Conditions: End Stage Renal Disease Thrombosis
Keywords: Hemodialysis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

Brief summary:
This study evaluates the safety and efficacy of AB002 (E-WE thrombin) in patients with end stage renal disease on chronic hemodialysis. Two dose levels will be evaluated in two cohorts. Within each cohort the patients will be randomized to receive either AB002 (E-WE thrombin) or placebo (at a ratio of 2:1 active: placebo).

Detailed description:

Arms:
arm 1: Participants will receive a single dose of 1.5 mcg/kg E-WE thrombin. arm 2: Participants will receive a single dose of 3.0 mcg/kg E-WE thrombin. arm 3: Participants will receive a single dose of placebo

Interventions: intervention 1: AB002 Dose 1 intervention 2: AB002 Dose 2 intervention 3: placebo
Intervention descriptions: intervention 1: AB002 (E-WE thrombin) 1.5 mcg/kg administered on Day 1 as a single intravenous infusion intervention 2: AB002 (E-WE thrombin) 3.0 mcg/kg administered on Day 1 as a single intravenous infusion intervention 3: placebo administered on Day 1 as a single intravenous infusion

Protocol document:
ICF_002.pdf: 
APPROVED BY 
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MARCH 21, 2019 
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INFORMED CONSENT DOCUMENT 
AGREEMENT TO BE IN A RESEARCH STUDY 
 
NAME OF SPONSOR COMPANY: 
Aronora, Inc. 
 
PROTOCOL NUMBER AND TITLE OF STUDY: 
EWE-19-02: “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” 
 
NAME OF PERSON IN CHARGE OF THE  
RESEARCH STUDY (STUDY DOCTOR/ 
INVESTIGATOR): 
 
 
 
 
Thomas C. Marbury, M.D. 
 
TELEPHONE NUMBER(S), DAYTIME 
AND AFTER HOURS: 
(407) 240-7878
 
INTRODUCTION 
 
You are being asked to participate in the above-named research study. Before agreeing to participate in this 
research study, it is important that you read and understand this informed consent document and ask any 
questions that you may have.  
 
• 
This is a research study and your participation is voluntary.   
• 
The purpose of this study is to evaluate the safety and tolerability of a single dose of E-WE thrombin 
infused into the dialysis line during a 4-hour hemodialysis procedure. 
• 
The study should take about 7 weeks. 
• 
The study drug is “investigational”.  This means that it has not been approved by the United States Food 
and Drug Administration (FDA) for general use in the United States.  
• 
The main risks you should be aware of are headaches.  The complete list of risks / discomforts is listed 
later in this informed consent.   
• 
You will not receive any direct benefit from participating in this study. This study may help physicians 
and scientists learn things about the study drug that will help others.  
• 
This study is for research purposes only and is not intended to treat any medical condition. Your 
alternative is to not take part in the study. 
 
Please take the time to read the following information carefully and discuss it with others.  If this form contains 
any words that you do not understand, please ask the site medical team or staff to explain them to you. 
 
If you have decided that you want to take part, you will be asked to sign the informed consent form. You 
will get a copy of the signed form. Your decision to take part in this study is voluntary. That means you are 
free to decide to join this study or not join this study, and refusal to join will not affect your medical care. You 
are also free to stop study drug dosing and study-related activities at any time and without any reason.  
 
The pharmaceutical company sponsoring this study is Aronora, Inc. Orlando Clinical Research Center is being 
paid by Aronora, Inc. to conduct this study. 
 
You must be honest with the study doctor about your health history or it may not be safe for you to be in this 


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study. 
 
In this document, you may see the terms “medication” and “treatment”; these are terms used in research 
studies as mentioned above, this does not mean that you will be receiving medical treatment for any 
condition. These terms apply to the investigational study drug and parts of the study where you will be 
receiving this investigational product. 
 
PURPOSE OF THE STUDY 
 
Aronora, Inc. is sponsoring this study of an investigational drug called E-WE thrombin. The National Heart, 
Lung, and Blood Institute (NHLBI), part of the National Institutes of Health (NIH), is partially funding the 
study.  Investigational means that the drug being tested is not approved by the United States Food and Drug 
Administration (FDA) for general use in the United States, but may be tested in research studies such as 
this one.   
 
E-WE thrombin is being developed for the prevention and treatment of thrombotic and thromboembolic 
(i.e. blood clotting) diseases, such as arterial thrombosis and thromboembolism.  
 
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the 
circulatory system. 
 
The purpose of this study is to evaluate the safety and tolerability of a single dose of E-WE thrombin infused 
into the dialysis line during a 4-hour hemodialysis procedure in subjects with end-stage renal disease 
(ESRD). 
 
Up to 36 men and women, ages 18 to 80 will be enrolled in the study at 1 center in the United States.  
 
The study will last about 7 weeks and will involve a screening period, an 11 day/10 night stay at the study 
site and 1 follow up visit. 
 
STUDY DRUG DOSING 
 
This is a randomized, double-blind, placebo-controlled study. Randomized means the study treatment you 
take will be chosen by chance (like flipping a coin).  
 
Double-blind means that you and your study doctor will not know what study drug you are taking.  
The placebo is a substance that looks like a drug, but has no drug in it.  
 
Be aware that sometimes this form refers to both E-WE thrombin and placebo as “study drug”. 
 
You and the study doctor will not choose which group you will participate in; however, this information 
can be obtained if needed in an emergency. The study drug you receive will be assigned by chance, like the 
flip of a coin. 
 
If you agree to join this study and qualify, you will be assigned to 1 of 2 dosing groups as follow: 
 
• 
Group 1: 0.5 mcg/kg bolus dose administered into the dialysis line immediately followed by a 0.25 
mcg/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 mcg/kg. 
• 
Group 2: 1 mcg/kg bolus dose administered into the dialysis line immediately followed by a 0.5 


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mcg/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 mcg/kg. 
 
The amount of study drug/placebo you receive will depend on how much you weigh. There are 2 different 
doses: 1.5 and 3 micrograms of study drug for each kilogram of weight. A kilogram equals about 2.2 lbs.  
So, for example, if you weighed 70 kilograms (154 pounds), and you received (1.5 mcg/kg), your dose 
would be 1.5 times 70, which means you would receive 105 micrograms of study drug/placebo. 
 
The study drug /placebo will be given to you as a single infusion dose (over 4 hours) on Day 1. The study 
drug/placebo will be infused into the dialysis line immediately at the start of a hemodialysis treatment. 
 
SCREENING VISIT 
 
Before any study procedures being performed, you will be asked to sign this informed consent. Before the 
study starts, you will be asked to do some procedures to find out if you qualify to be in the study. This 
process is called “Screening.” 
 
• 
You will be asked about your health, how you are feeling, your use of alcohol and tobacco products as 
well as your medical history. 
• 
Your demographics will be collected (such as age, sex, race, ethnicity, date of birth). 
• 
A full physical exam will be done.  
• 
Your height, weight, body temperature, breathing rate and blood pressure and heart rate will be 
measured. 
• 
You will be asked about any medications. (over the counter, prescription, herbal supplements or 
vitamins)  
• 
You will have an electrocardiogram (ECG) to measure the electrical activity of your heart. You may 
be asked to remove your blouse or shirt for the ECG.  
• 
Blood and urine will be collected for laboratory testing. (must be fasting for a minimum of 4 hours 
before clinical lab tests) 
• 
You will have a test for alcohol and drugs of abuse.  
• 
You will have a blood test for hepatitis B and C (an infection of the liver) and HIV. State law requires 
that positive test results for hepatitis/HIV be reported to a local health agency. You will be asked to 
sign a separate HIV consent. 
o The results of these tests are expected to stay confidential. There is a chance that a breach in 
confidentiality could happen; this means that people that were not originally supposed to have this 
information could see these results. For example, it is possible for a court of law to get health or 
study records without your permission.  Please speak to the study staff or your personal doctor, if 
you want to know more about what it could mean to you if somebody outside of this research study 
has access to this information. 
• 
If you are female, you will have a pregnancy test. Females who might be postmenopausal will have a 
blood test done to confirm that they are post-menopausal. If you are a female of childbearing potential 
(capable of becoming pregnant), you will not be eligible to participate in this study. 
 
After all screening tests have been done, if you are determined to be eligible to continue in the study, you 
will return to the clinic to check-in and start the evaluation period (7 days before dosing). 
 
 
 


Protocol number: EWE-19-02 
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STUDY PROCEDURES 
 
Please note the exact schedule for the procedures described in this consent form are subject to change.  
Some procedures may not be performed, and some may be added or moved to other study days.   
 
DAY -8 (Check-In) / EVALUATION PERIOD (DAY -8 THROUGH DAY -1) 
 
You will come to the research clinic to begin the evaluation/confinement period. During the evaluation 
period (Day -8 through Day -1) you will have hemodialysis treatment according to your dialysis schedule.  
       
Day -8: 
The following procedures will be done: 
 
• 
Your medical and medication history will be reviewed and updated if needed. Tell the staff about any 
prescription drugs, over-the counter medicines, herbal and vitamin supplements you are taking. This is 
very important. 
• 
A physical exam will be done. 
• 
Your weight will be measured. 
• 
Your vital signs including blood pressure, heart rate, temperature and breathing rate will be measured.  
• 
Electrocardiograms (ECG) will be done. 
• 
Blood and urine will be collected for laboratory testing.  
• 
You will have a test for drugs of abuse and alcohol. 
• 
If you are female, you will have a pregnancy test.  
 
Day -7, Day -5, Day -2/ Hemodialysis day: 
The following procedures will be done: 
 
• 
Your weight will be measured. 
• 
Blood samples will be collected before and after hemodialysis for laboratory testing. 
• 
Your vital signs including blood pressure, heart rate, temperature and breathing rate will be measured.  
• 
You will be asked about any medications you might have taken or negative side effects that you might 
have experienced. 
• 
Dialysate samples will be collected. Fluid which passes through the dialyzer will be collected. Dialysate 
sample will be taken for future analysis (e.g., assessment of urea or drug in the dialysate). Samples will 
be stored for up to 5 years. 
• 
Fistula or graft for dialysis access will be assessed for bleeding and any abnormality (bleeding and 
visual assessment). 
 
Day -6, Day -4, Day -3, and Day -1: 
The following procedures will be done: 
 
• 
You will be asked about any medications you might have taken or negative side effects that you might 
have experienced. 
• 
Your weight will be measured. 
 
By the end of the evaluation period the study doctor will determine if you are eligible to continue into the 
study. If you will not be able to continue in the study, the study doctor will explain why. 
 


Protocol number: EWE-19-02 
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The sponsor and study doctor reserve the right to make the final decision on subject selection for 
participation into the study. This may occur as late as just before dosing. Each subject will need to meet 
study requirements again at check-in. 
 
DAY 1 (DOSING DAY) / HEMODIALYSIS DAY   
 
While you are in the clinic, you will have the following tests done: 
 
• 
You will be asked about any medications you might have taken or negative side effects that you might 
have experienced. 
• 
Your vital signs, including body temperature, blood pressure, heart rate and breathing rate will be 
measured multiple times before and after receiving the study drug/ placebo. 
• 
ECG will be done. 
• 
Your weight will be measured. 
• 
Blood and urine samples will be collected for laboratory testing before and after hemodialysis. 
• 
A physical exam will be done.  
• 
After an overnight fast of at least 4 hours, the study staff will give you the study drug. Refer to section 
“STUDY DRUG DOSING”. 
• 
Blood will be collected to find out the amount of study drug /placebo in your body. A sample will be 
obtained before you receive the study drug, then at up to 8 times after receiving the study drug. 
• 
A blood sample will be collected for immunogenicity analysis (to find out your immune response). 
• 
Dialysate samples will be collected. 
• 
Bleeding and visual assessments will be completed. 
 
DAY 2  
 
The following procedures will be done: 
 
• 
You will be asked about any medications you might have taken or negative side effects that you might 
have experienced. 
• 
Blood samples will be collected to find out the amount of study drug/placebo is present in your body. 
• 
Blood sample will be collected for laboratory testing. 
• 
Your weight will be measured. 
 
DAY 3 / HEMODIALYSIS DAY AND DISCHARGE  
 
The following procedures will be completed on Day 3 or early termination: 
 
• 
You will be asked about any medications you might have taken or negative side effects that you might 
have experienced 
• 
Your weight will be measured. 
• 
Your vital signs, including body temperature, blood pressure, heart rate and breathing rate will be 
measured. 
• 
ECG will be done. 
• 
A physical exam will be done. 
• 
Blood and urine samples will be collected for laboratory testing. 
• 
Dialysate samples will be collected. 
• 
Bleeding and visual assessments will be completed. 
 


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You will be discharged from the clinic after all the Day 3 procedures have been completed. You will be 
required to return to the clinic for a follow up visit on Day 14.   
 
During the study, you will be monitored closely for possible side effects. You will be asked about any 
symptoms or illnesses that you may experience. Additional physical exams may be performed at the 
discretion of the study doctor. You should report any changes in your physical or mental condition, or any 
side effects that you may have during the study. In addition, you will be asked to inform the investigator 
and/or study staff of any medications, procedures or therapies you are taking while you are participating in 
this study. 
 
Your participation in the study will be completed when all the study procedures and the review of the 
medical and safety evaluations have been done. You may require longer observation in the clinic or 
additional laboratory testing based on the effects of the medication or the results of the laboratory tests 
 
FOLLOW UP VISIT PROCEDURES  
 
You will be required to return to the clinic on Day 14 for a follow up visit. Anyone who receives study 
drug/ placebo will be asked to return for this visit. 
 
• 
A blood sample will be collected for coagulation tests and immunogenicity analysis. 
• 
You will be asked how you are feeling and about whether you have taken any medications since your 
last visit. 
 
BLOOD SAMPLE COLLECTION 
 
Blood samples may be drawn from an intravenous catheter (a tube that is left in your arm).  The catheter 
will be inspected, maintained and may be changed, if necessary.  If the use of the catheter is not possible, 
the blood samples will be taken by individual needle-sticks from a vein in your arm.  
 
The total amount of blood drawn is approximately 236 mL (a little less than one cup). For comparison, the 
standard blood donation is about 480 mL (about half liter, or two U.S. cups).  
 
This total volume does not include discarded blood from pre-draws used to remove fluid from flushed 
catheters which is approximately 1 mL per blood draw. Additional blood samples may be drawn during the 
study if the study doctor considers it necessary for monitoring your health. It is possible that more than one 
attempt to obtain a blood sample may be necessary. 
 
SUBJECT RESPONSIBILITIES 
 
As a participant in this study, you have certain responsibilities to help ensure your safety. These 
responsibilities are listed below: 
 
• 
Provide truthful information about your health history. 
• 
Complete all required visits.  
• 
Participate in all study-related procedures as required by the study.  
• 
Follow the restrictions listed in the section below. 
• 
Use contraception as described later in this document. 
 
 


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• 
Report all changes in your health, side effects, and medical problems immediately to the site medical 
team, even if you do not think they are related to the study. 
• 
Inform the site medical team or staff if you decide to discontinue your participation. If you decide to 
drop out of the study after receiving any study medication, you will be required to complete at least one 
follow-up visit. 
 
RESTRICTIONS 
 
For your own safety, it is important that you follow without exception the Clinical Research Center In-
House Guidelines. Violations of these In-House Guidelines may make it necessary to remove you from the 
study. If you are taken out of this study because you are unable to follow the In-House Guidelines, you may 
not be asked to take part in other studies done at this research clinic.   
 
During your stay in the Research Center, you must follow the study rules about tobacco, alcohol, or any 
unauthorized drugs. 
 
• 
Smoking is not permitted at any time in the building. Subjects are prohibited from smoking during 
study confinement. 
• 
Food and beverages will be provided during your stay at the research center except when fasting is 
required. You will be served standard meals and snacks according to a uniform daily diet and according 
to the study procedures. You may not bring your own food or beverages.  
• 
You must not take certain medicines before and during the study. The study staff will discuss this with 
you. Please tell the study staff about all of the medications, drugs, and supplements you are taking.  
This includes any bought with a prescription or over-the-counter. If you have any questions about any 
medication, please ask the study staff before taking it. 
• 
You must not have received a study drug or participated in another clinical trial within 30 days prior 
Day – 8 admission. 
• 
Beverages or foods containing caffeine and/ or, xanthine (coffee, tea, cola, chocolate, etc.) are not 
allowed 48 hours before receiving the study drug and throughout the period of sample collection. 
• 
You must not consume any alcohol (beer, wine, liquor) starting 48 hours before receiving the study 
drug and throughout the period of sample collection. 
• 
You must not engage in strenuous exercise 72 before receiving the study drug and while participating 
in this study.  
 
It is very important that you follow all the rules, restrictions, and instructions given by the staff. If you do 
not follow the restrictions or follow the guidance of the study staff, there can be a risk to your health and/or 
false study results.   
 
VOLUNTEERING TO BE IN THE STUDY AND WITHDRAWAL OF YOUR CONSENT TO 
PARTICIPATE IN THIS STUDY 
 
The study doctor, the sponsor company, IntegReview IRB, or the FDA may take you out of the study 
without your permission, at any time, for the following reasons: 
 
• 
If you do not follow the study doctor’s instructions  
• 
If we find out you should not be in the study 
• 
If the research study is stopped 
• 
If participation in the research study becomes harmful to your health 
 


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It is your choice if you want to be in the research study. No one can force you to be in the research study. 
You may decide to stop your study participation which may include stopping any further assessments or 
contact by the study staff. This is considered a withdrawal of your consent from participation in this study.  
 
It is important that you inform your study doctor of your decision to withdraw your consent by providing 
written notice to the study doctor. If you leave the study, no more information about you will be collected 
for this study. However, the sponsor will continue to retain and use all research results and any biological 
samples that have already been collected for the study evaluation (as per local regulations). 
 
You can discuss further regular medical care with the study doctor. The choice to withdraw from research 
study will not affect your medical care. 
 
If you drop out or are removed from the research study after having taken the study drug, you may be asked 
to come back to the clinic for a follow-up visit. At this visit you will have discharge procedures performed 
and blood tests to ensure that there are no changes to your current health status. You will be asked about 
any changes in your health or in the medications you are taking. 
 
POSSIBLE RISKS AND SIDE EFFECTS 
 
If you do not understand what any of these side effects mean, please ask the study doctor or study staff to 
explain these terms to you.  
 
The most common side effect in a 21 normal healthy volunteer study included headache.  
 
Because the study drug is investigational, there may be side effects that we do not yet know about.  There 
may be rare and unknown side effects. Some of these may be life threatening.  
 
The study drug (E-WE thrombin) is being developed to treat or prevent blood clots and, therefore, taking 
the study drug may increase your risk for bleeding or bruising. While the study drug has been developed 
specifically with the intent to reduce blood clotting inside blood vessels without increasing the risk of 
bleeding, risks of side effects in humans cannot be established without testing the effects of the study drug 
in human subjects.  
 
The study drug is a therapeutic enzyme, produced using recombinant (DNA molecules formed by laboratory 
methods) DNA technology in a cell culture, and there are risks associated with taking this type of biological 
study drug which include allergic reactions to the active and inactive ingredients, such as rash, swelling, 
hives, difficulty breathing, blood pressure changes, among others. Although unlikely, a severe and life-
threatening allergic reaction may be possible. 
 
Throughout the duration of the study, you will not receive heparin during your hemodialysis sessions. This 
may put you at a higher risk of developing clotting within the dialyzer cartridge during hemodialysis 
sessions. Because the study drug (E-WE thrombin) is being developed to treat or prevent blood clots, you 
may be less likely to develop blood clots during hemodialysis after receiving the study drug. However, if 
you are randomly selected to receive placebo you will undergo five consecutive hemodialysis sessions 
without heparin anticoagulation, which may increase the risk of developing clots within the dialyzer during 
hemodialysis.  
 
 
 


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You must tell the study doctor or study staff about all side effects that you have. If you are not honest about 
your side effects, you may harm yourself by staying in this study.  
 
Until you know how the drug(s) will affect you, you should use caution by avoiding stairs, not driving a 
car or working with machinery. 
 
