialysis line during a 4 hour HD 
procedure. Cohort 1 will be completed prior to initiation of Cohort 2. 
Planned doses will be as follows: 
Cohort 1: 0.5 µg/kg bolus dose administered into the dialysis line immediately followed by a 
0.25 µg/kg/hour continuous infusion dose into the dialysis line over 4 hours of E-WE 
thrombin or matching placebo, for a total dose of 1.5 µg/kg. 
Cohort 2: 1 µg/kg bolus dose administered into the dialysis line immediately followed by a 
0.5 µg/kg/hour continuous infusion dose into the dialysis line over 4 hours of E-WE 
thrombin or matching placebo, for a total dose of 3 µg/kg. 
Hour 0 will correspond to the beginning of E-WE thrombin bolus administration. The time of 
bolus administration and the times at which the infusion is started and stopped must be 
recorded. 

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The patient weight recorded at check-in will be used to calculate the study drug dose. 
Should the need arise to change the infusion rate (i.e., due to an AE), changes to the infusion 
rate and the times at which those changes are made will be documented. 
12.2 Dose Modification 
The dose and administration of the study drug to any patient within a cohort may not be 
modified. If necessary, a patient must be discontinued for the reasons described in 
Section 11.3. 
12.3 Method of Assigning Patients to Treatment Groups 
Each patient will be assigned a unique identification number upon screening. Patients who 
complete the study screening assessments and meet all the eligibility criteria will be assigned 
a unique randomization identification number at the time of dosing, different from the 
screening number, and will receive the corresponding product, according to a randomization 
scheme generated at Celerion. 
Patients will be enrolled in Cohort 1 or Cohort 2 with Cohort 1 to be completed prior to the 
initiation of Cohort 2.  
In each cohort, an attempt will be made to enroll at least 50% of females and at least 30% of 
a race/ethnic minority group. An attempt will also be made to approximately match key 
characteristics, including sex, average age, and weight between cohorts. 
In each cohort, patients will be randomized to receive either E-WE thrombin or matching 
placebo maintaining a 2:1 ratio  
If replacement patients are used, the replacement patient number will be 100 more than the 
original (e.g., Patient No. 101 will replace Patient No. 1). 
12.4 Blinding 
This is a double-blind, placebo-controlled study. 
12.4.1 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 CRU 
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, patients, or 
members of the staff responsible for the monitoring and evaluation of safety assessments. 
12.4.2 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. 

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Breaking of the blind is expressly forbidden except in the event of a medical emergency 
where the identity of the drug must be known in order to properly treat the patient, 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 patient only. In the event that the emergency is one, in which it appears 
that the other patients may be at imminent risk, the blind may be broken for all patients 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. 
12.4.2.1 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, 
and the database is officially locked.  
12.4.3 Treatment Compliance  
A qualified designee (e.g. nurse) will be responsible for administering and monitoring the 
timed dose. Before and after the bolus/infusion dose, the qualified designee will visually 
inspect the syringe to ensure that the patient has received the entire dose. In the case of 
incomplete dosing, a few milliliters of blood could be drawn back into the dosing syringe and 
carefully reinjected to ensure administration of the complete dose; this will be reported.   

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13. STUDY ASSESSMENTS AND PROCEDURES 
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 patient safety. 
For this study, the primary assessment is safety and tolerability. Safety will be determined by 
evaluating AEs (including HD vascular access site reactions), physical examinations, 
bleeding time from the HD vascular access sites, vital sign measurements, 12-lead ECGs, 
clinical laboratory parameters, including but not limited to, hematology, serum chemistry 
profile, coagulation, and urinalysis, 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. 
13.1 Screening 
Within 28 days prior to check-in on Day -8, medical history and demographic data, including 
name, sex, age, race, ethnic minority group, body weight (kg), height (cm), BMI (kg/m2) and 
history of tobacco use will be reported. Each patient will have a physical examination, vital 
sign measurements (heart rate, blood pressure, temperature, and respiratory rate), 12-lead 
ECG, and the laboratory tests of hematological, coagulation, hepatic and renal function and 
additional tests as noted in Section 13.2.7. 
13.2 Safety and Tolerability Assessments 
13.2.1 Body Weight 
Body weight (kg) will be measured daily up to Day 3 and before and after each HD session 
as outlined in the Study Events Flow Chart (Section 6). 
13.2.2 Physical Examination  
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. 
Abbreviated physical examinations will include at the minimum, examination of respiratory, 
cardiovascular, and gastrointestinal systems, with the option for further examination of 
additional systems as necessary based on reported symptoms/AEs. 
Symptom-driven physical examination may be performed at other times if deemed necessary 
by the PI or designee. 