ADDITIONAL RISKS OR DISCOMFORTS 
 
Blood Draws: 
 
The risks of taking blood may include fainting, pain, nerve damage, redness, bleeding and/or bruising. 
Rarely, there may be a small blood clot or infection at the site of the needle puncture. If you feel faint tell 
the study staff right away. 
 
Two indwelling, intravenous catheters may be inserted in one arm to collect blood samples. An indwelling 
catheter is a special needle device designed to be placed in a vein, and then to remain in the vein for a period 
of time. This could cause: infection, pain, redness, bruising, local swelling due to IV fluid (saline/ heparin 
flush that will be used to keep the indwelling catheter open) accidentally entering the tissue rather than the 
vein, blood clots, which may cause inflammation, swelling and pain. It is possible that the catheter will stop 
working and may have to be replaced in a different vein. 
 
Blood Pressure: 
 
The blood pressure cuff may also cause discomfort or bruising to the upper arm.  
 
Electrocardiogram (ECG): 
 
The ECG test is a recording of the electrical activity of your heart. The sticky pads used may be cold when 
applied and sometimes cause some discomfort such as redness or itching. If the hair under the patches needs 
to be shaved, irritation from shaving also could occur. You may experience some skin irritation from the 
electrode adhesive or develop contact dermatitis (a skin condition caused by contact between skin and some 
substance) which may appear as lighter as or darker than the surrounding skin for possibly an extended 
period of time. 
 
Digital Photos 
 
In the event of any physical abnormal finding, digital photos will be taken of the areas. The photos will be 
taken in a manner so that there is no way you could be identified in the pictures.   
  
Your image may be sent electronically to the sponsor. The photographs or electronic images will be labeled 
with your study number and not your name. People working for the Sponsor, the FDA, and IRB will have 
access to your photographs if they have a valid reason for seeing them. Valid reasons include but are not 
limited to, monitoring or auditing the study, to assess the skin condition or to determine the cause of the 
skin condition. When the study is over, your photograph or electronic image will be stored with the study 
files indefinitely. Your picture will not be used for teaching purposes and will not be published in any 
medical journal. You may be asked to have additional tests to assess the condition. The Study Doctor will 
discuss this with you before any other tests are done. You are giving the site permission to take photos of 
the area indicated by signing this consent form. 
 


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BIRTH CONTROL, DANGERS OF PREGNANCY AND BREASTFEEDING 
 
The effects of the study drug on an unborn child are not known Only females who are not able to get 
pregnant are allowed to be enrolled in this research study.  
 
Females who are not able to get pregnant are defined as being permanently sterile (due to hysterectomy 
[removal of uterus], bilateral salpingectomy [removal of both ovaries and fallopian tubes], bilateral 
oophorectomy [removal of ovaries], or confirmed tubal occlusion more than 6 months prior to first dose of 
study drug) or postmenopausal (defined as at least 12 months without a period without an alternative 
medical cause). If you think that you have become pregnant during the study, it is important that you inform 
the study doctor immediately.  
 
Male subjects 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 (such 
as one of the methods identified above for female subjects) from the time of Screening until 90 days after 
study drug administration. Male subjects must agree not to donate sperm for a period of 90 days after the 
last dose of the study drug. 
 
Even if you use birth control during the study, there is a chance your partner could become pregnant. A 
pregnancy test is not always right, especially in the early stages of pregnancy. If your partner becomes 
pregnant, you must inform the study doctor immediately. The study doctor may request to track the 
pregnancy and report the outcome to the Sponsor. 
 
Unknown Risks 
 
There may be additional risks that are currently unknown and unanticipated related to taking the study drug.  
There may be rare and unknown side effects. Some of these may be life threatening. 
 
You might have side effects or discomforts that are not listed in this form. Some side effects may not be 
known yet. New ones could happen to you. If new risks associated with the dosing of study drug are 
identified during the study, you will be told about them. 
 
SAFEGUARDS 
 
You must tell the study doctor about all of your past and present experiences with pain relievers, diseases, 
addictions, drinking habits, and allergies of which you are aware, and all drugs and medications which you 
are presently taking including vitamins and any herbal supplements. 
 
CONFIDENTIALITY 
 
Information about you and your participation in the study will be kept confidential according to applicable 
privacy laws and any policies of your study doctor and the sponsor. Your original study records may contain 
your name, address, health information and other personal data (“Personally Identifiable Information”). 
These study records will be kept by your study doctor as required by applicable law and the sponsor. These 
records may be held forever. 
 
 
 


Protocol number: EWE-19-02 
Thomas C. Marbury, M.D. 
Informed Consent 
 
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USE OF YOUR STUDY RECORDS 
 
The study results may be looked at to make sure the study is being done correctly. The sponsor may work 
with other companies and government agencies for reasons related to the study. In order for this to take 
place, these companies and government agencies will have access to the original records or the data 
contained in the records and may copy some of the information, which may contain your Personally 
Identifiable Information. These companies and government agencies include: 
 
• 
Regulatory authorities including in other countries, such as the FDA  
• 
Other government agencies  
• 
IntegReview IRB 
• 
Contracted Monitors/Auditors and other individuals or companies used by the sponsor to help with the 
study 
• 
Affiliated companies of the sponsor 
 
After the study doctor shares your records with the sponsor and others, the laws may no longer protect the 
privacy of your records. If all information that does or can identify you is removed from your records, the 
remaining information may be used or shared for other purposes. 
 
Your results will be coded with numbers and initials. Companies and government agencies (for example 
the FDA and IntegReview, the IRB for this research study) will not know your name unless it is necessary 
for purposes relevant to a study. The results of a study may be shown in publications or at meetings. You 
will not be identified by name. Under certain circumstances, some test results will be reported to health 
authorities as required by law. Note that once your test results or samples leave the US, they are not 
protected by the same laws in other countries. 
 
The sponsor and its affiliated companies may use and disclose your records and health information collected 
for this study to conduct additional clinical or data research studies or to develop proposals for new studies.  
The sponsor also may use the information about you in the study to improve the design and efficiency of 
future research studies.  
 
The Institutional Review Board (IRB), IntegReview, and accrediting agencies may inspect and copy your 
records, which may have your name on them. Therefore, total confidentiality cannot be guaranteed. If the 
study results are presented at meetings or printed in publications, your name will not be used. 
 
If a medical emergency happens, your study results may be given to emergency medical staff. If you decide 
to stop being in a study, the information already gathered will still be kept in the study database. 
 
A description of this clinical trial will be available on http://www.clinicaltrials.gov  as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time.  
 
NEW INFORMATION 
 
You will be informed, in writing, of any new or important findings that are learned during this study that 
might influence your choice to start or remain in the study. You may be asked to sign an updated consent 
form. 
 
 
 


Protocol number: EWE-19-02 
Thomas C. Marbury, M.D. 
Informed Consent 
 
Page 12 of 18 
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MARCH 21, 2019 
 
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ADDITIONAL COSTS  
 
There will be no cost to you for participating in this research study. 
 
PAYMENT FOR PARTICIPATION IN THIS STUDY  
 
You will be paid up to $ 2,700.00 for being in this study, depending on which group you are in. This is to 
help compensate you for your time and travel. If your research study participation is ended because of a 
positive drug screen, you will not get any compensation. 
 
If after being enrolled in the research study, your participation in the study is ended for any other reason 
besides a positive drug screen, you will receive compensation based on the visits and/or days that you have 
completed. You will not receive payment for partially completed days/visits. Payment is outlined below. 
  
Completion of Screening:    $  50.00 
Completion of Day -8:         $ 125.00 
Completion of Day -7 :        $ 250.00 
Completion of Day -6 :        $ 250.00 
Completion of Day -5 :        $ 250.00 
Completion of Day -4 :        $ 250.00 
Completion of Day -3 :        $ 250.00 
Completion of Day -2 :        $ 250.00 
Completion of Day -1 :        $ 250.00  
 
Completion of Day 1:           $ 250.00 
Completion of Day 2:           $ 250.00 
Completion of Day 3:           $ 150.00 
 
Completion of Follow-up:    $  125.00 
 
                                 Total: $ 2,700.00 
 
Schedule of payments: 
 
• 
1st payment of $ 2,575.00 within 7days of Day 3 completion 
• 
2nd payment of $ 125.00 within 7 days of Follow-up completion 
 
If you choose to leave or are withdrawn from the study for any reason, you will receive payment within 7 
days of your last study visit.  
 
If you are requested to complete any unscheduled visits due to a side effect or safety follow up, you will 
receive $50.00 each additional visit for your time and travel.   
 
In addition, you will be asked to read and sign a document entitled “Site Guidelines” which outlines 
penalties for certain violations of the rules for when you are staying at the clinic.   
 
In agreeing to take part in this study, you will be acting as an independent contractor, not as an employee 
of Orlando Clinical Research Center. Payments made to you for taking part in this study will be reported 
to the IRS as income, as required by law. No taxes are deducted from your check. You are responsible for 
reporting this compensation on state and federal tax returns and for the payment of any taxes that are due 
on this compensation. You will be required to provide your Social Security number or tax identification 
number to Orlando Clinical Research Center. If you get more than $600.00 in one calendar year from 
Orlando Clinical Research Center, you will get a 1099 tax form the following January. 
 
 
 


Protocol number: EWE-19-02 
Thomas C. Marbury, M.D. 
Informed Consent 
 
Page 13 of 18 
APPROVED BY 
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MARCH 21, 2019 
 
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IN CASE OF STUDY RELATED INJURY 
 
It is important that you follow carefully all the instructions given by the study doctor and his/her staff 
regarding this study. 
 
If you become ill or are physically injured as a result of participation in this study, please contact the study 
doctor right away and you will be treated or referred for treatment. 
 
The sponsor Aronora, Inc., will pay the costs of this treatment to the extent that such treatment is not paid 
by your medical insurance or by third party or governmental programs. For this to happen, the injury, in 
the opinion of the study doctor and the sponsor must be confirmed to have been a direct result of your 
participation in this study in accordance with the study directions. No other financial compensation will be 
offered by the sponsor.  No long-term medical care or financial compensation for research-related injuries 
will be offered by the NIH or the Federal Government. If you would like further information about 
compensation for research-related injuries, please ask the study doctor.  
 
Please be aware that some insurance plans may not pay for research-related injuries. You should contact 
your insurance company for more information. 
 
LEGAL RIGHTS 
 
You will not lose any of your legal rights to which you are otherwise entitled by signing this consent form. 
 
CONTACT INFORMATION 
 
If you have any questions, concerns, or complaints during this study, or if you think you may have 
experienced a research-related injury, you should contact the study doctor or study staff: 
 
Thomas C. Marbury, M.D. 
(407) 240-7878, 24-hours a day 
 
If you are unable to reach anyone at the number(s) listed above and you require immediate (life 
threatening) medical attention, please go to the nearest emergency room. 
 
If you do not want to talk to the study doctor or study staff, if you have concerns or complaints about the 
research, or to ask questions about your rights as a study subject you may contact IntegReview. IntegReview’s 
policy indicates that all concerns/complaints are to be submitted in writing for review at a convened IRB 
meeting to: 
 
Mailing Address:            OR            Email Address: 
Chairperson 
IntegReview IRB 
3815 S. Capital Of Texas Highway 
Suite 320 
Austin, Texas 78704 
integreview@integreview.com 
 
 
 


Protocol number: EWE-19-02 
Thomas C. Marbury, M.D. 
Informed Consent 
 
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APPROVED BY 
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MARCH 21, 2019 
 
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If you are unable to provide your concerns/complaints in writing or if this is an emergency situation 
regarding subject safety, contact our office at: 
 
512-326-3001 or 
toll free at 1-877-562-1589 
between 8 a.m. and 5 p.m. Central Time 
 
IntegReview has approved the information in this consent form and has given approval for the study doctor 
to do the study. This does not mean IntegReview has approved your being in the study. You must consider 
the information in this consent form for yourself and decide if you want to be in this study. 
 
CONFIDENTIALITY AND AUTHORIZATION TO COLLECT, USE AND DISCLOSE 
PERSONAL MEDICAL INFORMATION  
 
A federal regulation called the “Health Insurance Portability and Accountability Act” (HIPAA) describes 
how protected health information (PHI) may be used, disclosed (shared), and made accessible to you. This 
privacy rule is designed to protect the confidentiality of PHI. Please read this form carefully as it describes 
your rights regarding the use or disclosure of your PHI under this authorization.  
 
You are being asked to allow the use of your PHI because this study may be performed only by collecting 
and using this information. Your study records will be kept confidential as described in this form. Unless 
required by law, your name will not be disclosed outside the research clinic. Your name will be available 
only to the following people or agencies: the study doctor and staff; and authorized representatives of the 
study doctor; the sponsor and its affiliates and people or companies working for or with the sponsor, ethics 
committees (IRB), health authority inspectors, such as the US Food & Drug Administration; NIHLB and 
their contractors, study monitors and auditors; Emergency medical personnel and Authorized Clinical 
Research Organization representatives. The above mentioned individuals will use the personal information 
collected as part of this study, including your medical records (“Study Information”) to check that the study 
is conducted correctly and to ensure the accuracy of the Study Information. These people are all obligated 
to maintain confidentiality by the nature of their work, or are bound by confidentiality agreements. If 
required, the Study Doctor may contact your personal physician to collect additional medical information 
and your past medical history. 
 
The sponsor and the groups above will use your health information: 
 
• 
To complete this research 
• 
To evaluate the results of the study 
• 
To check that the study is being done properly 
• 
To obtain marketing approval for new products resulting from this research 
• 
The sponsor and its affiliated companies may also use and disclose your de-identified records and health 
information collected for this study to conduct additional clinical or data research studies or to develop 
proposals for new studies or to improve the design and efficiency of future research studies.  
 
The study doctor may only share your Study Information with people whom you have permitted to see it. 
However, once your Study Information is shared as authorized, it may no longer be protected by Federal or 
state law and may be re-disclosed without your permission.  
 
While participating in this study, the study doctor will replace your name with a special code that identifies 
you. This code, along with your study information, will be used by the study sponsor, and their 


Protocol number: EWE-19-02 
Thomas C. Marbury, M.D. 
Informed Consent 
 
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representatives (the “Sponsor”), for the study purposes mentioned above and to help establish whether the 
study drug is safe and effective. The sponsor may share your coded information, as necessary, with other 
members of the Sponsor’s worldwide group of related companies, people and companies who work with 
the sponsor and who work within the scope of this consent ethics committees and regulatory agencies such 
as the US Food & Drug Administration, the national health authorities. 
 
In addition, if you withdraw from this study, you have the right to request of your study doctor that your 
blood samples be destroyed. If you request that your samples be destroyed, all data generated up to the time 
of the request will be used for the study, but no other additional data will be generated from your samples. 
The Sponsor is responsible for the destruction of remaining samples at the end of the storage period. 
 
The people, companies, and agencies listed above that have access to your information may be located in 
countries of the European Economic Area (EEA); the United States; and other countries around the world. 
You should be aware that some countries may not offer the same level of privacy protection as you are used 
to in the country where you live or where this study is conducted. However, the sponsor will keep any 
information it receives to the same standard of confidentiality as far as permitted by applicable local law.  
 
The study information will be kept confidential within the limits of the law and used only for this study as 
well as combined with other studies as applicable, for pooled analysis and interpretation needed for any 
regulatory submissions linked to this compound. If the results of this study are published or presented in a 
meeting, you will not be named and nobody will be able to tell that you were in the study from the 
publication or presentation. 
 
Your participation in this study is voluntary and you may cancel this consent at any time and without any 
reason and will not involve any penalty or loss of access to treatment or other benefits to which you are 
entitled.  If you withdraw your permission, no new health information will be gathered unless you have a 
side effect related to the study.   
 
If you withdraw from the study but do not withdraw your Authorization, new health information may be 
collected until this study ends. This Authorization will not expire unless revoked. To revoke your 
Authorization, you must write to the study doctor, stating that you are revoking your Authorization to Use 
and Disclose Protected Health Information at:  
 
Thomas C. Marbury, M.D. 
Orlando Clinical Research Center 
5055 S. Orange Avenue 
Orlando, FL 32809 
 
The sponsor will continue to retain and use all research results that have already been collected for the study 
evaluation. All biological samples that have already been collected may be retained and analyzed at a later 
date (as per local regulations). 
 
You have the right to review your Study Information and medical records and request changes to the Study 
Information if it is not correct. However, please note that during the study, access to Study Information may 
be limited if it weakens the integrity of the research. You may have access to the Study Information held 
by the Study Doctor at the end of the study. 
 
If you have any questions about the collection and use of information about you, or would like to exercise 
rights that you may have regarding this information, you should ask your Study Doctor. 


Protocol number: EWE-19-02 
Thomas C. Marbury, M.D. 
Informed Consent 
 
Page 16 of 18 
APPROVED BY 
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MARCH 21, 2019 
 
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THE REASON FOR INSTITUTIONAL REVIEW BOARDS AND INFORMED CONSENT 
 
What is a consent form? 
The informed consent document contains information required by federal regulations. The informed 
consent document must be approved by an Institutional Review Board (IRB). 
 
What is an Institutional Review Board (IRB)? 
An Institutional Review Board (IRB) is a group of people that reviews research studies. The main goal of 
this review is to protect the rights and well-being of the human subjects participating in research studies. 
 
IntegReview, the IRB for this study 
IntegReview is an IRB whose board members provide IRB services across the United States, Japan, and 
Latin America. 
 
To meet requirements of the law, the IntegReview Boards currently include:  
 
• 
Doctors  
• 
Pharmacists  
• 
Nurses  
• 
Toxicologists (people who study the harmful effects of chemicals)  
• 
Other specialists 
• 
Others who do not have a background in science/medicine 
 
PRIMARY CARE PHYSICIAN NOTIFICATION 
 
If you agree, your primary care physician will be informed of your participation in the study. Indicate your 
choice by initialing only one (1) section below. 
 
_______ 
Initials 
 
I do not have a primary care physician 
 
_______ 
Initials 
I do not want my primary care physician notified 
 
_______ 
Initials 
 
I would like my primary care physician notified and below is my physician’s contact 
information. 
 
Physician’s Name: _________________________________________ 
 
 
Address: _________________________________________________ 
               _________________________________________________ 
 
 
Phone No.: _______________________________________________ 
 
 
 


Protocol number: EWE-19-02 
Thomas C. Marbury, M.D. 
Informed Consent 
 
Page 17 of 18 
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MARCH 21, 2019 
 
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AGREEMENT TO BE IN THE STUDY 
 
This consent form contains important information to help you decide if you want to be in the study. If you 
have any questions that are not answered in this consent form, ask one of the study staff.  
 
Please answer YES or NO to the following questions: 
 
A. 
Is this document in a language you understand? 
 
 
 
 
 
 
 
 
B. 
Do you understand the information in this consent form?  
 
 
 
 
 
 
C. 
Have you been given enough time to ask questions and talk about the study? 
 
 
 
 
D. 
Have all of your questions been answered to your satisfaction? 
 
 
 
 
 
 
E. 
Do you think you received enough information about the study? 
 
 
 
 
 
 
F. 
Do you volunteer to be in this study of your own free will and without being  
pressured by the investigator or study staff? 
 
 
 
 
 
 
 
 
G. 
Do you know that you can leave the study at any time without giving 
a reason and without affecting your health care? 
 
 
 
 
 
 
 
 
H. 
Do you know that your health records from this study may be reviewed 
by the sponsor company and by government authorities? 
 
 
 
 
 
 
 
I. 
Do you know that you cannot be in another study while you are in this study? 
 
 
 
 
J. 
Do you authorize the use and disclosure of your medical information? 
 
 
 
 
 
K. 
Do you know that you cannot be in another study while you are in this study?         _____________ 
 
IF YOU ANSWERED “NO” TO ANY OF THE ABOVE QUESTIONS, 
OR YOU ARE UNABLE TO ANSWER ANY OF THE ABOVE QUESTIONS, 
YOU SHOULD NOT SIGN THIS CONSENT FORM. 
 
____________________________________________ 
Printed Name of Adult Study Subject 
 
____________________________________________  
 
 
 
 
Signature of Adult Study Subject  
 
 
 
          Date 
 
       
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________ 
Printed Name of Person Explaining Consent Form 
 
____________________________________________   
  
 
 
 
Signature of Person Explaining Consent Form 
 
 
          Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
You will be given a signed and dated copy of this informed consent to keep. 


Protocol number: EWE-19-02 
Thomas C. Marbury, M.D. 
Informed Consent 
 
Page 18 of 18 
APPROVED BY 
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MARCH 21, 2019 
 
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CONSENT FOR SUBJECTS WHO ARE VISUALLY IMPAIRED 
 
The study subject has indicated that he/she is visually impaired.  The consent document has been read to 
the subject by a member of the study staff, discussed with the subject by a member of the study staff, and 
the subject has been given an opportunity to ask questions of the study staff.    
 
______________________________ 
Printed Name of Impartial Witness  
 
 
Signature of Impartial Witness*  
 
 
 
 
 
Date  
 
*Impartial Witness:  A person, who is independent of the study, who cannot be unfairly influenced by 
people involved with the study, who attends the informed consent process if the subject cannot read, and 
who reads the informed consent and any other written information provided to the subject. 
 
You will receive a signed and dated copy of this consent form to keep. 
 

Prot_000.pdf: 
 
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 
 
Page 7 
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 


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


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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: 
 


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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. 


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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.  


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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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CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 16 
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 


CONFIDENTIAL  
CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 17 
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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CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 18 
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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CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 19 
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, 


CONFIDENTIAL  
CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 20 
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 


CONFIDENTIAL  
CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 21 
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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Page 46 
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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CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
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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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Page 53 
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 


CONFIDENTIAL  
CA26622 (EWE-19-02), Final Protocol Amendment 2 22April2020 
 
Page 54 
(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. 
 
 


CONFIDENTIAL  
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Page 55 
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 

SAP_001.pdf: 
 Statistical Analysis Plan 
 
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 
 
Protocol No: EWE-19-02  
US IND No.: 18154 
Final Protocol Date: 15 March 2019 
Amendment One Date: 01 May 2019 
 
 
Compound Name: E-WE thrombin (AB002) 
 
 
Celerion Project CA26622 
Final Version 1.0 
Date: 18 September 2019 
 
Aronora, Inc. 
4640 SW Macadam Avenue, Ste 200A 
Portland, Oregon 97239, USA 
 
Celerion 
621 Rose Street, Lincoln, Nebraska 68502, USA 
100 Alexis-Nihon Boulevard, Suite 360, Montreal, QC, H4M 2N8, Canada  
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 2 of 88 
Statistical Analysis Plan Signature Page 
Compound Name: E-WE thrombin (AB002) 
Protocol: EWE-19-02 
Study Title: 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 
Issue Date: 18 September 2019 
 
Signature:_____________________________________ 
Date:_______________ 
Mohammad Abu-Rashid, BPharm, MPhil 
Senior Scientist, Clinical Pharmacology & Pharmacometrics,  
Data Management and Biometrics, Celerion 
100 Alexis Nihon Blvd., Suite 360 
Montreal, Quebec H4M 2N8, Canada 
 
Signature:_____________________________________ 
Date:_______________ 
Nancy Wang, PhD 
Associate Director, Biostatistics 
Data Management and Biometrics, Celerion 
Lincoln, Nebraska, USA 
 
Signature:_____________________________________ 
Date:_______________ 
Norah Verbout, PhD 
Senior Scientist 
Aronora, Inc. 
Portland, Oregon 97239, USA 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 3 of 88 
Table of Contents 
1. 
INTRODUCTION .......................................................................................................... 5 
2. 
OBJECTIVES AND ENDPOINTS................................................................................. 5 
2.1 
Objectives ............................................................................................................. 5 
2.2 
Endpoints .............................................................................................................. 6 
3. 
STUDY DESIGN ........................................................................................................... 6 
4. 
ANALYSIS POPULATIONS......................................................................................... 8 
4.1 
Analysis Populations ............................................................................................. 8 
4.2 
Preliminary Data and Interim Analysis .................................................................. 8 
5. 
TREATMENT DESCRIPTIONS ................................................................................... 8 
6. 
PHARMACO DYNAMIC ANALYSIS .......................................................................... 9 
6.1 
Pharmacodynamic Assessment .............................................................................. 9 
6.1.1 Drug Efficacy .......................................................................................... 10 
6.1.2 Efficiency of HD ..................................................................................... 11 
6.1.3 Internal Analysis by the Sponsor:............................................................. 11 
6.2 
Measurements and Collection Schedule............................................................... 11 
6.3 
Bioanalytical Method .......................................................................................... 12 
6.4 
Investigational Product and PD Analyte Information ........................................... 12 
6.4.1 E-WE Thrombin (APC-PCI) .................................................................... 12 
6.5 
APC-PCI Concentrations..................................................................................... 12 
6.6 
Data Summarization and Presentation ................................................................. 12 
6.6.1 APC-PCI ................................................................................................. 12 
7. 
SAFETY ...................................................................................................................... 13 
7.1 
Subject Discontinuation ...................................................................................... 14 
7.2 
Demographics ..................................................................................................... 14 
7.3 
Adverse Events ................................................................................................... 14 
7.4 
Clinical Laboratory Tests (Serum Chemistry, Hematology, Coagulation 
and Urinalysis) .................................................................................................... 14 
7.5 
Vital Signs .......................................................................................................... 15 
7.6 
Weight ................................................................................................................ 15 
7.7 
Electrocardiogram ............................................................................................... 15 
7.8 
Concomitant Medications .................................................................................... 16 
7.9 
Physical Examination .......................................................................................... 16 
7.10 Vascular Access Site Reaction ............................................................................ 16 
7.11 Bleeding Time ..................................................................................................... 16 
7.12 Medical History .................................................................................................. 16 
7.13 Immunogenicity .................................................................................................. 16 
8. 
SUMMARY OF CHANGES FROM PROTOCOL-PLANNED ANALYSIS................ 16 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 4 of 88 
9. 
SUMMARY TABLES AND FIGURES ....................................................................... 16 
9.1 
In-text Summary Tables and Figures ................................................................... 17 
9.2 
Section 14 Summary Tables and Figures ............................................................. 18 
9.3 
Section 16 Data Listings ...................................................................................... 21 
10. TABLE AND FIGURE SHELLS ................................................................................. 24 
10.1 In-text Summary Tables Shells ............................................................................ 25 
10.2 Figures Shells ...................................................................................................... 32 
10.3 Section 14 Summary Tables Shells ...................................................................... 37 
11. LISTING SHELLS ....................................................................................................... 56 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 5 of 88 
1. INTRODUCTION 
The following statistical analysis plan (SAP) provides the framework for the 
summarization of the data from this study. The SAP may change due to unforeseen 
circumstances. Any changes made from the planned analysis within the protocol, 
after the unblinding, or locking of the database will be documented in the clinical 
study report (CSR). The section referred to as Table Shells within this SAP describes 
the traceability of the tables, figures, and listings (TFLs) back to the data. Note that 
the header for this page will be the one used for the main body of the CSR.  
Any additional exploratory analyses not addressed within this statistical analysis plan 
(SAP) and/or driven by the data, or requested by Aronora Inc., will be considered out 
of scope and must be described in the CSR.  
2. OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
The primary objective of the study is: 
• To assess the safety and tolerability of a single dose of E-WE thrombin 
infused into the dialysis line during a 4-hour hemodialysis (HD) procedure in 
patients with end stage renal disease (ESRD). 
The secondary objectives of the study are as follows: 
• 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 (Kt/V and URR).  
 
Note:   Kt/V = volume of fluid completely cleared of urea [K = dialyzer clearance 
(mL/min), t = time of dialysis] and V = volume of water a patient’s body 
contains.  
URR = Urea reduction ratio 
Formulas to calculate Kt/V and URR are located in Section 6.1.2. 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 6 of 88 
 
2.2 
Endpoints 
Primary outcome measures: 
• The safety and tolerability of E-WE thrombin following administration of the 
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: 
• Pharmacodynamics 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. 
 
3. 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 centre 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: 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 7 of 88 
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 five times and will be assessed for all scheduled procedures and 
endpoints before and after each HD session, 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. 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. 
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. 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 8 of 88 
 
4. ANALYSIS POPULATIONS 
4.1 
Analysis Populations 
Safety Population 
All patients who received the study drug (active or matching placebo) will be 
included in the safety evaluations. 
Pharmacodynamic Population 
All patients who received the study drug (active or placebo) and had at least one 
postdose measurement of any of the PD assessment will be included in the PD 
evaluation. 
4.2 
Preliminary Data and Interim Analysis 
Celerion has not been contracted to complete any interim safety and PD analyses. 
5. TREATMENT DESCRIPTIONS 
Patients will receive a total dose of either 1.5 µg/kg E-WE thrombin, 3.0 µg/kg E-WE 
thrombin, or matching placebo on Day 1. 
Planned doses for each cohort of the study are as follows: 
Cohort 1:  Total dose of 1.5 µg/kg E-WE thrombin or matching placebo on Day 1 
Cohort 2:  Total dose of 3.0 µg/kg E-WE thrombin or matching placebo on Day 1 
The patients’ weight recorded at check-in will be used to calculate the study drug 
dose. 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 9 of 88 
Treatments will be described as follows: 
Cohort 
Treatment 
Short 
Description 
(used in text) 
Long Description (used in 
Tables Figures and Listings) 
Cohorts 1 & 2 
P 
Placebo (Pooled) 
0.5/1.0 µg/kg bolus dose of 
matching placebo followed by 
a 0.25/0.5 µg/kg/hour 
continuous infusion over 4 
hours for a total dose of 
1.5/3.0 µg/kg (Pooled 
matching placebo of 
Treatments A and B) 
Cohort 1 
A 
1.5 µg/kg E-WE 
thrombin 
0.5 µg/kg bolus dose of E-WE 
thrombin followed by a 0.25 
µg/kg/hour continuous 
infusion over 4 hours for a 
total dose of 1.5 µg/kg 
Cohort 2 
B 
3.0 µg/kg E-WE 
thrombin 
1.0 µg/kg bolus dose of E-WE 
thrombin followed by a 0.5 
µg/kg/hour continuous 
infusion over 4 hours for a 
total dose of 3.0 µg/kg 
 
6. PHARMACODYNAMIC ANALYSIS  
Plasma APC-PCI will be measured as a surrogate biomarker of drug exposure. 
APC-PCI will be used to detect the magnitude and duration of action of E-WE 
thrombin.  
No pharmacokinetic (PK) or statistical analysis will be required for APC-PCI. 
Individual, mean, and median data for APC-PCI will be presented graphically for all 
treatments (2 active dose levels and pooled placebo).  
6.1 
Pharmacodynamic Assessment 
Pharmacodynamic assessments will include evaluation of the efficacy of E-WE 
thrombin and the efficiency of HD. 


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6.1.1 Drug Efficacy 
Efficacy of antithrombotic activity will be evaluated by thrombus accumulation 
within the dialyzer. Thrombus accumulation will be evaluated by visual inspection of 
the venous chamber and dialyzer membrane at the end of HD procedures and by a 
gradation using a standardized visual assessment scale. The dialyzer cartridge will be 
rinsed, visually inspected, graded, and photographed on 4 sides. The dialysis venous 
chamber will be visually inspected, graded and photographed. The number of dialyzer 
cartridges used for each HD session will be recorded.  
Visual inspection of clotting in dialysis venous chamber will be recorded at the end of 
dialysis on Days -7, -5, -2, 1, and 3 with the following categories: 
 
1 = No detectable clotting  
2 = Presence of fibrinous ring or minimum clot affecting less than 5% of chamber 
space 
3 = Clot formation (affecting more than 5% of but less than 25% of chamber space) 
4 = Clot formation (affecting more than 25% of but less than 50% of chamber space) 
5 = Clot formation (affecting more than 50% of but less than 75% of chamber space) 
6 = Clot formation (affecting more than 75% of chamber space) 
7 = Occluded (also assess the category of clot that caused occlusion) 
 
Visual inspection of clotting in the dialysis filter will be recorded at the end of 
dialysis on Days -7, -5, -2, 1, and 3 with the following categories: 
 
1 =  No clotting, clean filter or few blood streaks (affecting less than 5% of the fibers 
seen at the surface of dialyzer), 
2 =  Blood streaks affecting more than 5% but less than 25 % of the fibers seen at the 
surface of the dialyzer, 
3 =  Blood streaks affecting more than 25% but less than 50 % of the fibers seen at 
the surface of the dialyzer, 
4 =  Blood streaks affecting more than 50% but less than 75 % of the fibers seen at 
the surface of the dialyzer, 
5 =  Blood streaks affecting more than 75% of the fibers seen at the surface if the 
dialyzer, 
 6 =  Occluded (also assess the category of streaking at the time of occlusion) 
 
Clotting categories will be listed and frequency summarized by Treatment and Day 
for all subjects in the Safety Population (2 active dose levels and pooled placebo). 
Note:  Plasma and dialysate samples will be frozen and sent to Sponsor along with the 
used and rinsed dialyzer cartridges and venous drip chambers for potential 
internal evaluation of plasma protein C, dialysate urea, and total protein 
accumulation within the dialyzer cartridge. Dialysate samples will be stored for 
up to 5 years following the last dosing for future analysis. 


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6.1.2 Efficiency of HD 
Efficiency of HD will be assessed by 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. 
BUN: Samples for BUN will be collected pre- and post-dialysis on Days -7, -5, -2, 1, 
and 3.  
 
The change in BUN values on Days -7, -5, -2, 1, and 3 will be calculated by 
subtracting the post-dialysis BUN from the pre-dialysis BUN values for each day 
separately. BUN values will be listed and summarized by treatment and Day in tables 
and figures for all subjects in the PD Population (2 active dose levels and pooled 
placebo). 
 
URR and Kt/V: The derived PD parameters urea reduction ratio (URR) and Kt/V 
will be calculated from the pre- and post-dialysis BUN values on Days -7, -5, -2, 1, 
and 3.  
URR will be calculated using the following formula:  
URR = (1-(post-dialysis BUN/ pre-dialysis BUN))*100 
Kt/V will be calculated using the following formula:  
𝑠𝑠𝑠𝑠𝐾𝐾𝐾𝐾
𝑉𝑉= − ln(𝑅𝑅−(0.008 × 𝑡𝑡)) + (4 −(3.5 × 𝑅𝑅)) × 𝑈𝑈𝑈𝑈
𝑊𝑊𝑊𝑊 
Where  
R = BUN Post-dialysis/BUN Pre-dialysis 
 
 
 
t = Time of HD  
 
 
 
UF = Pre-dialysis patient weight – Post-dialysis patient weight 
 
 
 
Wt = Post-dialysis weight of patient. 
 
URR and Kt/V values will be listed and summarized by treatment and Day in tables 
for all subjects in the PD Population (2 active dose levels and pooled placebo).  
6.1.3 Internal Analysis by the Sponsor:  
The following analyses may be performed by the Sponsor for internal purposes; these 
results may be included in the appendices of the CSR. 
• Protein C Analysis 
• Dialysate Analysis 
• Analysis of Protein Accumulation Within the Dialyzer Cartridge 
Full details are located in the protocol. 
6.2 
Measurements and Collection Schedule 
APC-PCI: For all patients, blood samples for the determination of APC-PCI will be 
collected on Day 1 at predose (hour 0, at least 1 hour prior the start of HD session) 
and at 0.167, 0.5, 1, 2, 4, 6, and 24 hours after E-WE thrombin bolus dose. 


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Statistical Analysis Plan, 18 September 2019 
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All APC-PCI concentration data will be included in the individual concentration-time 
plots (based on actual sample times), and in the mean concentration-time plots (based 
on nominal sample times). However, if there are any significant deviations from 
nominal sample times, some concentration data may be excluded from mean 
concentration-time plots and/or additional concentration-time plots of the mean data 
may be provided. All deviations and excluded data will be provided and discussed in 
the CSR. 
Protein C: For all patients, blood samples for the determination of protein C will be 
collected at the start and end of dialysis on Days -7, -5, -2 and 3. On Day 1, samples 
will be collected at predose (hour 0, at least 1 hour prior the start of HD session) and 
at 0.167, 0.5, 1, 2, 4, 6, and 24 hours after E-WE thrombin bolus dose.  
6.3 
Bioanalytical Method  
Plasma concentrations of APC-PCI will be determined using an enzyme-linked 
immunosorbent assay (ELISA) validated with respect to accuracy, precision, 
linearity, sensitivity, and specificity at Celerion, Lincoln, Nebraska. The analytical 
range (lower limit of quantitation [LLOQ] – upper limit of quantitation [ULOQ]) for 
APC-PCI is expected to be 0.02 – 1.00 ng/mL. 
Blood samples for protein C will be shipped to Aronora.  
6.4 
Investigational Product and PD Analyte Information 
6.4.1 E-WE Thrombin (APC-PCI) 
E-WE thrombin is a purified protein produced by recombinant DNA technology in a 
bacterial (Escherichia coli) cell culture system. 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.  
6.5 
APC-PCI Concentrations 
Plasma concentrations of APC-PCI as determined at the collection times and per the 
bioanalytical method described in Section 6.2 and Section 6.3, respectively, will be 
presented graphically for all treatments (2 active dose levels and pooled placebo). 
6.6 
Data Summarization and Presentation  
6.6.1 APC-PCI 
All plasma APC-PCI concentrations and descriptive statistics will be generated using 
SAS® version 9.3 or higher. A concentration table will be presented for pooled 
placebo samples without descriptive statistics. 


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Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
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Plasma concentrations of APC-PCI will be listed and summarized by treatment and 
time points for all subjects in the PD population. Plasma concentrations will be 
presented with the same level of precision as received from the bioanalytical 
laboratory. Summary statistics, including sample size (n), arithmetic mean (Mean), 
standard deviation (SD), coefficient of variation (CV%), standard error of the mean 
(SEM), minimum, median, and maximum will be calculated for all nominal 
concentration time points. Excluded subjects will be included in the concentration 
listings, but will be excluded from the summary statistics and noted as such in the 
tables.  
For the calculation of APC-PCI summary statistics, plasma concentrations below the 
limit of quantitation (BLQ) prior to the first quantifiable concentration will be set to 0 
and as missing elsewhere. All BLQ values will be presented as “BLQ” in the 
concentration listings and footnoted accordingly.  
Mean, median, and individual concentration-time profiles will be presented on linear 
scale. Linear mean plots will be presented with and without SD.  
The level of precision for APC-PCI, URR, and Kt/Vsummary statistic will be 
presented as follows:  
 
• Minimum/maximum: in same precision as in the bioanalytical/clinical 
laboratory database 
• Mean/median: in one more level of precision than minimum/maximum 
• SD/SEM: in one more level of precision than Mean/median 
• n will be presented as an integer  
• CV% will be presented to the nearest tenth 
  
 
7. SAFETY  
All case report form (CRF) data will be listed by subject and chronologically by 
assessment time points. This will include rechecks, unscheduled assessments, and 
early termination.  
Applicable continuous variables will be summarized using n, arithmetic mean, SD, 
minimum, median, and maximum. Data from subjects who received the placebo 
treatment will be pooled across cohorts. 
The level of precision will be presented as follows: minimum/maximum in the same 
precision as in the database, mean/median in one more precision level than 
minimum/maximum, SD in one more precision level than mean/median, and n will be 
presented as an integer. Percentages of total frequency counts, if presented, will be 
reported as whole numbers. 