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13.2.3 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 signs will be performed with patients in a seated position following a 5 minute rest 
period, except when they are supine or semi-reclined because of study procedures and/or AEs 
(e.g. nausea, dizziness) or if deemed necessary by the PI or designee. 
When scheduled prior to HD, vital signs will be performed within 1 hour prior to the start of 
the HD. When scheduled post-dose, vital signs will be performed within approximately 
15 minutes of the scheduled time point.  
13.2.4 ECG Monitoring 
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 performed with patients in a semi-recumbent position following a 5 minute rest 
period. All ECG tracings will be reviewed by the PI or designee. 
When scheduled post-dose, ECGs will be performed within approximately 20 minutes of the 
scheduled time point. 
13.2.5 Vascular Access Site Reaction Assessment 
The monitoring of AEs will include assessment of HD vascular access fistula (or AV graft) 
site reactions. The preferred vascular access is an established AV fistula (or AV graft). Well 
established and reaction-free AV graft is an alternative, but less preferred access option, as it 
is more prone to complications. Patients who are hemodialyzed through catheters are not 
included in the study. Therefore, inspection of the AV fistula (or AV graft) and surrounding 
area will be performed. Any new abnormal findings inconsistent with past skin injuries as 
expected in patients on chronic HD will be reported as AEs. AV fistula (or AV graft) site 
reactions will be evaluated as outlined in the Study Events Flow Chart (Section 6). Prior to 
HD, the AV fistula (or AV graft) site will be examined for inflammation, infection, or flow 
abnormalities (including occlusion of the fistula or graft). When scheduled post-dose, 
injection site examinations will be performed within approximately 20 minutes after 
completion of the HD session. Reactions will be rated according to the FDA Guidance for 
Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials [11] as follows: 

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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. 
13.2.6 Bleeding of Access Site 
Evaluation of bleeding and bleeding time from the HD vascular access sites on the AV fistula 
or AV graft using the ladder or buttonhole technique will be performed as per Study Events 
Flow Chart (Section 6).  
Following HD, the needle will be removed from the vascular access site and immediately 
followed by the placement of the dressing (i.e., gauze). Pressure will be applied manually by 
a clinical associate for 10 minutes before checking for evidence of bleeding around the 
dressing. If there is still some bleeding, pressure will be applied back at the site for 
5 minutes. The site will then be checked again for evidence of bleeding; this procedure will 
be repeated every 5 minutes until bleeding has stopped. Once bleeding has stopped, a new 
gauze dressing is applied and then taped. To ensure consistency when applying the pressure, 
the clinical staff will have received adequate training and an attempt will be made to have the 
same associates perform this test.  
The time to clot will be recorded. 
 

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13.2.7 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 (TT) 
 
• BUN 
• Bilirubin (total and direct) 
• Alkaline phosphatase 
• AST 
• ALT 
• Lactate dehydrogenase 
• Albumin 
• Sodium 
• Potassium 
• Bicarbonate 
• Chloride 
• Glucose  
• Creatinine** 
Urinalysis┼ 
 
Additional Tests 
• pH 
• Specific gravity 
• Protein*** 
• Glucose 
• Ketones 
• Bilirubin 
• Blood*** 
• Nitrite*** 
• Urobilinogen 
• Leukocyte esterase*** 
 
• HIV test 
• HBsAg 
• HCV 
• Saliva drug screen 
 Opiates 
 Amphetamines 
 Cocaine 
 Cannabinoids  
• Saliva or breath alcohol screen 
• Serum pregnancy test  
(for females only) 
• FSH (for postmenopausal females only) 
* 
Samples for serum chemistry will be obtained following a fast of at least 4 hours, however, in case of 
dropouts or rechecks, patients may not have fasted for 4 hours prior to 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. 
┼ 
May not be performed for anuric patients. 
 