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Statistical Analysis Plan, 18 September 2019 
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Where individual data points are missing because of dropouts or other reasons, the 
data will be summarized based on reduced denominators. 
7.1 
Subject Discontinuation 
Subjects will be summarized by number of subjects dosed, completed, and 
discontinued the study with discontinuation reasons by treatment (two dose levels and 
pooled placebo) and study overall. 
7.2 
Demographics 
Descriptive statistics will be calculated for continuous variables (age, weight, height, 
and body mass index) and frequency counts will be provided for categorical variables 
(race, ethnicity, and sex) by treatment and overall. Age will be derived from date of 
birth to date of informed consent. 
7.3 
Adverse Events 
All adverse events (AEs) occurring during this clinical trial will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA®), Version 21.1.  
All AEs captured in the database will be listed in by-subject data listings including 
verbatim term, coded term, treatment, severity, relationship to study medication, and 
action; however, only treatment-emergent AEs (TEAEs) will be summarized.  
A TEAE is defined as an AE that is starting or worsening at the time of or after study 
drug administration. Each TEAE will be attributed to a treatment based on the onset 
date and time of the AE. If the onset time of an AE is missing and the onset date is 
the same as the treatment dosing date, then the AE will be considered treatment 
emergent. If the onset date of an AE is missing, then the AE will be considered 
treatment emergent.  
TEAEs will be tabulated by System Organ Class (SOC) and Preferred Term. 
Summary tables will include number of subjects reporting the AE and as percent of 
number of subjects dosed by treatment and overall. The number of AEs will be 
tabulated in a similar manner. Tables which tabulate the number of TEAEs by 
severity and relationship to study treatment will also be included.  
Serious adverse events (SAEs), if present, will also be listed. Applicable narratives 
will be included in the CSR.  
7.4 
Clinical Laboratory Tests (Serum Chemistry, Hematology, Coagulation and 
Urinalysis) 
Safety serum chemistry, hematology and urinalysis tests are performed at Screening, 
Day -8 check-in, and end of HD on Day 3.  For anuric patients, urinalysis may not be 
performed. Coagulation is collected at Screening, Day -8 check-in, start and end of 


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HD on Days -7, -5, -2, 1, and 3, and at Follow-up. Platelet count is collected at start 
and end of HD on Days -7, -5, -2, 1, and 3.  
Out-of-range values and clinically significant results will be listed.  
For serum chemistry and hematology laboratory values, descriptive statistics will be 
presented for each laboratory test by assessment time point and treatment. Change 
from baseline will be summarized in a similar manner. Baseline is defined as the 
result closest and prior to dose which may include unscheduled results. This will 
typically be the result collected at Day -8 check-in. Postdose unscheduled events or 
early termination results will not be included in summaries. 
For each serum chemistry and hematology laboratory test, a shift table will be 
developed to compare the frequency of the results at baseline (above normal, normal, 
or below normal) with the respective postdose results.  
For coagulation tests (aPTT, PT/INR, fibrinogen, and TT) and platelet count on HD 
days, summary will be for pre- and post-HD and fold change. Coagulation parameters 
and platelet count will be listed and presented together since they have the same 
timepoints. Urinalysis test results will be listed only. 
7.5 
Vital Signs 
Vital signs tests (HR, BP, RR and T) will be assessed at Screening, Day -8 check-in, 
within one hour prior to start of HD on Days -7, -5, -2, 1 and 3 and 1 hour postdose 
on Day 1.  
 
Vital sign results will be summarized by treatment and time point. Change from 
baseline will be summarized in a similar way. Baseline is defined as the result closest 
and prior to the dose on Day 1, which may include unscheduled results, whichever is 
later. Postdose unscheduled events will not be included in summaries. 
7.6 
Weight 
Weight will be assessed at Screening, Day -8 check-in, at start and end of HD on 
Days -7, -5, -2, 1 and 3.  Weight will be summarized by treatment and time point. 
7.7 
Electrocardiogram  
Safety ECGs (HR, PR, QRS, QT and Fridericia correction QTcF) will be assessed at 
Screening, Day -8 check-in, Hour 0.5 postdose Day 1 and end of HD on Day 3. 
 
ECG parameters will be summarized by dose level, pooled placebo, and time point. 
Change from baseline will be summarized in a similar way. Baseline is defined as the 
result closest and prior to the dose from Day -8 check-in, which may include 
unscheduled results, whichever is later. Postdose unscheduled events will not be 
included in summaries. 
 


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Statistical Analysis Plan, 18 September 2019 
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The QTcF values that are > 450 ms and increase from baseline > 30 ms will be 
flagged in the data listings. 
7.8 
Concomitant Medications 
All concomitant medications recorded during the study will be coded with the WHO 
Dictionary Version September 2018, B3 and listed. 
7.9 
Physical Examination 
Full physical examinations will be performed at Screening, Day -8 check-in and end 
of HD on Day 3. Abbreviated physical examination will be performed at Hour 0.167 
on Day 1 or at other times, at the PI’s or designee’s discretion. Abnormal findings 
will be reported as medical history or adverse events. All data found in the CRF will 
be listed.  
7.10 
Vascular Access Site Reaction 
Vascular access site reaction will be assessed at predose and 4 hours post dose on 
Day 1 and at start and 20 minutes post HD on Day 3. Any new abnormal findings 
inconsistent with past skin injuries as expected in patient on chronic HD will be 
reported and summarized as AEs. All data collected on the CRF will be listed. 
7.11 
Bleeding Time 
The time to clot (bleeding time) will be recorded following hemodialysis after the 
needle is removed from the vascular access site on Days -7, -5, -2, 1, and 3.  
Summary statistics will be calculated for time to clot by treatment and assessment 
timepoint. 
7.12 
Medical History 
All medical and surgical histories recorded in the study will be coded with 
MedDRA®, Version 21.1, and listed. 
7.13 
Immunogenicity 
Blood samples for immunogenicity assessment will be performed at predose on Day 1 
and follow-up. Data will be provided as an appendix.  
8. SUMMARY OF CHANGES FROM PROTOCOL-PLANNED ANALYSIS 
The analyses described in this SAP are aligned with those analyses described in the 
protocol. 
9. SUMMARY TABLES AND FIGURES 
Summary tables and figures are numbered following the International Conference on 
Harmonization (ICH) structure but may be renumbered as appropriate during the 
compilation of the tables and figures for the CSR. Note that all PD, immunogenicity 
and Safety summary tables and figures will be generated using SAS® Version 9.3 or 


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higher and/or using Phoenix® WinNonlin® Version 7.0 or higher for summary PD 
TFLs, as appropriate.  
9.1 
In-text Summary Tables and Figures 
The following is a list of table and figure titles that will be included in the text of the 
CSR. Tables and figures will be numbered appropriately during compilation of the 
CSR. 
Section 10: 
Table 10-1 
Subject Disposition Summary  
Section 11: 
Tables 
Table 11-1 
Demographic Summary  
Table 11-2 
Summary of Clotting in the Dialysis Venous Chamber – Days -7 to 3 
(PD Population) 
Table 11-3 
Summary of Clotting in the Dialysis Filter – Days -7 to 3 (PD 
Population) 
Table 11-4 
Summary of Difference Between Pre- and Post-dialysis BUN and 
URR – Days -7 to 3 (PD Population) 
Table 11-5 
Summary of Kt/V Values (PD Population) 
 
Figures 
Figure 11-1 
Arithmetic Mean Plasma APC-PCI Concentration Versus Time 
Following Administration of 1.5 and 3.0 µg/kg E-WE Thrombin – Day 
1 (Linear Scale) (PD Population) 
Figure 11-2 
Median Plasma APC-PCI Concentration Versus Time Following 
Administration of 1.5 and 3.0 µg/kg E-WE Thrombin – Day 1 (Linear 
Scale) (PD Population) 
Figure 11-3 
Arithmetic Mean Pre- and Post-dialysis BUN Values Versus Time – 
Days -7 to 3 (Linear Scale) (PD Population) 
 
Section 12: 
Table 12-1 
Adverse Event Frequency by Treatment - Number of Subjects 
Reporting the Event (% of Subjects Dosed) 


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9.2 
Section 14 Summary Tables and Figures 
The following is a list of table and figure titles that will be included in Section 14 of 
the report. Table and figure titles may be re-numbered as appropriate during the 
compilation of the report.  
14.1 
Demographic Data Summary Tables  
The following is a list of table and figure titles that will be included in Section 14 of 
the report. Table and figure titles may be renumbered as appropriate during the 
compilation of the report. 
Table 14.1.1 Summary of Disposition (Safety Population) 
Table 14.1.2 Summary of Demographics (Safety Population) 
14.2 
Pharmacodynamic Data Summary Tables and Figures  
14.2.1. Plasma APC-PCI Tables and Figures 
Table 14.2.1.1.1 Plasma APC-PCI Concentrations (unit) Following 
Administration of 1.5 µg/kg E-WE Thrombin – Day 1 (PD 
Population) 
Table 14.2.1.1.2 Plasma APC-PCI Concentrations (ng/mL) Following 
Administration of 3.0 µg/kg E-WE Thrombin – Day 1 (PD 
Population) 
Table 14.2.1.1.3 Plasma APC-PCI Concentrations (ng/mL) Following 
Administration of Placebo – Day 1 (Pooled)  
Figure 14.2.1.2.1 Arithmetic Mean (SD) Plasma APC-PCI Concentration 
Versus Time Profiles Following Administration of 1.5 and 
3.0 µg/kg E-WE Thrombin – Day 1 (Linear Scale) (PD 
Population) 
Figure 14.2.1.2.2 Arithmetic Mean Plasma APC-PCI Concentration Versus 
Time Profiles Following Administration of 1.5 and 3.0 µg/kg 
E-WE Thrombin – Day 1 (Linear Scale) (PD Population) 
Figure 14.2.1.2.3 Median Plasma APC-PCI Concentration Versus Time 
Profiles Following Administration of 1.5 and 3.0 µg/kg 
E-WE Thrombin – Day 1 (Linear Scale) (PD Population) 
 
14.2.2  Clotting in the Dialysis Venous Chamber Tables 
Table 14.2.2.1 Frequency of Clotting in the Dialysis Venous Chamber 
Days -7 to 3 (PD Population) 


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14.2.3  Clotting in Dialysis Filter Tables 
Table 14.2.3.1 Frequency of Clotting in the Dialysis Filter Days -7 to 3 (PD 
Population) 
 
14.2.4 
BUN Tables and Figures  
Table 14.2.4.1.1 Individual and Mean Difference between Pre- and 
Post-dialysis BUN Values (unit) and URR – Days -7 to 3 – 
1.5 µg/kg E-WE Thrombin on Day 1 (PD Population) 
Table 14.2.4.1.2 Individual and Mean Difference between Pre- and 
Post-dialysis BUN Values (unit) and URR – Days -7 to 3 – 
3.0 µg/kg E-WE Thrombin on Day 1 (PD Population) 
Table 14.2.4.1.3 Individual and Mean Difference between Pre- and Post-
dialysis BUN Values (unit) and URR – Days -7 to 3 –
Placebo (Pooled) (PD Population) 
Programmer Note:  
For Tables 14.2.4.1.1 through 14.2.4.1.3, the difference will 
be calculated as follows: (Pre-dialysis – Post-dialysis). 
Figure 14.2.4.2.1 Arithmetic Mean (SD) Pre- and Post-dialysis BUN Values – 
Days -7 to 3 (Linear Scale) (PD Population) 
Figure 14.2.4.2.2 Arithmetic Mean Pre- and Post-dialysis BUN Values – Days 
-7 to 3 (Linear Scale) (PD Population) 
 
14.2.5 
Kt/V Tables  
Table 14.2.5.1.1 Individual and Mean Kt/V Values (unit) – 1.5 µg/kg E-WE 
Thrombin on Day 1 (PD Population) 
Table 14.2.5.1.2 Individual and Mean Kt/V Values (unit) – 3.0 µg/kg E-WE 
Thrombin on Day 1 (PD Population) 
Table 14.2.5.1.3 Individual and Mean Kt/V Values (unit) – Placebo (Pooled) 
(PD Population) 
 
14.3 
Safety Data Summary Tables  
14.3.1 
Displays of Adverse Events 
Table 14.3.1.1 Treatment-emergent Adverse Event Frequency by Treatment 
– Number of Subjects Reporting the Event (% of Subject 
Dosed) (Safety Population) 
Table 14.3.1.2 Treatment-emergent Adverse Event Frequency by Treatment 
– Number of Adverse Events (% of Total Adverse Events) 
(Safety Population) 


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Table 14.3.1.3 Treatment-emergent Adverse Event Frequency by Treatment, 
Severity, and Relationship to Drug – Number of Adverse 
Events (Safety Population) 
14.3.2 
Listings of Deaths, other Serious and Significant Adverse Events 
Table 14.3.2.1 Serious Adverse Events (Safety Population)  
<if no serious adverse event occurred, a statement ‘No 
serious adverse event is reported’> 
14.3.3 
Narratives of Deaths, other Serious and Certain other 
Significant Adverse Events 
14.3.4 
Abnormal Laboratory Value Listing (each patient) 
Table 14.3.4.1 Out-of-Range Values and Recheck Results – Serum 
Chemistry (Safety Population) 
Table 14.3.4.2 Out-of-Range Values and Recheck Results – 
Hematology/Coagulation (Safety Population) 
Table 14.3.4.3 Out-of-Range Values and Recheck Results – Urinalysis 
(Safety Population) 
14.3.5 
Displays of Other Laboratory, Vital Signs, Electrocardiogram, 
Physical Examination, and Other Safety Data 
Table 14.3.5.1 Clinical Laboratory Summary and Change from Baseline – 
Serum Chemistry (Safety Population) 
Table 14.3.5.2 Clinical Laboratory Shift from Baseline – Serum Chemistry 
(Safety Population) 
Table 14.3.5.3 Clinical Laboratory Summary and Change from Baseline – 
Hematology (Safety Population) 
Table 14.3.5.4 Clinical Laboratory Shift from Baseline – Hematology 
(Safety Population) 
Table 14.3.5.5 Clinical Laboratory Summary and Change from Baseline – 
Coagulation and Platelet Count (Safety Population) 
Table 14.3.5.6 Vital Sign Summary and Change from Baseline (Safety 
Population) 
Table 14.3.5.7 Summarization of Weight (Safety Population)  
Table 14.3.5.8 12-Lead Electrocardiogram Summary and Change from 
Baseline (Safety Population) 
Table 14.3.5.9 Summarization of Bleeding Time (Safety Population)  
 


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9.3 
Section 16 Data Listings 
Data listings are numbered following the ICH structure but may be renumbered as 
appropriate during the compilation of the TFLs for the CSR. The following is a list of 
appendix numbers and titles that will be included as data listings: 
16.1 
Study Information 
Appendix 16.1.9 
Statistical Methods 
Appendix 16.1.10.1 
Clinical Laboratory Reference Ranges 
16.2 
Subject Data Listings 
16.2.1 
Subject Discontinuation 
Appendix 16.2.1 
Study Completion/Early Termination (Safety 
Population) 
16.2.2 
Protocol Deviations 
Appendix 16.2.2 
Protocol Deviations 
16.2.3 
Subjects Excluded from Pharmacodynamic Analyses 
Appendix 16.2.3 
Subjects Excluded from Pharmacodynamic Analyses 
<Note: Appendices 16.2.2 and 16.2.3 are generated in MS Word for inclusion 
in the study report.> 
16.2.4 
Demographic Data 
Appendix 16.2.4.1 
Demographics (Safety Population) 
Appendix 16.2.4.2 
Physical Examination (Safety Population)  
Appendix 16.2.4.3 
Medical and Surgical History (Safety Population) 
Appendix 16.2.4.4 
Alcohol Screen (Safety Population) 
Appendix 16.2.4.5 
Saliva Drug Screen (Safety Population) 
Appendix 16.2.4.6 
Tobacco Use (Safety Population) 
 
16.2.5 
Compliance and/or Drug Concentration Data 
Appendix 16.2.5.1 
Subject Eligibility at Screening (Safety Population) 
Appendix 16.2.5.2 
Subject Eligibility at Check-In (Safety Population) 
Appendix 16.2.5.3 
Test Compound Administration (Safety Population) 


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Appendix 16.2.5.4 
Blood Draw Times for E-WE Thrombin PD (APC-PCI)  
(Safety Population) 
Appendix 16.2.5.5 
Blood Draw Times for Protein C (Safety Population) 
Appendix 16.2.5.6 
Blood Draw Times for Immunogenicity (Safety 
Population) 
Appendix 16.2.5.7 
Blood Draw Times for Dialysate Analysis for Kt/V and 
URR (Safety Population) 
Appendix 16.2.5.8 
Dialysate Collection (Safety Population) 
Appendix 16.2.5.9.1 Dialyzer Assessment (I of V) – Hemodialysis Start and 
End Times (Safety Population) 
Appendix 16.2.5.9.2 Dialyzer Assessment (II of V) - Circuit Arterial and 
Venous Pressure and Blood Flow Rate (Safety 
Population) 
Appendix 16.2.5.9.3 Dialyzer Assessment (III of V) –Number and Volume 
of Saline Flushes (Safety Population) 
Appendix 16.2.5.9.4 Dialyzer Assessment (IV of V) – Clotting in Dialysis 
Venous Chamber (Safety Population) 
Appendix 16.2.5.9.5 Dialyzer Assessment (V of V) – Clotting in Dialysis 
Filter (Safety Population) 
Appendix 16.2.5.10 
Non-Study Procedures (Safety Population) 
Appendix 16.2.5.11 
Prior and On-Study Concomitant Medications (Safety 
Population) 
16.2.6 
Individual Pharmacodynamic Response Data 
Individual APC-PCI Figures 
Appendix 16.2.6.1.1 Individual Plasma APC-PCI Concentration Versus 
Time Profiles Following Administration of 1.5 µg/kg 
E-WE Thrombin (Linear) for <Subject #> 
Appendix 16.2.6.1.2 Individual Plasma APC-PCI Concentration Versus 
Time Profiles Following Administration of 3.0 µg/kg 
E-WE Thrombin (Linear) for <Subject #> 
Individual BUN Figures 
Appendix 16.2.6.2.1 Individual Pre- and Post-dialysis BUN Values Versus 
Time – Days -7 to 3 (Linear Scale) for <Subject #> 
16.2.7 
Adverse Events Listings 
Appendix 16.2.7.1.1 Adverse Events (I of II) (Safety Population) 
Appendix 16.2.7.1.2 Adverse Events (II of II) (Safety Population) 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 23 of 88 
Appendix 16.2.7.2 
Adverse Event Preferred Term Classification (Safety 
Population) 
16.2.8 
Listings of Individual Laboratory Measurements and Other 
Safety Observations 
Appendix 16.2.8.1.1 Clinical Laboratory Report - Serum Chemistry (Safety 
Population)  
Appendix 16.2.8.1.2 Clinical Laboratory Report - Hematology (Safety 
Population) 
Appendix 16.2.8.1.3 Clinical Laboratory Report – Coagulation and Platelet 
Count (Safety Population) 
Appendix 16.2.8.1.4 Clinical Laboratory Report - Urinalysis (Safety 
Population) 
Appendix 16.2.8.1.5 Clinical Laboratory Report – Additional Tests (Safety 
Population) 
Appendix 16.2.8.1.6 Clinical Laboratory Report - Comments (Safety 
Population) 
<Note: Appendices 16.2.8.1.5 and 16.2.8.1.6 will be removed if not applicable> 
Appendix 16.2.8.2 
Vital Signs (Safety Population) 
Appendix 16.2.8.3 
12-Lead Electrocardiogram (Safety Population) 
Appendix 16.2.8.4 
Vascular Access Site Reaction Assessment (Safety 
Population) 
 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 24 of 88 
10. TABLE AND FIGURE SHELLS  
The following table shells provide a framework for the display of data from this 
study. The shells may change due to unforeseen circumstances. These shells may not 
be reflective of every aspect of this study, but are intended to show the general layout 
of the tables that will be presented and included in the final report. Unless otherwise 
noted, all in-text tables will be presented in Times New Roman as close as possible to 
font size 12 to fit on a portrait page and all post-text tables will be presented in 
Courier New font size 9. These tables will be generated off of the Celerion ADaM 
structure. ADaM datasets are created in accordance with CDISC guidance (ADaM 
Model 2.1 and ADaM implementation guide 1.1). 
   