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13.2.8 Adverse Events 
13.2.8.1 Adverse Event Definition 
AE will be defined as any untoward medical occurrence during the study, associated or not 
with the use of E-WE thrombin in the study patients, whether or not considered drug-related. 
TEAE is an AE that occurs after administration of the study drug or matching placebo. 
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 that is temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product [12]. 
13.2.8.2 Monitoring 
Patients will be monitored for AEs from check-in through completion of the study. Patients 
will be asked how they are feeling once per day during confinement and at each 
return/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 licensed medical provider, either at the CRU 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). The outcome may be classified as 
resolved, improved, unchanged, worse, fatal, or unknown (lost to follow up). 
13.2.8.3 Reporting 
All AEs that occurred during this clinical study (i.e., before, during, and after exposure of 
ESRD patients to E-WE thrombin) will be recorded. This design is to improve Sponsor 
ability to obtain reliable initial information about drug safety yet reducing the number of 
study patients needed to generate useful information.  
AEs and SAEs, including those related to study participation (e.g., protocol-mandated 
intervention), will be recorded from the time of patient check-in until study completion.  
AEs will be coded using the most current Medical Dictionary for Regulatory Activities 
(MedDRA)® available at Celerion. 
The PI or designee will review each event and assess its relationship to study drug (likely, 
probably, possibly, unlikely, or unrelated) and severity. The date and time of onset, time 
relationship to drug dosing, duration, and outcome of each event will be noted.  

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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 participant’s 
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 participant’s clinical state 
Likely 
 Is a known effect of the drug (e.g. listed in IB) 
 Time sequence from administering drug is reasonable 
 Event stops upon stopping drug and 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) [11]. 
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. 

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13.2.8.4 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 
[12]. The institutional review board (IRB) will be notified of the Alert Reports as per FDA 
regulations. 
An 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 
risk information described in the general investigational plan or elsewhere in the current 
application, as amended. 
If a SAE occurs to a patient on this study, contact the Sponsor personnel listed in Section 3. 
13.3 Hemodialysis Procedure and Blood Clots in the Dialyzer Cartridge 
Patients will undergo HD 5 times from Day -7 to Day 3 as delineated in the Study Events 
Flow Chart (Section 6). For each patient, the HD will last approximately 4 hours as per 
patient standard schedule which will be the same throughout the study. 
Clots may develop in the HD circuit when patients are undergoing heparin-free HD. Pressure 
within the HD circuit is continuously monitored, and an increase automatically signals 
development of blockage. Should clotting within the circuit occur, site standard operating 
procedures will be followed to replace the clotted dialyzer and resume HD. It may be 
performed under the supervision of the PI, if appropriate. It is important to note that 
replacement of the dialyzer cartridge is a safe procedure for the patient. While studies 

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suggest that there is no risk of thromboembolic complications should this occur, clotting and 
complete occlusion of the dialyzer circuit could result in up to ~228 mL of blood loss. This is 
preventable by timely intervention and replacement. 
The hemoglobin levels will be followed more closely in patients that require replacement of 
the dialyzer during HD. 
If the patient clots the hemodialyzer or the dialysis circuit in the pre-treatment observation 
period (from Day -8 to Day 1 prior to dosing) at least twice during one HD session, they may 
be discontinued from the study at the discretion of the PI. If the patient repeatedly clots the 
hemodialyzer or dialysis circuit during each HD session, continuation of the patient in the 
study will be at the PI’s discretion. However, available data obtained from such subjects will 
be included in the analyses.  
13.4 Immunogenicity 
Blood samples for immunogenicity assessment will be performed as per Study Events Flow 
Chart (Section 6).  
13.4.1 Blood Sampling and Processing for Immunogenicity 
Blood samples for immunogenicity assessments (i.e., E-WE thrombin and 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 1 blood 
collection tube of 4.5 mL, containing 3.2% sodium citrate, and processed into three plasma 
aliquots of at least 0.5 mL each.  
For the determination of antibodies to WT thrombin, whole blood samples will be collected 
in a 5 mL blood collection tube, without anticoagulant, and processed to three serum aliquots 
of at least 0.5 mL each.  
Samples will be shipped to the analytical laboratory for analysis at the end of the study.  
Instructions for blood sampling, collection, processing, and sample shipment will be 
provided separately. 
13.4.2 Analytical Method 
Assessment of ADA will be performed by Haemtech Biopharma Services, Inc. (refer to 
Section 3). Development of antibodies to E-WE thrombin or WT thrombin will be monitored 
using a multi-tiered approach that will include screening, confirmatory, and if applicable, 
antibody titer and neutralizing antibody assays. 
13.5 Pharmacodynamic Assessment – APC-PCI 
13.5.1 Blood Sampling and Processing 
For all patients, blood samples for the determination of APC-PCI will be collected in 4 mL 
sodium heparin blood collection tubes at scheduled time points as delineated in the Study 
Events Flow Chart (Section 6) and processed to plasma.  

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The sample times and Hour 0 are in relation to the beginning of E-WE thrombin bolus 
administration.  
The allowable time deviation window for sample collection is as follows: 
Scheduled Post-dose Sampling Time 
Allowed Time Deviation Window 
0.0 - 4 hours 
≤ ± 2 minutes 
> 4 - 24 hours  
≤ ± 10 minutes 
> 24 hours 
≤ ± 30 minutes 
 
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. 
Instructions for blood sampling, collection, processing, and sample shipment will be 
provided separately. 
13.5.2 Analytical Method 
Plasma sample analysis for APC-PCI will be performed by Celerion using a qualified 
enzyme-linked immunosorbent assay method. 
13.6 Pharmacodynamic Assessments – Drug Efficacy and Efficiency of HD 
Pharmacodynamic assessments will include evaluation of the efficacy of E-WE thrombin and 
the efficiency of HD. For all patients, PD assessments will be performed at scheduled time 
points as delineated in the Study Events Flow Chart (Section 6).  
Efficacy of antithrombotic activity will be evaluated by thrombus accumulation: 
• thrombus accumulation will be evaluated by visual inspection of the dialyzer 
membrane at the end of HD procedures and by a gradation using a standardized visual 
assessment scale [11]. The dialyzer cartridge will be rinsed, visually inspected, 
graded, and photographed on 4 sides. The number of dialyzer cartridges used for each 
HD session will be recorded.  
Efficiency of HD will be assessed by using BUN levels: 
• BUN levels before and after dialysis will be used to determine urea removed by 
4 hours of dialysis (Kt/V and URR) after E-WE thrombin active treatment versus 
pre-treatment and placebo. 
13.7 Internal Analyses 
The following analyses may be performed by the Sponsor for internal purposes and results 
will not be included in the study report. 

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13.7.1 Protein C Analysis 
For all patients, blood samples for the determination of protein C will be collected in 2 mL 
blood collection tubes containing 3.2% sodium citrate 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 the time of E-WE thrombin bolus 
administration.  
The allowable time deviation window for sample collection is as follows: 
Scheduled Post-dose Sampling Time 
Allowed Time Deviation Window 
0.0 - 4 hours 
≤ ± 2 minutes 
> 4 - 24 hours  
≤ ± 10 minutes 
> 24 hours 
≤ ± 30 minutes 
Platelet poor plasma samples obtained by centrifugation of citrated blood will be shipped to 
Aronora. 
Instructions for blood sampling, collection, processing, and sample shipment will be 
provided separately. 
13.7.2 Dialysate Analysis 
A 10 mL dialysate sample will be taken as delineated in the Study Events Flow Chart 
(Section 6). 
Instructions for the sample collection, processing, and sample shipment will be provided 
separately. 
The samples will be sent to Aronora and will be stored for up to 5 years following the last 
dosing for future analysis.  
13.7.3 Analysis of Protein Accumulation Within the Dialyzer Cartridge 
Following visual assessment and photography of the HD cartridge at the end of the procedure 
the used and rinsed dialyzer cartridge will be frozen and sent to Aronora for total protein 
accumulation evaluation. 
Instructions for the cartridge collection, processing, photography and cartridge shipment will 
be provided separately. 

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13.8 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 patients 
only) and serum pregnancy (for 
female patients only). 
1 
16  
16 
On-study hematology and serum 
chemistry (this includes serum 
pregnancy for female patients only 
when scheduled at the same time) 
2 
12.5 
25 
On-study coagulation (aPTT, 
PT/INR, fibrinogen, and TT)  
12 
3.5 
42 
On-study platelet count only ** 
Up to 10 
3.5 
Up to 35 
On-study BUN only ** 
Up to 10 
3.5 
Up to 35 
Blood for PD (APC-PCI) (ships to 
Celerion) 
8 
4 
32 
Blood for protein C (ships to 
Aronora) 
16 
2 
32 
Blood for plasma immunogenicity 
(E-WE thrombin plasma ADA) 
(ships to Haemtech Biopharma) 
2 
4.5 
9 
Blood for serum immunogenicity 
(WT thrombin serum ADA) (ships 
to Haemtech Biopharma) 
2 
5 
10 
Total Blood Volume (mL)→ 
Up to 236*** 
* Represents the largest collection tube that may be used for this (a smaller tube may be used). 
** Platelet count and BUN values will be taken from the hematology, serum chemistry samples when these are 
scheduled to be collected at the same time. Samples will not be taken twice at the same timepoint. 
*** If additional safety or PD analysis is necessary to obtain sufficient plasma/serum for analysis, additional 
blood may be obtained (up to a maximum of 50 mL). 
 