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 25 of 88 
 
10.1 
In-text Summary Tables Shells 
In-text Table 10-1 will be in the following format: 
 
Table 10-1 
Subject Disposition Summary 
 
Table 10-1  
Subject Disposition Summary (Safety Population) 
 
Disposition 
1.5 µg/kg E-WE Thrombin 3.0 µg/kg E-WE Thrombin Placebo (Pooled) 
Overall 
Dosed 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Completed 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Discontinued 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
 
<Reason1> 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
 
<Reason2> 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
Source: Table 14.1.1 
Program:  /CAXXXXX/sas_prg/stsas/intext/t_disp.sas  DDMMMYYYY  HH:MM 
 
 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 26 of 88 
 
In-text Table 11-1 will be in the following format: 
 
Table 11-1 
Demographic Summary  
 
Trait 
Category/ 
Statistics 
 
 
1.5 µg/kg E-WE 
Thrombin 
 
 
3.0 µg/kg E-WE 
Thrombin 
Placebo (Pooled) 
 
 
Overall 
Sex 
Male 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Female 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Race 
Asian 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
 
Black or African American 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
 
White 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Ethnicity 
Hispanic or Latino 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
 
Not Hispanic or Latino 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Age* (yrs) 
n 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
X.XX 
X.XX 
X.XX 
X.XX 
 
Minimum 
XX 
XX 
XX 
XX 
 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
 
Maximum 
XX 
XX 
XX 
XX 
Weight (kg) 
n 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
X.XX 
X.XX 
X.XX 
X.XX 
 
Minimum 
XX 
XX 
XX 
XX 
 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
 
Maximum 
XX 
XX 
XX 
XX 
*Age is calculated at the time of first dosing. 
BMI = Body mass index 
Source: Table 14.1.2 
Program:  /CAXXXXX/sas_prg/stsas/intexttest/t_dem.sas  DDMMMYYYY  HH:MM 
 
Programmer note:  also include height and BMI


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 27 of 88 
 
Table 11-2 
Summary of Clotting in the Dialysis Venous Chamber – Days -7 to 3 
(PD Population) 
      Clotting in the Dialysis Venous Chamber 
 
 
 
Time 
Point 
Treatments 
1.5 µg/kg E-WE Thrombin 
3.0 µg/kg E-WE Thrombin 
Placebo (Pooled) 
 
 
Category 
 
Post-dialysis 
 
 
[n=xx] 
 
 
Category 
 
Post-dialysis 
 
 
[n=xx] 
 
 
Category 
 
Post-dialysis 
 
 
[n=xx] 
 
1 
2 
3 
4 
5 
6 
7 
1 
2 
3 
4 
5 
6 
7 
1 
2 
3 
4 
5 
6 
7 
Day -7 
X 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Day -5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Day -2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Day 1* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Day 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Category: 
1 = No detectable clotting 
2 = Presence of fibrinous ring or minimum clot affecting less than 5% of chamber space, 
3 = Clot formation (affecting more than 5% of but less than 25% of chamber space), 
4 = Clot formation (affecting more than 25% of but less than 50% of chamber space), 
5 = Clot formation (affecting more than 50% of but less than 75% of chamber space), 
6 = Clot formation (affecting more than 75% of chamber space), 
7 = Occluded (also assess the category of clot that caused occlusion) 
 
a-n=xx 
* -  Single IV doses of 1.5, 3.0 µg/kg E-WE Thrombin or placebo were administered on Day 1 
Values will be presented as arithmetic mean  
 
 
Source: Table 14.2.2.1  
Program:  /CAXXXXX/sas_prg/stsas/intext/t_ae.sas  DDMMMYYYY  HH:MM 
 
Notes for Generating the Actual Table: 
 
• 
n will be presented as an integer (with no decimal); 
• 
Internal template ITPar1, with the following changes: n will be presented in the column 
title with more additional columns to be created. 
 
Program:  /CAXXXXX/sas_prg/pksas/intext-pk-tables.sas   DDMMMYYYY  HH:MM 
Program:  /CAXXXXX/sas_prg/pksas/adam_intext_pkparam.sas   DDMMMYYYY  HH:MM 


Aronora, Inc. 
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Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 28 of 88 
 
Table 11-3 
Summary of Clotting in the Dialysis Filter – Days -7 to 3 (PD 
Population) 
 
Clotting in Dialysis Filter 
 
 
 
Time 
Point 
Treatments 
1.5 µg/kg E-WE Thrombin 
3.0 µg/kg E-WE Thrombin 
Placebo (Pooled) 
 
 
Category 
 
Post-dialysis 
 
 
[n=xx] 
 
 
Category 
 
Post-dialysis 
 
 
[n=xx] 
 
 
Category 
 
Post-dialysis 
 
 
[n=xx] 
 
1 
2 
3 
4 
5 
6 
1 
2 
3 
4 
5 
6 
1 
2 
3 
4 
5 
6 
Day -7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Day -5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Day -2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Day 1* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Day 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Category: 
1 = No clotting, clean filter or few blood streaks (affecting less than 5% of the fibers seen at the surface of dialyzer), 
2 = Blood streaks affecting more than 5% but less than 25 % of the fibers seen at the surface of the dialyzer, 
3 = Blood streaks affecting more than 25% but less than 50 % of the fibers seen at the surface of the dialyzer, 
4 = Blood streaks affecting more than 50% but less than 75 % of the fibers seen at the surface of the dialyzer, 
5 = Blood streaks affecting more than 75% of the fibers seen at the surface if the dialyzer, 
6 = Occluded (also assess the category of streaking at the time of occlusion) 
 
a-n=xx 
* -  Single IV doses of 1.5, 3.0 µg/kg E-WE Thrombin or placebo were administered on Day 1 
Values will be presented as arithmetic mean  
 
Source: Table 14.2.3.1  
Program:  /CAXXXXX/sas_prg/stsas/intext/t_ae.sas  DDMMMYYYY  HH:MM 
 
Notes for Generating the Actual Table: 
 
• 
n will be presented as an integer (with no decimal); 
• 
Summary statistics will be presented with same precision as defined in post-text shells  
• 
Internal template ITPar1, with the following changes: n will be presented in the column 
title with more additional columns to be created. 
 
Program:  /CAXXXXX/sas_prg/pksas/intext-pk-tables.sas   DDMMMYYYY  HH:MM 
Program:  /CAXXXXX/sas_prg/pksas/adam_intext_pkparam.sas   DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 29 of 88 
 
 
Table 11-4 
Summary of Difference between Pre- and Post-dialysis BUN and URR – Days -7 to 3 (PD Population) 
 
Mean Blood Urea Nitrogen (Reference Range xx – xx <units>) and  URR (Reference Range xx – xx <%>) 
 
 
Time 
Point 
Treatments 
1.5 µg/kg E-WE Thrombin 
3.0 µg/kg E-WE Thrombin 
Placebo (Pooled) 
 
Pre-
dialysis 
 
(Unit) 
[n=xx] 
 
Post-
dialysis 
 
(Unit) 
[n=xx] 
 
Difference 
 
 
(Unit) 
[n=xx] 
 
URR 
(%) 
 
(Unit) 
[n=xx] 
 
Pre-
dialysis 
 
(Unit) 
[n=xx] 
 
Post-
dialysis 
 
(Unit) 
[n=xx] 
 
Difference 
 
 
(Unit) 
[n=xx] 
 
URR 
(%) 
 
(Unit) 
[n=xx] 
 
Pre-
dialysis 
 
(Unit) 
[n=xx] 
 
Post-
dialysis 
 
(Unit) 
[n=xx] 
 
Difference 
 
 
(Unit) 
[n=xx] 
 
URR 
(%) 
 
(Unit) 
[n=xx] 
Day -7 
XXX.X 
XXX.X 
XX.X 
XX.X 
XXX.X 
XXX.X 
XX.X 
XX.X 
XXX.X 
XXX.X 
XX.X 
XX.X 
Day -5 
XXX.Xa 
XXX.X  
XX.X 
XX.X 
XXX.X  
XXX.X  
XX.X 
XX.X 
XXX.X  
XXX.X  
XX.X 
XX.X 
Day -2 
XXX.X  
XXX.X  
XX.X 
XX.X 
XXX.X  
XXX.X  
XX.X 
XX.X 
XXX.X  
XXX.X  
XX.X 
XX.X 
Day 1* 
XXX.X 
XXX.X 
XX.X 
XX.X 
XXX.X 
XXX.X 
XX.X 
XX.X 
XXX.X 
XXX.X 
XX.X 
XX.X 
Day 3 
XXX.X 
XXX.X 
XX.X 
XX.X 
XXX.X 
XXX.X 
XX.X 
XX.X 
XXX.X 
XXX.X 
XX.X 
XX.X 
Difference = Pre-dialysis - Post-dialysis 
a-n = xx 
URR = (1-(post-dialysis BUN/ pre-dialysis BUN))*100 
* -  Single IV doses of 1.5, 3.0 µg/kg E-WE Thrombin or placebo were administered on Day 1 
Values will be presented as arithmetic mean  
 
Source: Tables 14.2.4.1.1 through 14.2.4.1.3 
Program:  /CAXXXXX/sas_prg/stsas/intext/t_ae.sas  DDMMMYYYY  HH:MM 
 
Notes for Generating the Actual Table: 
 
• 
n will be presented as an integer (with no decimal); 
• 
Summary statistics will be presented with same precision as defined in post-text shells  
• 
Internal template ITPar1, with the following changes: n will be presented in the column title with more additional columns to be 
created. 
 
Program:  /CAXXXXX/sas_prg/pksas/intext-pk-tables.sas   DDMMMYYYY  HH:MM 
Program:  /CAXXXXX/sas_prg/pksas/adam_intext_pkparam.sas   DDMMMYYYY  HH:MM


Aronora, Inc. 
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Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 30 of 88 
 
Table 11-5 
Summary of Kt/V Values (PD Population) 
Single pool Kt/V 
 
 
Time 
Point 
Treatments 
1.5 µg/kg E-WE Thrombin 
3.0 µg/kg E-WE Thrombin 
Placebo (Pooled) 
R 
(unit) 
[n=xx] 
t 
(unit) 
[n=xx] 
UF 
(unit) 
[n=xx] 
Wt 
(unit) 
[n=xx] 
Kt/V 
(unit) 
[n=xx] 
R 
(unit) 
[n=xx] 
t 
(unit) 
[n=xx] 
UF 
(unit) 
[n=xx] 
Wt 
(unit) 
[n=xx] 
Kt/V 
(unit) 
[n=xx] 
R 
(unit) 
[n=xx] 
t 
(unit) 
[n=xx] 
UF 
(unit) 
[n=xx] 
Wt 
(unit) 
[n=xx] 
Kt/V 
(unit) 
[n=xx] 
Day -7 
XX.X XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X XX.X XX.X 
XX.X 
XX.X 
Day -5 
XX.X XX.X 
XX.X 
XX.Xa 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X XX.X XX.X 
XX.X 
XX.X 
Day -2 
XX.X XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X XX.X XX.X 
XX.X 
XX.X 
Day 1* 
XX.X XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X XX.X XX.X 
XX.X 
XX.X 
Day 3 
XX.X XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X XX.X XX.X 
XX.X 
XX.X 
a-n=xx 
* -  Single IV doses of 1.5, 3.0 µg/kg E-WE Thrombin or placebo were administered on Day 1 
Values will be presented as arithmetic mean  
 
R= post-dialysis BUN/pre-dialysis BUN))*100 
t = Time of HD 
UF =  Pre-dialysis Weight – Post-dialysis Weight 
Wt = Post-dialysis weight of patient 
Kt/V = −ln(R −(0.008 × t)) + (4 −(3.5 × R)) ×
UF
Wt 
 
Source: Tables 14.2.5.1.1 through 14.2.5.1.3 
Program:  /CAXXXXX/sas_prg/stsas/intext/t_ae.sas  DDMMMYYYY  HH:MM 
 
Notes for Generating the Actual Table: 
• 
n will be presented as an integer (with no decimal); 
• 
Summary statistics will be presented with same precision as defined in post-text shells  
• 
Internal template ITPar1, with the following changes: n will be presented in the column title with more additional columns to be 
created. 
 
Program:  /CAXXXXX/sas_prg/pksas/intext-pk-tables.sas   DDMMMYYYY  HH:MM 
Program:  /CAXXXXX/sas_prg/pksas/adam_intext_pkparam.sas   DDMMMYYYY  HH:MM 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 31 of 88 
 
In-text Table 12-1 will be in the following format: 
 
Table 12-1  Adverse Event Frequency by Treatment - Number of Subjects Reporting the 
Event (% of Subjects Dosed) 
 
Adverse Event* 
1.5 µg/kg E-WE 
Thrombin 
3.0 µg/kg E-WE 
Thrombin 
Placebo (Pooled) 
Overall 
Number of Subjects With TEAEs 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Number of Subjects Without TEAEs 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
System Organ Class 1 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
 
Preferred Term 1 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
 
Preferred Term 2 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
System Organ Class 2 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
 
Preferred Term 1 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
 
Preferred Term 2 
     X (X%) 
     X (X%) 
     X (X%) 
     X (X%) 
*Adverse events are classified according to MedDRA Version 21.1. 
TEAEs = Treatment-emergent adverse events 
If a subject has 2 or more clinical adverse events, the subject is counted only once within a category. The same subject may appear in 
different categories. 
Source: Table 14.3.1.1 
Program:  /CAXXXXX/sas_prg/stsas/intext/t_ae.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 32 of 88 
 
10.2 
Figures Shells 
In-text Figures 11-1, 11-2, post-text Figures 14.2.1.2.1 through 14.2.1.2.3, and Individual 
Listings in 16.2.6.1.1, and 16.2.6.1.2, will be in the following format: 
 
Figure 14.2.1.2.1 
 
 
Arithmetic Mean (SD) Plasma APC-PCI Concentration Versus Time Profiles 
Following Administration of 1.5 and 3.0 µg/kg E-WE Thrombin – Day 1 
(Linear Scale) (PD Population) 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 33 of 88 
 
Figure 14.2.1.2.2 
 
Arithmetic Mean Plasma APC-PCI Concentration Versus Time Profiles 
Following Administration of 1.5 and 3.0 µg/kg E-WE Thrombin – Day 1 
(Linear Scale) (PD Population) 
 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 34 of 88 
 
Figures 11-3, 14.2.4.2.1, 14.2.4.2.2 and individual listings in 16.2.6.2.1 will be listed as per 
the above formats with connecting the mean values between the pre- and post-dialysis results 
within the same day but without connecting the values between days. 
 
o y-axis: <Bun> (unit) 
o  X-axis: Day 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 35 of 88 
 
Figures in Appendices 16.2.6.1.1 and 16.2.6.1.2 will be in the following format:  
 
Appendix 16.2.6.1.1 
 Individual Plasma APC-PCI Concentrations Versus Time Profiles Following Administration 
of 1.5 µg/kg E-WE Thrombin (Linear Scale) for <Subject #> 
 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 36 of 88 
 
Notes for Generating the Actual Individual Figure: 
 
 
 
o y-axis: Plasma APC-PCI Concentration (unit) 
o  X-axis: Hours From Start of Dose 
 
 
Figure Legend: Use the Short Description as presented in Section 5. 
 
 
 
Program:  /CAXXXXX/sas_prg/pksas/indgraph-all.sas    
DDMMMYYYY  HH:MM 
Program:  /CAXXXXX/sas_prg/pksas/adam_indgraph.sas   
 
DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 37 of 88 
 
10.3 
Section 14 Summary Tables Shells 
                                                                                                                            
                                                                                        Page 1 of X 
 
                             
 
 
 Table 14.1.1  Summary of Disposition Safety Population) 
 
                                                           Dose Level of E-WE Thrombin  
                                                          ----------------------------  Placebo 
                                    Disposition              1.5 µg/kg    3.0 µg/kg     (Pooled)   Overall       
                                    ----------------------------------------------------------------------- 
                                    Dosed                       X (XX%)     X (XX%)     X (XX%)   X (XX%) 
                                    Completed                   X (XX%)     X (XX%)     X (XX%)   X (XX%) 
                                    Discontinued                X (XX%)     X (XX%)     X (XX%)   X (XX%) 
                                      <Reason 1>                X (XX%)     X (XX%)     X (XX%)   X (XX%) 
                                      <Reason 2>                X (XX%)     X (XX%)     X (XX%)   X (XX%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /CAXXXXX/sas_prg/stsas/tab PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 38 of 88 
 
    
                                                                                                                                 Page 1 of X 
 
Table 14.1.2  Demographic Summary (Safety Population) 
 
                                                                     Dose Level of E-WE Thrombin 
                                           Category/                ----------------------------- Placebo 
                         Trait             Statistics                1.5 µg/kg    3.0 µg/kg       (Pooled)   Overall                
                         --------------------------------------------------------------------------------------------- 
                         Sex                Male                       X ( XX%)     X ( XX%)       X (XX%)    X (XX%) 
                                            Female                     X ( XX%)     X ( XX%)       X (XX%)    X (XX%) 
 
 
                         Race               Asian                      X ( XX%)     X ( XX%)       X (XX%)    X (XX%) 
                                            Black or African           X ( XX%)     X ( XX%)       X (XX%)    X (XX%) 
                                            American       
                                            White                      X ( XX%)     X ( XX%)       X (XX%)    X (XX%) 
 
                         Ethnicity          Hispanic or Latino         X ( XX%)     X ( XX%)       X (XX%)    X (XX%) 
                                            Not Hispanic or Latino     X ( XX%)     X ( XX%)       X (XX%)    X (XX%) 
 
                         Age* (yrs)         n                                X            X              X         X 
                                            Mean                          XX.X         XX.X           XX.X      XX.X 
                                            SD                            X.XX         X.XX           X.XX      X.XX 
                                            Minimum                         XX           XX             XX        XX 
                                            Median                        XX.X         XX.X           XX.X      XX.X 
                                            Maximum                         XX           XX             XX        XX 
 
                         Weight (kg)        n                                X            X              X         X 
                                            Mean                          XX.X         XX.X           XX.X      XX.X 
                                            SD                            X.XX         X.XX           X.XX      X.XX 
                                            Minimum                         XX           XX             XX        XX 
                                            Median                        XX.X         XX.X           XX.X      XX.X 
                                            Maximum                         XX           XX             XX        XX 
 
Programmer Note:  This is just a mock table shell. Please use the race categories listed in the CRF. 
                  Please also include Height (cm) and BMI (kg/m2). 
 
 
 
 
Note: *Age is calculated at the time of informed consent. 
 
Program:  /CAXXXXX/sas_prg/stsas/tab PROGRAMNAME.sas  DDMMMYYYY  HH:MM 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 39 of 88 
 
 
Tables 14.2.1.1.1 through 14.2.1.1.3 will be in the following format:  
 
Table 14.2.1.1.1  Plasma APC-PCI Concentrations (unit) Following Administration of 1.5 µg/kg E-WE Thrombin – Day 1 (PD Population)       
 
Subject --------------------------------- Sample Times (hr) -------------------------------- 
 
Number Predose 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
------------------------------------------------------------------------------------------------------- 
X 
BLQ 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
X 
BLQ 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
X 
BLQ 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
------------------------------------------------------------------------------------------------------- 
n 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
CV% 
. 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
SEM 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Minimum 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
Maximum 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
------------------------------------------------------------------------------------------------------- 
For the calculation of summary statistics, values that are below the limit of quantitation (BLQ) of <X> ng/mL are treated as 0 
before the first quantifiable concentration and as missing elsewhere. 
. = Value missing or not reportable. 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 40 of 88 
 
Notes for Generating the Actual Table: 
 
• 
Please use CPConc1 template 
• 
Per study design needs, the following changes are made to this table relative to Celerion standard: columns <Treatment Sequence> and 
<Study Period> will be removed; 
• 
Concentrations will be presented to the same precision as in the bio data; 
• 
Summary statistics presentation with respect to the precision of the bio data or clinical laboratory data: n = integer; Mean and 
Median +1; SD and SEM +2, Minimum and Maximum +0, CV% to 1 decimal; 
• 
PK Time points are: predose (hour 0) and 0.167, 0.5, 1, 2, 4, 6, and 24 hours post E-WE Thrombin bolus dose; 
• 
For Table 14.2.1.1.3 there will be no summary statistics. 
 