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14. STATISTICAL CONSIDERATIONS 
Data will be handled and processed according to Celerion Standard Operating Procedures, 
which are written based on the principles of GCP. 
14.1 Sample Size Determination 
The sample size chosen for this study was selected without statistical considerations. The 
sample size of 36 patients in total (18 per cohort with a ratio of 2:1 of active study 
drug:matching placebo) has been designed to meet the study safety, tolerability, and PD 
objectives.  
14.2 Population for Analyses 
Safety Population: All patients who received the study drug (active or matching placebo) will 
be included in the safety evaluations. 
PD Population: All patients who received the study drug (active or matching placebo) and 
had at least one post-dose measurement of any of the PD assessment will be included in the 
PD evaluations.  
14.3 Statistical Analyses 
Detailed methodology for summary and statistical analyses of the data collected in this study 
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.  
14.3.1 Safety and Tolerability Analyses 
All safety data will be populated in the individual CRFs. All safety data will be listed by 
patients. 
The placebo patients from all cohorts will be pooled into a single placebo group for all 
summaries and presentations. 
Dosing dates and times will be listed by patient. 
Incidence and time of bleeding from the HD access sites on the AV fistula (or AV graft), as 
described in Section 13.2.6, will be counted and recorded. Active treatment versus 
pre-treatment, placebo, and post-treatment results will be compared. 
AEs will be coded using the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA®) available at Celerion and summarized by treatment (2 active dose 
levels and pooled placebo) for the number of patients reporting the treatment emergent 
adverse event (TEAE) and the number of TEAEs reported. A by-patient AE data listing 
including verbatim term, coded term, treatment, severity, and relationship to study drug will 
be provided.  

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Safety data including ECGs, vital signs assessments, clinical laboratory results, and vascular 
access site reaction will be summarized by treatment (2 active dose levels and pooled 
placebo) and point of time of collection. 
Descriptive statistics using appropriate summary statistics will be calculated for quantitative 
safety data as well as for the difference to baseline, when appropriate. In addition, a shift 
table describing out of normal range shifts will be provided for clinical laboratory results.  
Concomitant medications will be listed by patient and treatment (2 active dose levels and 
pooled placebo) and coded using the most current version of the World Health Organization 
drug dictionary available at Celerion. Medical history will be listed by patient. 
14.3.2 Immunogenicity Analyses 
When applicable, antibody titer will be reported and summarized descriptively.  
14.3.3 Pharmacodynamic Analyses 
Placebo patients from Cohort 1 and Cohort 2 will be pooled for analysis. 
Individual, mean, and median data for APC-PCI will be presented graphically for all 
treatments (2 active dose levels and pooled placebo). 
Analysis will include assessments of drug efficacy and efficiency of HD. These will include 
changes in thrombus accumulation and measurement of urea removed by 4 hours of dialysis 
(Kt/V and URR). 
The change from baseline in endpoints will be summarized by treatment (2 active dose levels 
and pooled placebo) and at each scheduled time point using descriptive statistics. The 
baseline values are any value observed from Day -8 to Day 1, prior to E-WE thrombin 
administration. An average of predose values may be used as baseline, as applicable. Any 
values after a single dose of E-WE thrombin are regarded as post-baseline values.   
The change from baseline variables will be calculated as the post-baseline value minus the 
value at baseline. 
Additional analyses may be performed as deemed necessary upon review of the data. 
 
 