 
Program:  /CAXXXXX/sas_prg/pksas/pk-conc-tables.sas    
DDMMMYYYY  HH:MM 
Program:  /CAXXXXX/sas_prg/pksas/pk-conc-tables-sig.sas   DDMMMYYYY  HH:MM 
Program:  /CAXXXXX/sas_prg/pksas/adam_conc.sas   
 
DDMMMYYYY  HH:MM 
  
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 41 of 88 
 
Tables 14.2.2.1 will be in the following format: 
 
                                                                                                                                               Page 1 of X 
 
  
  
 
 
Table 14.2.2.1  Summary of Clotting in Dialysis Venous Chamber Days -7 to 3 (PD Population) 
 
 
                                      1.5 µg/kg E-WE Thrombin     3.0 µg/kg E-WE Thrombin      Placebo (Pooled)            
                                   --------------------------- --------------------------- ---------------------------            
                                            Category*                    Category*                  Category*                     
                                   --------------------------- --------------------------- ---------------------------                                       
         Day       Time Point       1   2   3   4   5   6   7   1   2   3   4   5   6   7   1   2   3   4   5   6   7    
  -------------------------------------------------------------------------------------------------------------------- 
         Day -7    Post HD          X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X    
 
         Day -5    Post HD          X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X    
 
         Day -2    Post HD          X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X    
 
         Day 1     Post HD          X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X    
 
         Day 3     Post HD          X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X   X    
 
 
 
 
   Note: *Category:1 = No detectable clotting 
   2 = Presence of fibrinous ring or minimum clot affecting less than 5% of chamber space, 
                   3 = Clot formation (affecting more than 5% of but less than 25% of chamber space), 
                   4 = Clot formation (affecting more than 25% of but less than 50% of chamber space), 
                   5 = Clot formation (affecting more than 50% of but less than 75% of chamber space), 
                   6 = Clot formation (affecting more than 75% of chamber space), 
                   7 = Occluded (also assess the category of clot that caused occlusion) 
  HD: hemodialysis 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 42 of 88 
 
Tables 14.2.3.1 will be in the following format: 
 
                                                                                                                                               Page 1 of X 
 
  
 
 
 
 
Table 14.2.3.1  Summary of Clotting in the Dialysis Filter (Safety Population) 
 
 
                                   1.5 µg/kg E-WE Thrombin  3.0 µg/kg E-WE Thrombin       Placebo (Pooled)       
                                   ------------------------ ------------------------ ------------------------           
                                          Category*               Category*                  Category*                
                                   ------------------------ ------------------------ ------------------------                                     
         Day       Time Point       1   2   3   4   5   6     1   2   3   4   5   6    1   2   3   4   5   6   
  ----------------------------------------------------------------------------------------------------------- 
         Day -7    Post HD          X   X   X   X   X   X     X   X   X   X   X   X    X   X   X   X   X   X   
 
         Day -5    Post HD          X   X   X   X   X   X     X   X   X   X   X   X    X   X   X   X   X   X   
 
         Day -2    Post HD          X   X   X   X   X   X     X   X   X   X   X   X    X   X   X   X   X   X   
 
         Day 1     Post HD          X   X   X   X   X   X     X   X   X   X   X   X    X   X   X   X   X   X   
 
         Day 3     Post HD          X   X   X   X   X   X     X   X   X   X   X   X    X   X   X   X   X   X   
 
 
 
 
 
   Note: *Category:1 = No clotting, clean filter or few blood streaks (affecting less than 5% of the fibers seen at the surface of dialyzer), 
                   2 = Blood streaks affecting more than 5% but less than 25 % of the fibers seen at the surface of the dialyzer, 
                   3 = Blood streaks affecting more than 25% but less than 50 % of the fibers seen at the surface of the dialyzer, 
                   4 = Blood streaks affecting more than 50% but less than 75 % of the fibers seen at the surface of the dialyzer, 
                   5 = Blood streaks affecting more than 75% of the fibers seen at the surface if the dialyzer, 
                   6 = Occluded (also assess the category of streaking at the time of occlusion) 
  HD: hemodialysis 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 43 of 88 
 
Tables 14.2.4.1.1 through 14.2.4.1.3 will have the following format: 
 
Table 14.2.4.1.1 Individual and Mean Difference between Pre- and Post-dialysis BUN Values (unit) and URR – Days -7 to 3 – 1.5 µg/kg E-WE 
Thrombin on Day 1 (PD Population) 
 
                                         
 
 
 
 
 
 
 
 
 
 
<continue with HD Days -5, -2, 1 and 3>   
                                      ----------------------------------------------- 
Subject 
 
Pre- 
dialysis 
Post- 
dialysis Difference 
 
   URR 
 
 
 
 
 
Number 
Day 
(unit) 
(unit) 
(unit) 
    (%) 
 
 
 
 
    --------------------------------------------------------------------------------- 
X 
-7 
XXX 
X.XX 
XXX 
XXX 
 
 
 
 
X 
-7 
XX.X 
X.XX 
XXX 
XXX 
 
 
 
 
X 
-7 
XX.X 
X.XX 
XXX 
XXX 
 
 
 
 
X 
-7 
X.XX 
X.XX 
XXX 
XXX 
 
 
 
 
X 
-7 
XXX 
X.XX 
XXX 
XXX 
 
 
 
 
    --------------------------------------------------------------------------------- 
n 
XX 
XX 
XX 
XX 
XX 
 
 
 
 
Mean 
XXX.X 
XXX.X 
XXX.X 
X.XXX 
XXX.X 
 
 
 
 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
 
 
 
 
CV% 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
 
 
 
SEM 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
 
 
 
 
Minimum 
XX.X 
XX.X 
XX.X 
X.XX 
XXX 
 
 
 
 
Median 
XX.XX 
XX.XX 
XX.XX 
X.XXX 
XXX.X 
 
 
 
 
Maximum 
XXX 
XXX 
XXX 
X.XX 
XXX 
 
 
 
 
    ----------------------------------------------------------------------- 
1.5 µg/kg: On Day 1, 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total dose 
of 1.5 µg/kg 
 
Difference = Pre-dialysis - Post-dialysis 
 
footnotes: 
Difference = Pre-dialysis - Post-dialysis  
Single IV dose of 1.5 µg/kg E-WE Thrombin was administered on Day 1 
URR = (1-(post-dialysis BUN/ pre-dialysis BUN))*100 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 44 of 88 
 
Tables 14.2.5.1.1 through 14.2.5.1.3 will have the following format: 
 
Table 14.2.4.1.1 Individual and Mean Kt/V Values (unit) – 1.5 µg/kg E-WE Thrombin on Day 1 (PD Population) 
 
                                         
 
 
 
 
 
 
 
 
 
 
<continue with HD Days -5, -2, 1 and 3>   
                                      --------------------------------------------------------- 
Subject 
 
R 
    t 
    UF 
Wt 
Kt/V 
 
 
Number 
Day 
(unit) 
  (unit) 
(unit) 
(%) 
(unit) 
 
 
    ------------------------------------------------------------------------------------------- 
X 
-7 
XXX 
X.XX 
XXX 
XXX 
XXX 
 
 
X 
-7 
XX.X 
X.XX 
XXX 
XXX 
XXX 
 
 
X 
-7 
XX.X 
X.XX 
XXX 
XXX 
XXX 
 
 
X 
-7 
X.XX 
X.XX 
XXX 
XXX 
XXX 
 
 
X 
-7 
XXX 
X.XX 
XXX 
XXX 
XXX 
 
 
    ------------------------------------------------------------------------------------------- 
n 
XX 
XX 
XX 
XX 
XX 
XX 
 
 
Mean 
XXX.X 
XXX.X 
XXX.X 
X.XXX 
XXX.X 
XXX.X 
 
 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
 
 
CV% 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
 
SEM 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
 
 
Minimum 
XX.X 
XX.X 
XX.X 
X.XX 
XXX 
XXX 
 
 
Median 
XX.XX 
XX.XX 
XX.XX 
X.XXX 
XXX.X 
XXX.X 
 
 
Maximum 
XXX 
XXX 
XXX 
X.XX 
XXX 
XXX 
 
 
    ------------------------------------------------------------------------------------------- 
1.5 µg/kg: On Day 1, 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total dose 
of 1.5 µg/kg 
 
Footnotes: 
Single IV dose of 1.5 µg/kg E-WE Thrombin was administered on Day 1 
R = post-dialysis BUN/pre-dialysis BUN))*100 
t = Time of HD 
UF =  Pre-dialysis Weight – Post-dialysis Weight 
Wt = Post-dialysis weight of patient 
Kt/V = −ln(R −(0.008 × t)) + (4 −(3.5 × R)) ×
UF
Wt 
 
Program:  /CAXXXXX/sas_prg/pksas/xxxxxxxx.sas   DDMMMYYYY  HH:MM 
Program:  /CAXXXXX/sas_prg/pksas/xxxxxxxxx.sas   
DDMMMYYYY  HH:MM 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 45 of 88 
 
Page 1 of X 
 
Table 14.3.1.1 Treatment-Emergent Adverse Event Frequency by Treatment - Number of Subjects Reporting the Event  
(% of Subjects Dosed) (Safety Population) 
 
                                                                          
                                                   Dose Level of E-WE Thrombin 
                                                   --------------------------- Placebo 
     Adverse Event*                                 1.5 µg/kg    3.0 µg/kg     (Pooled)    Overall 
     ----------------------------------------------------------------------------------------------- 
     Number of Subjects Dosed                        XX ( XX%)    XX (XXX%)    XX ( XX%)   XX (XXX%) 
     Number of Subjects With TEAEs^                   X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
     Number of Subjects Without TEAEs^               XX ( XX%)    XX (XXX%)    XX ( XX%)   XX (XXX%) 
     ----------------------------------------------------------------------------------------------- 
     Nervous system disorders                         X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
          Dizziness                                   X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
          Headache                                    X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
          Presyncope                                  X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
     Respiratory, thoracic and mediastinal disorders  X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
          Dry throat                                  X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
          Oropharyngeal pain                          X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
          Sinus congestion                            X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
          Sneezing                                    X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
     General disorders and administration site        X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
     conditions 
          Fatigue                                     X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
          Thirst                                      X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
 
 
   
Note:  *Adverse events are classified according to MedDRA Version 21.1. ^ = Treatment-emergent adverse events 
        If a subject has 2 or more clinical adverse events, the subject is counted only once within a category. The same subject may appear  
        in different categories. 
 
Program:  /CAXXXXX/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 46 of 88 
 
Page 1 of X 
 
Table 14.3.1.2  Treatment-Emergent Adverse Event Frequency by Treatment - Number of Adverse Events  
(% of Total Adverse Events) (Safety Population) 
 
                                                           
                                                 
                                                   Dose Level of E-WE Thrombin 
                                                   --------------------------- Placebo 
     Adverse Event*                                 1.5 µg/kg    3.0 µg/kg     (Pooled)    Overall 
     ----------------------------------------------------------------------------------------------- 
     Number of TEAEs                                  X (100%)     X (100%)     X ( XX%)    X ( XX%) 
     ----------------------------------------------------------------------------------------------- 
     Nervous system disorders                         X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
          Dizziness                                   X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
          Headache                                    X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
          Presyncope                                  X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
     Respiratory, thoracic and mediastinal disorders  X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
          Dry throat                                  X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
          Oropharyngeal pain                          X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
          Sinus congestion                            X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
          Sneezing                                    X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
     General disorders and administration site        X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
     conditions 
          Fatigue                                     X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
          Thirst                                      X ( XX%)     X ( XX%)     X ( XX%)    X ( XX%) 
 
  
 
 
  
Note: *Adverse events are classified according to MedDRA Version 21.1. ^ = Treatment-emergent adverse events 
 
Program:  /CAXXXXX/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 47 of 88 
 
 
                                                                                                                       Page 1 of X 
 
Table 14.3.1.3  Treatment-Emergent Adverse Event Frequency by Treatment, Severity, and Relationship to Study Drug -  
Number of Adverse Events (Safety Population) 
 
 
                                                                  Severity                        Relationship to Study Drug 
                                 Number of   Number   -------------------------------  ----------------------------------------------- 
                       Cohort/   Subjects     of                        
 Adverse Event*        Treatment With TEAEs  TEAEs    Grade 1 Grade 2 Grade 3 Grade 4  Unrelated Unlikely Possibly  Probably  Likely 
 ------------------------------------------------------------------------------------------------------------------------------------      
 Dizziness               1/A       X           X         X       X      X       X        X          X         X        X        X 
                         X/X       X           X         X       X      X       X        X          X         X        X        X 
 Dry eye                 X/X       X           X         X       X      X       X        X          X         X        X        X  
 Dry mouth               X/X       X           X         X       X      X       X        X          X         X        X        X 
 Dry throat              X/X       X           X         X       X      X       X        X          X         X        X        X 
 Ear pain                X/X       X           X         X       X      X       X        X          X         X        X        X 
 Fatigue                 X/X       X           X         X       X      X       X        X          X         X        X        X 
 Headache                X/X       X           X         X       X      X       X        X          X         X        X        X 
 Dizziness               X/X       X           X         X       X      X       X        X          X         X        X        X 
 Hyperhidrosis           X/X       X           X         X       X      X       X        X          X         X        X        X 
 Laceration              X/X       X           X         X       X      X       X        X          X         X        X        X 
 Limb crushing injury    X/X       X           X         X       X      X       X        X          X         X        X        X 
 Muscle twitching        X/X       X           X         X       X      X       X        X          X         X        X        X 
 ------------------------------------------------------------------------------------------------------------------------------------ 
 1.5 µg/kg E-WE Thrombin           X           X         X       X      X       X        X          X         X        X        X 
 3.0 µg/kg E-WE Thrombin           X           X         X       X      X       X        X          X         X        X        X 
 Placebo (Pooled)                  X           X         X       X      X       X        X          X         X        X        X 
 Overall                          XX          XX         X       X      X       X        X          X         X        X        X 
 ------------------------------------------------------------------------------------------------------------------------------------ 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
     B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
         P = Placebo 
*Adverse events are classified according to MedDRA Version 21.1. TEAE = Treatment-emergent adverse events 
        If a subject experience the same adverse event (AE) at more than one level of severity during a treatment, each AE is counted  
        separately. If a subject experience the same AE at more than one level of drug relationship during a treatment, each AE is  
        counted separately. 
        Severity: Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially life-threatening 
 
Program:  /CAXXXXX/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 48 of 88 
 
Tables 14.3.4.1 to 14.3.4.3 will have the following format: 
Page 1 of X 
                
                   Table 14.3.4.1  Out-of-Range Values and Clinically Significant Results - Serum Chemistry (Safety Population) 
  
                                                                   Parameter1  Parameter2   Parameter3  Parameter4   Parameter5  
 Subject Cohort/    Age#/  Study                                     <Range>     <Range>      <Range>      <Range>     <Range>   
 Number  Treatment  Sex    Visit       Hour    Date       Time       (Unit)      (Unit)       (Unit)      (Unit)       (Unit)   
---------------------------------------------------------------------------------------------------------------------------------------- 
   X        1/A     XX/X   Screen      .       DDMMMYYYY  HH:MM:SS    XX H +                                             XX L   
                           Day X       XX      DDMMMYYYY  HH:MM:SS    XX L        XX L        XX H          XX L              
                           Unscheduled         DDMMMYYYY  HH:MM:SS                                          XX              
 
 
Programmer Notes:  Replace Parameter1, 2 etc. with actual lab tests in the study. Sort unscheduled assessment and early termination 
chronologically with other scheduled assessments.  
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
     B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                     dose of 3.0 µg/kg 
         P = Placebo 
       #Age is calculated at the time of first dosing. F = Female; M = Male  
       H = Above reference range, L = Below reference range                                                                     
       PI Interpretation: + = Clinically significant 
 
Program:  /CAXXXXX/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 49 of 88 
 
Tables 14.3.5.1 and 14.3.5.3 will be in the following format: 
                                                                                                             Page 1 of X 
Table 14.3.5.1  Clinical Laboratory Summary and Change from Baseline - Serum Chemistry (Safety Population) 
 
                                                                  Dose Level of E-WE Thrombin      Change from Baseline* 
                                                                  ---------------------------    --------------------------- 
    Laboratory Test   Reference                                        1.5      3.0    Placebo    1.5     3.0      Placebo       
    (unit)            Range       Time Point          Statistic      µg/kg    µg/kg   (Pooled)   µg/kg   µg/kg    (Pooled)  
    ------------------------------------------------------------------------------------------------------------------------  
    XXXXXXXXX (unit)  X.X-XX.X#   Screen              n                  XX       XX       XX     
                                                      Mean             X.XX     X.XX     X.XX     
                                                      SD              X.XXX    X.XXX    X.XXX    
                                                      Minimum          X.XX     X.XX     X.XX     
                                                      Median            X.X      X.X      X.X     
                                                      Maximum          XX.X     XX.X     XX.X     
 
                                  Baseline*           n                  XX       XX       XX     
                                                      Mean             X.XX     X.XX     X.XX     
                                                      SD              X.XXX    X.XXX    X.XXX    
                                                      Minimum          X.XX     X.XX     X.XX     
                                                      Median            X.X      X.X      X.X     
                                                      Maximum          XX.X     XX.X     XX.X     
 
                                  Day X, Hour X.XX    n                  XX       XX       XX      XX       XX       XX 
                                                      Mean             X.XX     X.XX     X.XX    X.XX     X.XX     X.XX 
                                                      SD              X.XXX    X.XXX    X.XXX   X.XXX    X.XXX    X.XXX 
                                                      Minimum          X.XX     X.XX     X.XX    X.XX     X.XX     X.XX 
                                                      Median            X.X      X.X      X.X     X.X      X.X      X.X 
                                                      Maximum          XX.X     XX.X     XX.X    XX.X     XX.X     XX.X 
 
                                 <include all timepoints>       
 
Note:  # = Lowest of the lower ranges and highest of the higher ranges are used. Refer to Appendix 16.1.10.1 for the breakdown. 
       * Baseline is defined as the result closest and prior to dose on Day 1. 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 50 of 88 
 
Tables 14.3.5.2 and 14.3.5.4 will be in the following format: 
Page 1 of X 
 
Table 14.3.5.2  Clinical Laboratory Shift From Baseline - Serum Chemistry (Safety Population)  
 
                                                      
                                                          Baseline* L                      Baseline* N                      Baseline* H 
Laboratory Test                                    -------------------------------   -----------------------------   ------------------------------ 
(unit)            Treatment       Time Point          L         N          H            L         N          H          L          N          H  
-------------------------------------------------- -------------------------------   -----------------------------   ------------------------------ 
XXXXXXX (unit)    XXX <units>   Day X, Hour X.XX     X         XX          X           X         XX         X          X          XX         X  
 
 
 
 
 
 
 
 
 
 
 
Note:  1.5 µg/kg: 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
                  dose of 1.5 µg/kg 
       3.0 µg/kg: 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                  dose of 3.0 µg/kg 
       Placebo = pooled placebo  
   N = Within Normal Range, L = Below Normal Range, H = Above Normal Range 
       * Baseline is defined as the result closest and prior to dose on Day 1. 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 51 of 88 
 
                                                                                                             Page 1 of X 
Table 14.3.5.5  Clinical Laboratory Summary – Coagulation and Platelet Count (Safety Population) 
 
                                                  1.5 µg/kg E-WE Thrombin  3.0 µg/kg E-WE Thrombin    Placebo (Pooled)  
                                                  -----------------------  -----------------------  -----------------------  
Laboratory Test   Reference    Time                                 Fold                     Fold                     Fold    
(unit)            Range       Point    Statistic  Pre-HD  Post-HD  Change  Pre-HD  Post-HD  Change  Pre-HD  Post-HD  Change  
---------------------------------------------------------------------------------------------------------------------------- 
XXXXXXXXX (unit)  X.X-XX.X#   Screen   n             XX                       XX                       XX     
                                       Mean        X.XX                     X.XX                     X.XX     
                                       SD         X.XXX                    X.XXX                    X.XXX     
                                       Minimum     X.XX                     X.XX                     X.XX     
                                       Median       X.X                      X.X                      X.X     
                                       Maximum     XX.X                     XX.X                     XX.X     
 
                              Day -8   n             XX                       XX                       XX     
                                       Mean        X.XX                     X.XX                     X.XX     
                                       SD         X.XXX                    X.XXX                    X.XXX     
                                       Minimum     X.XX                     X.XX                     X.XX     
                                       Median       X.X                      X.X                      X.X     
                                       Maximum     XX.X                     XX.X                     XX.X     
 
                              Day X    n             XX      XX       XX      XX      XX       XX      XX      XX       XX   
                                       Mean        X.XX    X.XX     X.XX    X.XX    X.XX     X.XX    X.XX    X.XX     X.XX   
                                       SD         X.XXX   X.XXX    X.XXX   X.XXX   X.XXX    X.XXX   X.XXX   X.XXX    X.XXX   
                                       Minimum     X.XX    X.XX     X.XX    X.XX    X.XX     X.XX    X.XX    X.XX     X.XX   
                                       Median       X.X     X.X      X.X     X.X     X.X      X.X     X.X     X.X      X.X   
                                       Maximum     XX.X    XX.X     XX.X    XX.X    XX.X     XX.X    XX.X    XX.X     XX.X   
 
                             <include all remaining HD days>       
 
Programmer note:  This table will include aPTT, PT, INR, PT/INR, fibrinogen, TT from coagulation and platelet count form hematology. 
for PT, INR and PT/INR, the pre-dialysis value will be the baseline value for that day and the “change from baseline” will be the fold 
change from baseline “ie. Post-dialysis / Pre-dialysis. 
 
Note:  # = Lowest of the lower ranges and highest of the higher ranges are used. Refer to Appendix 16.1.10.1 for the breakdown. 
       Fold change = Post-dialysis / Pre-dialysis 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 52 of 88 
 
 
                                                                                                                                               Page 1 of X 
 
                            Table 14.3.5.6  Vital Sign Summary and Change from Baseline(Safety Population) 
 
 
                                                         Dose Level of E-WE Thrombin     Change from Baseline* 
                                                         ---------------------------  --------------------------- 
                                                            1.5       3.0   Placebo     1.5      3.0    Placebo        
    Vital Sign(unit)      Time Point          Statistic    µg/kg     µg/kg  (Pooled)   µg/kg    µg/kg   (Pooled) 
    ------------------------------------------------------------------------------------------------------------- 
    XXXXXXXXX (unit)      Screen              n               XX        XX       XX    
                                              Mean          X.XX      X.XX     X.XX    
                                              SD           X.XXX     X.XXX    X.XXX    
                                              Minimum       X.XX      X.XX     X.XX    
                                              Median         X.X       X.X      X.X    
                                              Maximum       XX.X      XX.X     XX.X    
 
                          <Also include Days -8, -7, -5 and -2> 
 
                          Baseline*           n               XX        XX       XX    
                                              Mean          X.XX      X.XX     X.XX    
                                              SD           X.XXX     X.XXX    X.XXX    
                                              Minimum       X.XX      X.XX     X.XX    
                                              Median         X.X       X.X      X.X    
                                              Maximum       XX.X      XX.X     XX.X    
 
                          Day X, Hour X.XX    n               XX        XX       XX      XX        XX       XX 
                                              Mean          X.XX      X.XX     X.XX    X.XX      X.XX     X.XX 
                                              SD           X.XXX     X.XXX    X.XXX   X.XXX     X.XXX    X.XXX 
                                              Minimum       X.XX      X.XX     X.XX    X.XX      X.XX     X.XX 
                                              Median         X.X       X.X      X.X     X.X       X.X      X.X 
                                              Maximum       XX.X      XX.X     XX.X    XX.X      XX.X     XX.X 
 
 
Note: * Baseline is defined as the result closest and prior to the dose on Day 1. 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 53 of 88 
 
                                                                                                                                               Page 1 of X 
 
    Table 14.3.5.7 Summarization of Weight (Safety Population)  
 
 
 
                                     Dose Level of E-WE Thrombin  
                                     ---------------------------  
                                        1.5       3.0   Placebo       
      Time Point          Statistic    µg/kg     µg/kg  (Pooled)  
    ------------------------------------------------------------- 
      Screen              n               XX        XX       XX   
                          Mean          X.XX      X.XX     X.XX   
                          SD           X.XXX     X.XXX    X.XXX   
                          Minimum       X.XX      X.XX     X.XX   
                          Median         X.X       X.X      X.X   
                          Maximum       XX.X      XX.X     XX.X   
 
      Day -8, Check-in    n               XX        XX       XX   
                          Mean          X.XX      X.XX     X.XX   
                          SD           X.XXX     X.XXX    X.XXX   
                          Minimum       X.XX      X.XX     X.XX   
                          Median         X.X       X.X      X.X   
                          Maximum       XX.X      XX.X     XX.X   
 
      Day -7, Before HD   n               XX        XX       XX   
                          Mean          X.XX      X.XX     X.XX   
                          SD           X.XXX     X.XXX    X.XXX   
                          Minimum       X.XX      X.XX     X.XX   
                          Median         X.X       X.X      X.X   
                          Maximum       XX.X      XX.X     XX.X   
 
      <Also include before and after HD timepoints on Days -7, -5, -2, 1 and 3> 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 54 of 88 
 
                                                                                                                                               Page 1 of X 
 
         
Table 14.3.5.8  12-Lead Electrocardiogram Summary and Change from Baseline (Safety Population) 
 
                                                                                                          
                                                         Dose Level of E-WE Thrombin     Change from Baseline* 
                                                         ---------------------------  --------------------------- 
                                                            1.5       3.0   Placebo     1.5      3.0    Placebo        
    Measurement(unit)     Time Point          Statistic    µg/kg     µg/kg  (Pooled)   µg/kg    µg/kg   (Pooled) 
    ------------------------------------------------------------------------------------------------------------- 
    XXXXXXXXX (unit)      Screen              n               XX        XX       XX    
                                              Mean          X.XX      X.XX     X.XX    
                                              SD           X.XXX     X.XXX    X.XXX    
                                              Minimum       X.XX      X.XX     X.XX    
                                              Median         X.X       X.X      X.X    
                                              Maximum       XX.X      XX.X     XX.X    
 
                          Day -8 Check-in*    n               XX        XX       XX    
                                              Mean          X.XX      X.XX     X.XX    
                                              SD           X.XXX     X.XXX    X.XXX    
                                              Minimum       X.XX      X.XX     X.XX    
                                              Median         X.X       X.X      X.X    
                                              Maximum       XX.X      XX.X     XX.X    
 
                          Day 1, Hour X.XX    n               XX        XX       XX      XX        XX       XX 
                                              Mean          X.XX      X.XX     X.XX    X.XX      X.XX     X.XX 
                                              SD           X.XXX     X.XXX    X.XXX   X.XXX     X.XXX    X.XXX 
                                              Minimum       X.XX      X.XX     X.XX    X.XX      X.XX     X.XX 
                                              Median         X.X       X.X      X.X     X.X       X.X      X.X 
                                              Maximum       XX.X      XX.X     XX.X    XX.X      XX.X     XX.X 
 
                          Day 3, Hour X.XX    n               XX        XX       XX      XX        XX       XX 
                                              Mean          X.XX      X.XX     X.XX    X.XX      X.XX     X.XX 
                                              SD           X.XXX     X.XXX    X.XXX   X.XXX     X.XXX    X.XXX 
                                              Minimum       X.XX      X.XX     X.XX    X.XX      X.XX     X.XX 
                                              Median         X.X       X.X      X.X     X.X       X.X      X.X 
                                              Maximum       XX.X      XX.X     XX.X    XX.X      XX.X     XX.X 
 
 
Note: * Baseline is Day -8 Check-in. 
                       
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 55 of 88 
 
                                                                                                                                               Page 1 of X 
 
Table 14.3.5.9 Summarization of Bleeding Time (Safety Population) 
 
 
                                     Dose Level of E-WE Thrombin  
                                     ---------------------------  
                                        1.5       3.0   Placebo       
      Time Point          Statistic    µg/kg     µg/kg  (Pooled)  
    ------------------------------------------------------------- 
      Day -7              n               XX        XX       XX   
                          Mean          X.XX      X.XX     X.XX   
                          SD           X.XXX     X.XXX    X.XXX   
                          Minimum       X.XX      X.XX     X.XX   
                          Median         X.X       X.X      X.X   
                          Maximum       XX.X      XX.X     XX.X   
 
      Day -5              n               XX        XX       XX   
                          Mean          X.XX      X.XX     X.XX   
                          SD           X.XXX     X.XXX    X.XXX   
                          Minimum       X.XX      X.XX     X.XX   
                          Median         X.X       X.X      X.X   
                          Maximum       XX.X      XX.X     XX.X   
 
      Day -2              n               XX        XX       XX   
                          Mean          X.XX      X.XX     X.XX   
                          SD           X.XXX     X.XXX    X.XXX   
                          Minimum       X.XX      X.XX     X.XX   
                          Median         X.X       X.X      X.X   
                          Maximum       XX.X      XX.X     XX.X   
 
      <Also include Days 1 and 3> 
 
Programmer note: Bleeding time is recorded on the Dialyzer Assessment CRF page under item #4 as length of time of pressure on puncture site. 
 
Note:  Bleeding time in minutes was assessed immediately after the end of hemodialysis  
       and removal of the needles from the fistula or graft.  
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 56 of 88 
 
11. LISTING SHELLS 
The following listing shells provide a framework for the display of data from this study. The 
shells may change due to unforeseen circumstances. These shells may not be reflective of 
every aspect of this study, but are intended to show the general layout of the listings that will 
be presented and included in the final CSR. These listings will be generated off of the 
Celerion SDTM datasets (SDTM Tabulation Model 1.4 mapped in accordance with SDTM 
Implementation Guide 3.2). All listings will be presented in Courier New font size 9. 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 57 of 88 
 
Page 1 of X 
 
                                   Appendix 16.1.10.1  Clinical Laboratory Reference Ranges  
 
                                                                                           Reference 
        Laboratory Group           Test Name                     Sex         Age Category  Range           Unit      
        -------------------------------------------------------------------------------------------------------- 
        Serum Chemistry            Test Name                     XXXXXX      XX            XX – XX         units 
                                   Test Name                     XXXXXX      XX            XX – XX         units 
                                   Test Name                     XXXXXX      XX            XX – XX         units 
                                   Test Name                     XXXXXX      XX            XX – XX         units 
                                   Test Name                     XXXXXX      XX            XX – XX         units 
                                   Test Name                     XXXXXX      XX            XX – XX         units 
                                                                                                                     
        Hematology                 Test Name                     XXXXXX      XX            XX – XX         units 
                                   Test Name                     XXXXXX      XX            XX – XX         units 
                                   Test Name                     XXXXXX      XX            XX – XX         units 
                                   Test Name                     XXXXXX      XX            XX – XX         units 
                                   Test Name                     XXXXXX      XX            XX – XX         units 
 
 
 
<similar for remaining Laboratory Groups and Test Names> 
 
 
 
 
 
Programmer note:  Please add a column for site ID if multiple sites are used. 
 
 
 
 
 
 
 
 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 58 of 88 
 
 
                                                                                                                                 Page 1 of X 
 
           
 
 
 
Appendix 16.2.1  Study Completion/Early Termination (Safety Population) 
 
               Subject  Cohort/    Completed                Date of   
               Number   Treatment  Study?      Date       Last Contact  Reason for Discontinuation  Comments 
              ------------------------------------------------------------------------------------------------------------- 
                    X      1/A     Yes        DDMMMYYYY    DDMMMYYYY    
                    X      1/A     Yes        DDMMMYYYY    DDMMMYYYY    
                    X      1/P     Yes        DDMMMYYYY    DDMMMYYYY    
                    X      1/A     Yes        DDMMMYYYY    DDMMMYYYY    
                    X      1/A     No         DDMMMYYYY    DDMMMYYYY     XXXXXXXXXXXXXX             XXXXXXXX 
                    X      1/P     Yes        DDMMMYYYY    DDMMMYYYY    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
     B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                     dose of 3.0 µg/kg 
                 P = Placebo 
 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 59 of 88 
 
                                                                                                                                 Page 1 of X 
 
                                              Appendix 16.2.4.1  Demographics (Safety Population) 
                                                                                                                                
                                                                                                           Body Mass   Informed                    
        Subject  Cohort/     Date of      Age*                                         Height    Weight      Index      Consent 
        Number   Treatment   Birth       (yrs)    Gender    Race        Ethnicity      (cm)      (kg)       (kg/m2)       Date 
       -------------------------------------------------------------------------------------------------------------------------- 
          X         1/A      MMMYYYY       XX     AAAAAA    AAAAAAAA    AAAAAAAAAA      XXX      XX.XX       XX.XX     DDMMMYYYY 
          X         1/A      MMMYYYY       XX     AAAAAA    AAAAAAAA    AAAAAAAAAA      XXX      XX.XX       XX.XX     DDMMMYYYY 
          X         1/P      MMMYYYY       XX     AAAAAA    AAAAAAAA    AAAAAAAAAA      XXX      XX.XX       XX.XX     DDMMMYYYY 
 
 
 
 
 
 
 
 
 
 
 
 
Note: *Age is calculated from the date of informed consent. 
Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
               dose of 1.5 µg/kg  
       B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                       dose of 3.0 µg/kg 
                   P = Placebo 
  
       
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 60 of 88 
 
Page 1 of X 
 
 
Appendix 16.2.4.2  Physical Examination (Safety Population) 
 
  
     Subject  Cohort/     Study    Study                                                                       Clinical     
     Number   Treatment   Visit    Time     Date        Body System            Result   Abnormality            Significance 
  ----------------------------------------------------------------------------------------------------------------------------- 
       X        1/A       Screen            DDMMMYYYY   1. General Appearance  Abnormal XXXXXXXXXXXXXXXXXXXXX    NCS      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
     B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                     dose of 3.0 µg/kg 
                 P = Placebo 
  
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 61 of 88 
 
 
                                                                                                                                 Page 1 of X 
 
 
                      Appendix 16.2.4.3  Medical and Surgical Histories (Safety Population) 
  
 
                                                      Date of Diagnosis/Surgery 
 Subject  Cohort/                                     -------------------------                                         
 Number   Treatment  Seq # Description                   Start           End          Ongoing?                            
------------------------------------------------------------------------------------------------------ 
    X       1/A       X    XXXXXX  XXXXX XXXXXXX        MMYYYY                         Yes                                   
                      X    XXXXXXXXX                    MMMYYYY        MMMYYYY         No 
                      X    XXXXXXXX XXXXX XXXXXX        MMMYYYY        MMMYYYY         No   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
                     dose of 1.5 µg/kg  
             B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                             dose of 3.0 µg/kg 
                         P = Placebo 
 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 62 of 88 
 
 
 
                                                                                                                                 Page 1 of X 
 
 
         Appendix 16.2.4.4  
Alcohol Screen (Safety Population) 
  
 
                                                      
  Subject  Cohort/    Study   Visit                          Actual                                           
  Number   Treatment  Visit   Date        Type of Sample     Time      Result                           
----------------------------------------------------------------------------------------- 
     X      1/A       Screen  DDMMMYYYY      Breath          HH:MM     Negative                                   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 63 of 88 
 
 
                                                                                                                                 Page 1 of X 
 
 
           
 
 
 
Appendix 16.2.4.5  
Saliva Drug Screen (Safety Population) 
  
 
                                                      
 Subject  Cohort/    Study     Visit      Actual                                           
 Number   Treatment  Visit     Date        Time     Result    If Positive, list all that were positive:                       
---------------------------------------------------------------------------------------------------------- 
    X       1/A      Screen    DDMMMYYYY   HH:MM    Negative                                   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
     B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                     dose of 3.0 µg/kg 
                 P = Placebo 
 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 64 of 88 
 
 
 
Appendix 16.2.4.6  
Tobacco Use (Safety Population) 
 
 
 
                                                                    
        Subject  Cohort/     Visit        Tobacco        Start       Stop   
        Number   Treatment   Date         Use            Date        Date    
       --------------------------------------------------------------------------- 
          X         1/A      DDMMMYYYY    Never Used      
          X         1/A      DDMMMYYYY    Former User    DDMMMYYYY   DDMMMYYYY 
          X         1/P      DDMMMYYYY    Current User   DDMMMYYYY    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
                     dose of 1.5 µg/kg  
             B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                             dose of 3.0 µg/kg 
                         P = Placebo 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 65 of 88 
 
 
 
                                                                                                                               Page 1 of X 
 
                                           Appendix 16.2.5.1  Subject Eligibility at Screening (Safety Population) 
  
                     
              Subject  Cohort/   Study     Visit             Did subject meet 
              Number   Treatment Visit     Date         all eligibility criteria?    Criterion Not Met       Specify  
             ---------------------------------------------------------------------------------------------------------------------- 
                X         1/A    Screen    DDMMMYYYY              Yes         
                X         1/A    Screen    DDMMMYYYY              Yes  
                X         1/P    Screen    DDMMMYYYY              No                  EXCLUSION X            XXXXXXXXXXXXXXX XXXX        
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
                     dose of 1.5 µg/kg  
             B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                             dose of 3.0 µg/kg 
                         P = Placebo 
 
                                                                      
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 66 of 88 
 
                                                                                                                               Page 1 of X 
 
                                           Appendix 16.2.5.2  Subject Eligibility at Check-In (Safety Population) 
  
                                 
              Subject Cohort/    Study                      Does subject continue to meet 
              Number  Treatment  Visit            Date         criteria since Screening?        If No, specify  
             --------------------------------------------------------------------------------------------------------------------- 
                X        1/A     Day -8 Check-In  DDMMMYYYY              Yes         
 
 
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
                                                                      
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 67 of 88 
 
 
                                                                                                                                 Page 1 of X 
 
                               Appendix 16.2.5.3  Test Compound Administration (Safety Population) 
 
                                                                  Bolus           Dosing    Dosing 
  Subject  Cohort/    Study    Study                   Dose       Administration  Start     End                                                              
  Number   Treatment  Visit    Time      Date      Administered?  Time            Time      Time        Route        Form      Frequency                 
----------------------------------------------------------------------------------------------------------------------------------------- 
    X       1/A        Day 1   Hour 0  DDMMMYYYY      Yes         HH:MM:SS        HH:MM:SS  HH:MM:SS  IV Infusion   Injection    Once       
  
                                                                                              
 
  
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
 
 
 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 68 of 88 
 
                                                                                                                                 Page 1 of X 
 
Appendix 16.2.5.4 Blood Draw Times for E-WE Thrombin PD (APC-PCI) (Safety Population) 
  
 Subject  Cohort/    Study   Study    Collection   Actual                                         
 Number   Treatment   Day    Hour     Date         Time       Comments                                      
----------------------------------------------------------------------------------------- 
   X        1/A        X    Predose   DDMMMYYYY    XX:XX    XXXXXXXXXXX                                  
                            XX.XX     DDMMMYYYY    XX:XX                                            
                            XX.XX     DDMMMYYYY    XX:XX                                         
                            XX.XX     DDMMMYYYY    XX:XX    XXXXXXXXXX                                 
                            XX.XX     DDMMMYYYY    XX:XX                                                  
                            XX.XX     DDMMMYYYY    XX:XX                              
                            XX.XX     DDMMMYYYY    XX:XX                              
                      X     XX.XX     DDMMMYYYY    XX:XX   
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 69 of 88 
 
                                                                                                                                 Page 1 of X 
 
Appendix 16.2.5.5 Blood Draw Times for Protein C (Safety Population) 
  