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15. STUDY ADMINISTRATION 
15.1 Ethics 
15.1.1 Institutional Review Board 
This protocol will be reviewed by the 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. 
15.1.2 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[R2] 
Consolidated Guidance, November 2016). 
15.1.3 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. 
15.1.4 Confidentiality  
All members of the Investigator’s staff have signed confidentiality agreements. By signing 
this protocol, the Investigator and investigational staff will regard all information provided 
by the Sponsor and all information obtained during the course of the study as confidential.  
The Investigator must guarantee the privacy of the subjects taking part in the study. Subjects 
will be identified throughout documentation and evaluation by a unique subject study 
number. Throughout the study, a subject’s source data will only be linked to the Sponsor’s 
clinical study database or documentation via a unique identification number. If subject name 
appears on any study document, it must be redacted before the copy of the documents is 
supplied to the Sponsor. Any information concerning the subjects (clinical notes, 
identification numbers, etc.) must be kept on file by the Investigator who will ensure that it is 
revealed only to the Sponsor, IRB, or regulatory authorities for the purposes of trial 
monitoring, auditing or official inspections. As required, in the case of an event where 
medical expenses are the responsibility of the Sponsor, personal information, i.e., full name, 
social security details, etc., may be released to the Sponsor. Appropriate precautions will be 
taken to maintain confidentiality of medical records and personal information in strictest 
confidence and in accordance with local data protection laws. 

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15.2 Termination of the Study 
Celerion/CRU reserves the right to terminate the study in the interest of patient welfare. 
The Sponsor reserves the right to suspend or terminate the study at any time. 
15.3 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. 
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 
the statistical database lock. 
15.4 Direct Access to Source Data/Documents 
The PI must maintain, at all times, the primary records (i.e., source documents) of each 
patient’s data. Examples of source documents are laboratory reports, drug inventory, study 
drug label records, and CRFs that are used as the source. 
Celerion/CRU will ensure that the Sponsor, IRB, and inspectors from domestic and foreign 
regulatory authorities will have direct access to all study-related sites, source 
data/documents, and reports for the purpose of monitoring, auditing (ICH[E6(R2)] 5.1.2 & 
6.10) and inspection. In the event that other study-related monitoring should be done by other 
parties, they will be required to sign a confidentiality agreement prior to any monitoring and 
auditing. 
15.5 Drug Supplies, Packaging and Labeling 
The Sponsor will supply sufficient quantities of E-WE thrombin and matching 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 CRU and must be stored in 
a pharmacy or locked and secured in a storage facility with controlled temperature. The 
temperature and 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 (E-WE thrombin and 
matching placebo) supplied. At the conclusion of the study, any unused study drugs 

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(including placebo) as well as original containers (even if empty), will be retained by the 
CRU, 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. 
15.6 Data Handling and Record Keeping 
Celerion standard CRFs will be supplied. CRFs are produced, stored electronically, and are 
available to the designated study team members. Each CRF is reviewed and signed by the PI. 
The final signed CRFs are provided to the Sponsor on CD. 
All raw data generated in connection with this study, together with the original copy of the 
final report, will be retained by the CRU 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. 
15.7 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). 
15.8 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. 
15.9 Publication Policy 
All unpublished information given to Celerion or the CRU 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. 
 
 

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16. REFERENCES 
1. Aronora, Inc.: E-WE thrombin, AB002. Investigator’s Brochure. Version Number 2; 25 
February 2019. 
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. Lutz J., Jurk K., and Schinzel H. Direct oral anticoagulants in patients with chronic 
kidney disease: patient selection and special considerations. Int J Nephrol Renovasc Dis. 
2018;10:135-143. doi: 10.2147/ijnrd.s105771 
6. Schwab S.J., Onorato J.J., Sharar L.R., et al. Hemodialysis without anticoagulation. One-
year prospective Trial in Hospitalized Patients at Risk for Bleeding. Am J Med. 
1987;83:405-410.  
7. Stamatiadis D.N., Helioti H., Mansour M., et al. Hemodialysis for patients bleeding or at 
risk for bleeding, can be simple, safe and efficient Clin Nephrol. 2004;62(1):29-34. 
8. Caruana R. J., Raja M.R., and Bush J.V., et al. Heparin free dialysis: comparative data 
and results in high risk patients. Kidney Int. 1987;31:1351-1355. 
9. Cronin R.E., and Reilly R.F. Unfractionated heparin for hemodialysis: still the best 
option. Semin Dial 2010;23(5):510-515. Doi: 10.1111/j.1525-139X.2010.00770.x. 
10. Shen J.I., Mitani A.A., Chang T.I., et al. Use and safety of heparin-free maintenance 
hemodialysis in the USA. Nephrol Dial Transplant. 2013 Jun;28(6):1589-602. doi: 
10.1093/ndt/gft067. 
11. 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 
12. 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 
13. Ronco C., Brendolan A., Nalesso F., et al. Prospective, randomized, multicenter, 
controlled trial (TRIATHRON 1) on a new antithrombogenic hydrophilic dialysis 
membrane. Int J Artif Organs 2017;40(5):234-9