 Subject  Cohort/    Study   Study    Collection   Actual                                         
 Number   Treatment   Day    Hour     Date         Time       Comments                                      
----------------------------------------------------------------------------------------- 
   X        1/A       -7    Start HD  DDMMMYYYY    HH:MM    XXXXXXXXXXX                                  
                            End HD                 HH:MM 
                      -5    Start HD  DDMMMYYYY    XX:XX                                            
                            End HD                 HH:MM 
                      -2    Start HD  DDMMMYYYY    XX:XX                                         
                            End HD                 HH:MM 
                       1    Predose   DDMMMYYYY    XX:XX    XXXXXXXXXX                                 
                            XX.XX     DDMMMYYYY    XX:XX                                                  
                            XX.XX     DDMMMYYYY    XX:XX                              
                            XX.XX     DDMMMYYYY    XX:XX                              
                            XX.XX     DDMMMYYYY    XX:XX                                                  
                            XX.XX     DDMMMYYYY    XX:XX                              
                            XX.XX     DDMMMYYYY    XX:XX                              
                       2    XX.XX     DDMMMYYYY    XX:XX   
                       3    Start HD  DDMMMYYYY    XX:XX   
                            End HD                 HH:MM 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 70 of 88 
 
                                                                                                                                 Page 1 of X 
 
Appendix 16.2.5.6 Blood Draw Times for Immunogenicity (Safety Population) 
  
 Subject  Cohort/    Study  Study     Collection   Actual                                         
 Number   Treatment   Day   Hour      Date         Time       Comments                                      
-------------------------------------------------------------------------------------- 
   X        1/A        1    Predose   DDMMMYYYY    HH:MM      XXXXXXXXXXX                                  
                      14    Follow-up DDMMMYYYY    HH:MM                                            
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 71 of 88 
 
                                                                                                                                Page 1 of X 
 
Appendix 16.2.5.7 Blood Draw Times for Dialysate Analysis for Kt/V and URR (Safety Population) 
  
 Subject  Cohort/   Study    Study      Collection   Actual                                         
 Number   Treatment  Day     Hour       Date         Time       Comments                                      
-------------------------------------------------------------------------------------- 
   X        1/A       -7     Pre HD     DDMMMYYYY    HH:MM      XXXXXXXXXXX                                  
                             End of HD  DDMMMYYYY    HH:MM                                            
                      -5     Pre HD     DDMMMYYYY    HH:MM                                            
                             End of HD  DDMMMYYYY    HH:MM                                            
                      -2     Pre HD     DDMMMYYYY    HH:MM                                            
                             End of HD  DDMMMYYYY    HH:MM                                            
                       1     Pre HD     DDMMMYYYY    HH:MM                                            
                             End of HD  DDMMMYYYY    HH:MM                                            
                       3     Pre HD     DDMMMYYYY    HH:MM                                            
                             End of HD  DDMMMYYYY    HH:MM                                            
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
      HD = Hemodialysis 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 72 of 88 
 
                                                                                                                                 Page 1 of X 
 
Appendix 16.2.5.8 Dialysate Collection (Safety Population) 
  
 
Subject  Cohort/    Study    Study                     Collection   Actual                                         
 Number  Treatment   Day     Hour                      Date         Time       Comments                                      
-------------------------------------------------------------------------------------------------- 
   X        1/A       -7    30 min after start of HD   DDMMMYYYY    HH:MM      XXXXXXXXXXX                                  
                            3 hours after start of HD  DDMMMYYYY    HH:MM                                            
                      -5    30 min after start of HD   DDMMMYYYY    HH:MM                                            
                            3 hours after start of HD  DDMMMYYYY    HH:MM                                            
                      -2    30 min after start of HD   DDMMMYYYY    HH:MM                                            
                            3 hours after start of HD  DDMMMYYYY    HH:MM                                            
                       1    30 min after start of HD   DDMMMYYYY    HH:MM                                            
                            3 hours after start of HD  DDMMMYYYY    HH:MM                                            
                       3    30 min after start of HD   DDMMMYYYY    HH:MM                                            
                            3 hours after start of HD  DDMMMYYYY    HH:MM                                            
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
     B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                 P = Placebo 
      HD = Hemodialysis 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 73 of 88 
 
                                                                                                                                Page 1 of X 
 
Appendix 16.2.5.9.1 Dialyzer Assessment (I of V) – Hemodialysis Start and End Times( Safety Population) 
 
                             Hemodialysis 
 Subject  Cohort/    Study   ------------  Interrupted                                                             
 Number   Treatment   Day    Start  End    Prematurely?  Reason for Interruption   Specify                                      
--------------------------------------------------------------------------------------------------- 
   X         1/A       X     HH:MM HH:MM     Yes         XXXXXXXXXXXXXX            XXXXXXXXXX       
           
           
 
 
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 74 of 88 
 
                                                                                                                                 Page 1 of X 
 
Appendix 16.2.5.9.2 Dialyzer Assessment (II of V) -  Circuit Arterial and Venous Pressure and Blood Flow Rate(Safety Population) 
 
                           Time                                         Blood                       Dialysis/                      Ultra 
                           Relative  Arterial Pressure Venous Pressure  Flow   Time to Hemostasis   Venous        Dialysis Filter/ 
Filtration 
 Subject  Cohort/   Study  To         ---------------  --------------   Rate   -------------------  Chamber       Venous Chamber   Volume                    
 Number   Treatment  Day   Dialysis   Time     mmHg    Time    mmHg    mL/min  Time   Length (min)  Photographed?  Collected?      (mL)                      
-------------------------------------------------------------------------------------------------------------------------------------------- 
   X         1/A       X    0 Hour    HH:MM     XX     HH:MM    XX      XX    HH:MM     XX             Yes           Yes           XXX 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 75 of 88 
 
                                                                                                                                 Page 1 of X 
 
Appendix 16.2.5.9.3 Dialyzer Assessment (III of V) - Number and Volume of Saline Flushes(Safety Population) 
 
 
 
                             Saline   Time 
 Subject  Cohort/    Study   Flush     of    Volume     Total Volume        Total Number                                           
 Number   Treatment   Day    Number   Flush   (mL)      of Flushes (mL)      of Flushes                     
-------------------------------------------------------------------------------------- 
   X        1/A        X        1    HH:MM    XX          XXX                   XX 
                                2    HH:MM    XX      
                                3    HH:MM    XX      
                                4    HH:MM    XX      
                                5    HH:MM    XX      
                                6    HH:MM    XX      
 
 
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 76 of 88 
 
                                                                                                                                 Page 1 of X 
 
Appendix 16.2.5.9.4 Dialyzer Assessment (IV of V) – Clotting in Dialysis Venous Chamber (Safety Population) 
 
 
 
                                   Venous Chamber #1                Venous Chamber #2 (if needed)           
                           -----------------------------------  ----------------------------------- 
                                         Category*                            Category*             
 Subject  Cohort/   Study          ---------------------------          ---------------------------                                 
 Number   Treatment  Day   Time     1   2   3   4   5   6   7   Time     1   2   3   4   5   6   7  
--------------------------------------------------------------------------------------------------- 
   X        1/A       X    HH:MM    X   X   X   X   X   X   X   HH:MM    X   X   X   X   X   X   X  
 
                       
                       
                       
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
      *Category:1 = No detectable clotting, 2 = Presence of fibrinous ring or minimum clot affecting less than 5% of chamber space, 
                3 = Clot formation (affecting more than 5% of but less than 25% of chamber space), 
                4 = Clot formation (affecting more than 25% of but less than 50% of chamber space), 
                5 = Clot formation (affecting more than 50% of but less than 75% of chamber space), 
                6 = Clot formation (affecting more than 75% of chamber space), 
                7 = Occluded (also assess the category of clot that caused occlusion) 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 77 of 88 
 
                                                                                                                                 Page 1 of X 
 
Appendix 16.2.5.9.5 Dialyzer Assessment (V of V) – Clotting in Dialysis Filter (Safety Population) 
 
 
 
                                           End of Dialysis (or premature interruption) 
                            ------------------------------------------------------------------------ 
                                Dialysis Filter #1                 Dialysis Filter #2 (if needed) 
                            -----------------------------------  ----------------------------------- 
                                             Category*                            Category* 
Subject  Cohort/   Study             --------------------------           --------------------------                                
Number   Treatment  Day      Time     1   2   3   4   5   6       Time     1   2   3   4   5   6             
---------------------------------------------------------------------------------------------------- 
  X        1/A       X       HH:MM    X   X    X   X   X   X      HH:MM    X   X    X   X   X   X  
 
                      
                      
                      
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
      *Category:1 = No clotting, clean filter or few blood streaks (affecting less than 5% of the fibers seen at the surface of dialyzer), 
                2 = Blood streaks affecting more than 5% but less than 25 % of the fibers seen at the surface of the dialyzer, 
                3 = Blood streaks affecting more than 25% but less than 50 % of the fibers seen at the surface of the dialyzer, 
                4 = Blood streaks affecting more than 50% but less than 75 % of the fibers seen at the surface of the dialyzer, 
                5 = Blood streaks affecting more than 75% of the fibers seen at the surface if the dialyzer, 
                6 = Occluded (also assess the category of streaking at the time of occlusion) 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 78 of 88 
 
 
                                                                                                                                 Page 1 of X 
 
Appendix 16.2.5.10 Non-Study Procedures (Safety Population) 
 
                                                 Procedure 
 Subject Cohort/                   Assessment ----------------    Due to Medical Due to AE,  Overall Procedure     Procedure                                 
 Number  Treatment   Procedure        Date     Date       Time     History, seq#  AE page#     Interpretation    Findings/Comments                           
--------------------------------------------------------------------------------------------------------------------------------------- 
   X       1/A       None 
                     XXXXXXXXXXXXX DDMMMYYYY  DDMMMYYYY  HH:MM      XXXXXXX        XX        XXXXXXXXXXXXXXXX   XXXXXXXXXXXXXXXXXXXX   
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 79 of 88 
 
 
                                                                                                                                 Page 1 of X 
 
                               Appendix 16.2.5.11  Prior and On-Study Concomitant Medications (Safety Population) 
                                                                                                                                     
                                                                 Start              Stop                                    Prior   If Due 
Subject Cohort/   Any   Medication                           ---------------  -----------------  Fre-               Con-      to    to AE, 
Number  Treatment Med?  (WHO* Term)    Dosage    Form Route  Date      Time   Date       Time   quency Indication tinuing?  Study?  AE Page# 
-------------------------------------------------------------------------------------------------------------------------------------------- 
 X         1/A    No     None                                                                                                  
 X         1/A    Yes    ACETAMINOPHEN  620 mg   XXX  Oral   DDMMMYYYY HH:MM  DDMMMYYYY  HH:MM   Once  Toothache    No        X     XX  
                         (ACETAMINOPHEN) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
      *Concomitant medications are coded with World Health Organization (WHO) Drug Dictionary Version September 2018, B3. 
      Med = Medication  
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 80 of 88 
 
                                                                                                                                 Page 1 of X 
 
                                        Appendix 16.2.7.1.1  Adverse Events (I of II) (Safety Population) 
 
                                                                   Time From                                             
                                                                   Last Dose       Onset             Resolved         Duration  
 Subject  Cohort/                                                 ----------  ----------------   ----------------  ------------- 
 Number   Treatment  TE?^   Adverse Event*    Preferred Term      (DD:HH:MM)  Date       Time    Date       Time    (DD:HH:MM) 
-------------------------------------------------------------------------------------------------------------------------------- 
   X        1/A      None                                                                                                
   X        1/A      Yes    XXXXXXXXXXXXX     XXXXXXXXXX XXXXXXX   XX:XX:XX   DDMMMYYYY  XX:XX   DDMMMYYYY  XX:XX    XX:XX:XX  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
      *Adverse events are classified according to MedDRA Version 21.1. 
      ^TE = Treatment-emergent 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 81 of 88 
 
 
                                                                                                                                 Page 1 of X 
 
                                       Appendix 16.2.7.1.2  Adverse Events (II of II) (Safety Population) 
 
                                                                                              
                                                    Onset                                                   
 Subject Cohort/          Adverse             -----------------  Severity/                      Relationship to 
 Number  Treatment  TE?^  Event               Date        Time   Intensity  Serious  Outcome    Study Drug         Action 
 ----------------------------------------------------------------------------------------------------------------------------- 
   X       1/A      None                                                                                 
   X       1/A      Yes   XXXXXXXXXXXXXXXXXX  DDMMMYYYY   XX:XX   Grade 1   Not      Resolved   XXXXXXXXXXXXXXXX   XXXXXXXXX 
                                                                  Mild      serious 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
      ^TE = Treatment-emergent 
       
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 82 of 88 
 
 
 
 
                                                                                                                                Page 1 of X 
 
                              Appendix 16.2.7.2  Adverse Event Preferred Term Classification (Safety Population) 
 
                                                                                                                Onset      
 Subject Cohort/         Adverse                                                                          ------------------ 
 Number  Treatment TE?^  Event*                      Preferred Term             System Organ Class        Date       Time  
---------------------------------------------------------------------------------------------------------------------------- 
   X       1/A     Yes   XXXXXXX XXXXX XXXX XXXXXX   XXXXXXXXXX XXXXXXX         XXXXXXXXXXXXXXXXXXXXX     DDMMMYYYY  XX:XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
      *Adverse events are classified according to MedDRA Version 21.1. 
      ^TE = Treatment-emergent 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 83 of 88 
 
Appendices 16.2.8.1.1, 16.2.8.1.2, 16.2.8.1.4 and 16.2.8.1.5 will have the following format. 
 
                                                                                                                                 Page 1 of X 
 
                                   Appendix 16.2.8.1.1  Clinical Laboratory Report - Serum Chemistry (Safety Population) 
  
                                                                                                                                                
                                              Parameter1  Parameter2  Parameter3  Parameter4  Parameter5 Parameter6  
  Subject Cohort/    Age#/  Study              < Range>   < Range>    < Range>     < Range>   < Range>    < Range>        
  Number  Treatment  Sex    Visit                (Unit)     (Unit)      (Unit)       (Unit)     (Unit)     (Unit)      
  ------------------------------------------------------------------------------------------------------------------- 
    X       1/A      XX/X   Screen  DDMMMYYYY   XX H        XX          XX           XX         XX H       XX        
                              X     DDMMMYYYY   XX L +      XX L        XX           XX L       XX         XX        
 
 
 
Programmer Note:  Replace Parameter1, 2 etc. with actual lab tests in the study. Sort unscheduled assessment and early term chronologically 
with other scheduled assessments.   
 
 
 
 
Programmer Note: Please adjust layout based on what is actually in the database if necessary.  
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
      #Age is calculated from the date of first dosing. F = Female; M = Male 
H = Above reference range, L = Below reference range                                                                                         
PI interpretation: + = Clinically Significant 
                      
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 84 of 88 
 
 
             Appendix 16.2.8.1.3  Clinical Laboratory Report – Coagulation and Platelet Count (Safety Population) 
  
                                                                                                                                                
                                                     Parameter1  Parameter2  Parameter3  Parameter4  Parameter5 Parameter6  
  Subject Cohort/    Age#/  Study   Study             < Range>   < Range>    < Range>     < Range>   < Range>    < Range>        
  Number  Treatment  Sex    Visit   Hour    Date       (Unit)     (Unit)      (Unit)       (Unit)     (Unit)     (Unit)      
  ------------------------------------------------------------------------------------------------------------------------- 
    X       1/A      XX/X   Screen          DDMMMYYYY   XX H        XX          XX           XX         XX H       XX        
                              X      XX     DDMMMYYYY   XX L +      XX L        XX           XX L       XX         XX        
 
 
 
Programmer Note: A study hour column is included for coagulation and platelet count due to more frequent assessments. Replace Parameter1, 2 
etc. with actual lab tests in the study. Sort unscheduled assessment and early term chronologically with other scheduled 
assessments.   
 
 
 
Programmer Note: Please adjust layout based on what is actually in the database if necessary. Remove Other if no other tests. This listing 
includes PT/INR, fibrinogen, and TT from coagulation and platelet count from hematology.  
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
      #Age is calculated from the date of first dosing. F = Female; M = Male 
H = Above reference range, L = Below reference range                                                                                         
PI interpretation: + = Clinically Significant 
                      
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 85 of 88 
 
Appendix 16.2.8.1.6 Clinical Laboratory Report - Comments (Safety Population) 
 
 
Programmer Note:  Remove this listing if comments are not collected. 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 86 of 88 
 
 
                                                                                                                                Page 1 of X 
 
                                     Appendix 16.2.8.2  Vital Signs (Safety Population) 
  
 
                                                       Blood Pressure (mmHg)  Heart  Respi-    Tempera-                       
 Subject  Study                                        ---------------------  Rate   ration    ture        Weight           
 Number   Visit   Hour     Date       Time    Position   Systolic/Diastolic   (bpm)  (bpm)     (°C)         (kg)  
 --------------------------------------------------------------------------------------------------------------------- 
    X    Screen     .      DDMMMYYYY  XX:XX   Seated         XXX/ XX           XX    XX        XX.X         XX.X                 
         Day -8  Check-In  DDMMMYYYY  XX:XX   XXXXXXXX       XXX/ XX           XX    XX        XX.X         XX.X    
         Day -7  Pre HD    DDMMMYYYY  XX:XX   XXXXXX         XXX/ XX           XX    XX        XX.X         XX.X        
         Day -7  Post HD   DDMMMYYYY  XX:XX                                                                 XX.X  
 
 
 
 
Note: Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
 
Programmer Note: Sort unscheduled assessment and early term chronologically with other scheduled assessments.   
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 87 of 88 
 
 
                                                                                                                                 Page 1 of X 
 
                                            Appendix 16.2.8.3  12-Lead Electrocardiogram (Safety Population) 
 
                                                                   Heart                                                                      
  Subject  Cohort/     Study         Visit                         Rate     PR     QRS    QT    QTcF*                                       
  Number   Treatment   Visit  Hour   Date       Time   Result      (bpm)   (ms)    (ms)  (ms)   (ms)    Comments                             
  -------------------------------------------------------------------------------------------------------------------------- 
   X          1/A      Screen  .     DDMMMYYYY  XX:XX  Normal        XX     XXX     XX    XXX    XXX^#   XXXXXXXXX                         
                       Day X   XX.X  DDMMMYYYY  XX:XX  Normal        XX     XXX     XX    XXX    XXX                  
                       Day X   XX.X  DDMMMYYYY  XX:XX  Normal        XX     XXX     XX    XXX    XXX                 
 
 
 
 
Programmer Note: Sort unscheduled assessment and early term chronologically with other scheduled assessments.   
 
 
 
 
 
 
 
 
 
 
 
Note: QTcF* = QT corrected for heart rate using Fridericia’s correction. 
Abnormal, NCS = Abnormal, Not clinically significant 
^ = QTcF is > 450 ms 
# = QTcF change from baseline is > 30 ms 
      Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 


Aronora, Inc. 
E-WE thrombin, Protocol EWE-19-02 
Celerion, Clinical Study Report No. CA26622 
 
Statistical Analysis Plan, 18 September 2019 
Page 88 of 88 
 
                                                                                                                                 Page 1 of X 
 
Appendix 16.2.8.4 Vascular Access Site Reaction Assessment (Safety Population) 
 
Subject  Cohort/   Study    Study             Collection   Actual     Was a Reaction      If yes,                                 
 Number   Treatment  Day     Hour             Date         Time       Observed?        Grade (1,2 or 3)                                     
-------------------------------------------------------------------------------------------------------- 
   X        1/A       1     Predose           DDMMMYYYY    HH:MM          XXX               X                  
                            4 Hours postdose  DDMMMYYYY    HH:MM          XXX               X                       
                      3     Start of HD       DDMMMYYYY    HH:MM          XX                                      
                            20 min Post HD    DDMMMYYYY    HH:MM          XXX               X                      
 
 
 
 
 
 
 
 
 
Note:  Treatment: A = 0.5 µg/kg bolus dose of E-WE Thrombin followed by a 0.25 µg/kg/hour continuous infusion over 4 hours for a total 
             dose of 1.5 µg/kg  
      B = 1.0 µg/kg bolus dose of E-WE Thrombin followed by a 0.5 µg/kg/hour continuous infusion over 4 hours for a total 
                      dose of 3.0 µg/kg 
                  P = Placebo 
       HD = Hemodialysis 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM