Conditions: Venous Thromboembolism
Keywords: venous thromboembolism adhesion molecule P-selectin glycoprotein ligand 1 P-selectin venous thrombosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 207
Healthy volunteers: no

Brief summary:
The main purpose of this study is to determine if an investigational medication called SelK2 works in preventing a condition called "venous thromboembolism" (VTE) in patients having a total knee replacement. SelK2 has been designed to attach to a protein found on blood cells and blood vessels. By attaching to this protein, SelK2 is designed to decrease the inflammatory process in the blood vessel wall that leads to the formation of blood clots in the vessel (called thrombosis). By decreasing the inflammatory process, SelK2 may reduce the risk of VTE following joint replacement surgery. In addition, because SelK2 is not a blood thinner, it is expected that the risk for bleeding will also be reduced.

Detailed description:

Arms:
arm 1: I.V., single-dose (SelK2) and SC, QD for up to 10 ± 2 days (Enoxaparin) arm 2: SC, QD for up to 10 ± 2 days arm 3: I.V., single-dose

Interventions: intervention 1: SelK2 intervention 2: Enoxaparin
Intervention descriptions: intervention 1: I.V., single-dose intervention 2: SC, QD for up to 10 ± 2 days

Protocol document:
Prot_SAP_000.pdf: 
 
Clinical Study Protocol SELK2-00005 
 
 
 
 CONFIDENTIAL 
Version 2.0 
    
May 21, 2019 
 
i 
CLINICAL STUDY PROTOCOL 
 
Study Title: 
A Phase 2, Randomized, Active Comparator-Controlled, Open-Label, 
Adaptive Design Study to Assess the Safety and Efficacy of 
Intravenously-Administered SelK2 in Patients Undergoing Total Knee 
Arthroplasty. 
 
Protocol Amendment #1: SELK2-00005, version 2.0  
Date: May 21, 2019 
 
Original Protocol:  
SELK2-00005, version 1.0 
Date: September 4, 2018 
 
Drug Name: 
SelK2:  a function-blocking, humanized anti-PSGL-1 monoclonal 
antibody 
Investigational Phase: 
2 
 
Prepared by: 
Jonathan Stocker, Ph.D. 
 
Russell Rother, Ph.D. 
 
 
Sponsor: 
Tetherex Pharmaceuticals Corporation 
 
Jonathan Stocker, Ph.D. 
 
Executive Director, Clinical Development 
 
840 Research Parkway, Suite 512 
 
Oklahoma City, OK 73104 
 
Telephone:  (919) 819-2112 
 
Email:  jstocker@tetherex.com 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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SIGNATURE PAGE 
 
Clinical Study Protocol:   
 
SELK2-00005 
 
Protocol Amendment #1 Date:   
May 21, 2019 
 
Protocol Number: 
 
 
SELK2-00005, version 2.0 
 
 
Study Title:  A Phase 2, Randomized, Active Comparator-Controlled, Open-Label, Adaptive 
Design Study to Assess the Safety and Efficacy of Intravenously-Administered SelK2 in Patients 
Undergoing Total Knee Arthroplasty. 
 
The undersigned verify that they have read, understood, and concur with this protocol 
(SELK2-00005) and will comply with all study procedures defined in the protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
Jonathan Stocker, Ph.D. (signature) 
 
Executive Director, Clinical Development 
 
Tetherex Pharmaceuticals, Corp. 
Oklahoma City, OK 
 
 
 
 
 
 
 
 
 
Date 
Principal Investigator (signature) 
 
 
 
 
 
 
Principal Investigator (printed name) 
 
 


 
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PROTOCOL SYNOPSIS 
 
Name of Investigational Product: 
SelK2:  a function-blocking, humanized anti-PSGL-1 monoclonal antibody 
Name of Sponsor Company: 
Tetherex Pharmaceuticals Corporation 
Phase of Development: 
Phase 2 
Title of Study:  A Phase 2, Randomized, Active Comparator-Controlled, Open-Label, Adaptive 
Design Study to Assess the Safety and Efficacy of Intravenously-Administered SelK2 in Patients 
Undergoing Total Knee Arthroplasty. 
Number of Patients:  Approximately 190 patients; with up to 285 patients possible upon 
activation of the adaptive arm 
Number of Sites:  Approximately 25 clinical sites 
Study Population:  Male and female patients undergoing elective total knee arthroplasty (TKA) 
Study Duration:   
Each patient will participate in the study for up to 13 weeks, including an up to 30-day Screening 
Phase, 11-day Treatment Phase, and a 45-day Follow-up Phase.  The end of the trial will occur 
when the last study visit (Day 57) is completed for the last patient enrolled into this study. 
Study Objectives: 
The objectives of this study are to: 
- Investigate the efficacy of SelK2 as monotherapy in the prevention of VTE (composite of 
asymptomatic DVT detected by mandatory unilateral venography of the operated leg or 
confirmed symptomatic DVT, confirmed symptomatic PE or unexplained death) in patients 
undergoing primary unilateral TKA; 
- Assess the incidence of bleeding events (major bleeding events, clinically relevant non-major 
bleeding events, and minor bleeding events) in patients administered SelK2 and undergoing 
primary unilateral TKA; 
- Assess the overall safety and tolerability of SelK2 in this patient population; 
- Further describe the PK and PD of SelK2; 
- Evaluate the immunogenicity of single dose SelK2; and 
- To evaluate exploratory efficacy endpoints of inflammation and thrombosis.  
- Adaptive arm, if activated, assess the efficacy and safety of SelK2 when given in addition to 
enoxaparin for the prevention of venous thromboembolism (VTE) in patients undergoing 
primary unilateral TKA. 
Study Design: 
This clinical study is a multi-center, randomized, active comparator-controlled, open-label, 
adaptive design study to assess the safety and efficacy of SelK2 in the prevention of VTE events 
in patients undergoing TKA.  A total of approximately 190 patients planning to undergo unilateral 
TKA will be recruited into two arms of the study. 
 
The two arms of the study will enroll patients in a 1:1 ratio (approximately 95 patients in each 
arm) as shown below: 
 
1.) 7.5 mg/kg SelK2 (IV, single-dose) 
2.) Active Comparator (40 mg Enoxaparin, SC, QD) 
 
Patients planning to undergo scheduled TKA under general anesthesia who meet all the inclusion 
criteria and none of the exclusion criteria will be eligible for randomization into this study.  Prior 
to randomization, a Screening Phase consisting of clinical and laboratory evaluations will occur 
within 30 days prior to randomization to assess patient eligibility for this study.  Upon meeting all 
criteria, patients will be randomized into this study using a centralized randomization system. 


 
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Following randomization, patients randomized to the SelK2 arm will receive a single dose of 7.5 
mg/kg SelK2 via intravenous (IV) administration over a 30-minute time period at least 12 hours 
but not longer than 24 hours prior to the start of the TKA procedure.  Patients randomized to the 
enoxaparin arm will receive 40 mg enoxaparin administered SC 12 hours after TKA surgery 
followed by daily injections of 40 mg enoxaparin for at least 9 consecutive days post-surgery and 
up to the time point of the venography (with the option of giving an additional 40 mg enoxaparin, 
SC dose 12 hours prior to TKA surgery).   
 
For all patients, the TKA procedure will be done on Study Day 2.  Patients will be required to 
spend at least 2 nights after TKA procedure in the hospital, and patients, at the discretion of the 
PI, can remain in the hospital at least up to the day of the venography. 
 
All patients will be required to undergo unilateral ascending venography of the operated leg 10 ± 
2 days post-surgery (Study Day 11 ± 2 days).  After completion of the venogram, patients will be 
released from the clinical setting, and this will conclude the Treatment Phase of the study.   
 
The Follow-up Phase of this study will consist of two clinic visits on Days 21 and 57 and two 
follow-up telephone contacts on Days 29 and 43.  The final study visit occurs on Day 57 (Day 
57/Early Discontinuation Visit). 
 
Data on all asymptomatic deep vein thrombosis (DVT) as determined by venogram and 
symptomatic clinical VTE will be collected during both Treatment and Follow-up Phases of the 
study.  Bleeding events and other safety and clinical laboratory assessments including exploratory 
markers of inflammation and thrombosis, coagulation parameters and bleeding events will be 
performed throughout both the Treatment and Follow-up Phases.  Data on all suspected arterial 
thrombotic events will also be collected.  Blood samples will be collected for PK, PD, and 
immunogenicity analyses.   
 
A Central Independent Adjudication Committee (CIAC) will assess all venograms, symptomatic 
VTE outcomes (including DVT and PE), bleeding events, suspected stroke, any other suspected 
arterial thrombotic events, and death. Adjudicators will be blinded to treatment assignment.   
 
A Steering and Safety Committee will conduct ongoing reviews of all safety and efficacy data in 
an unblinded fashion. 
 
Adaptive Design:  The Steering and Safety Committee and Sponsor will review the accumulating 
efficacy and safety data at planned intervals, and based upon the safety and efficacy profile of 
SelK2 may decide to modify enrollment by adding a third study arm testing 7.5 mg/kg SelK2 
given in addition to enoxaparin (40 mg, SC, QD) and removal of the SelK2 only arm. The two 
remaining arms will enroll patients in a 2:1 ratio with two patients receiving SelK2 and 
Enoxaparin for every one patient receiving Enoxaparin only at doses shown below: 
 
1.) 7.5 mg/kg SelK2 (IV, single-dose) and 40 mg Enoxaparin, SC, QD 
2.) Active Comparator (40 mg Enoxaparin, SC, QD) 
 
 


 
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Criteria for Selection of Patients: 
Inclusion Criteria: 
1. Males or females, between 18 and 80 years of age, inclusive; 
2. Females must be non-pregnant and non-lactating, and either postmenopausal (>12 months 
since last menses) or using highly effective contraceptive measures as defined by the Clinical 
Trial Facilitation Group (CTFG) guidelines; 
3. Males, if engaged in sexual relations with a partner of child-bearing potential, must use highly 
effective contraceptive measures as defined by the Clinical Trial Facilitation Group (CTFG) 
guidelines; 
4. Planned to undergo elective, primary total unilateral TKA under general anesthesia; and 
5. Able to comprehend and willing to give written informed consent. 
 
Exclusion Criteria: 
Patients presenting with any of the following will not be included in the study: 
1. Body weight <50 kg at Screening; 
2. Previous deep vein thrombosis (DVT) of the leg or pulmonary embolism (PE) within the past 
year; 
3. Malignancy within 1 year, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated;  
4. Myocardial infarction, transient ischemic attack or stroke within the last 6 months; 
5. Patients at increased risk of bleeding because of history of increased bleeding tendency (i.e., 
history of bleeding diathesis) or any other condition that in the opinion of the Investigator 
increases risk of bleeding (e.g., recurrent gastrointestinal ulcer) or patients with a history of 
intracranial or intraocular bleeding;     
6. Brain, spinal, or ophthalmologic surgery within the past 3 months; 
7.   Cockcroft-Gault calculated creatinine clearance <30 mL/min at Screening (central lab will 
calculate the Cockcroft-Gault value); 
8.   Screening laboratory results as follows, or any other clinically significant abnormalities in 
screening laboratory values that, in the opinion of the PI, would render a patient unsuitable for 
inclusion: 
• 
ALT or AST >1.5x ULN 
• 
Total bilirubin >1.5x ULN 
• 
Platelet count <150,000 or recent (over the last 3 months) history of thrombocytopenia 
(e.g. platelet count <150,000); 
9.   Positive test for human immunodeficiency virus (HIV; by history of having HIV antibodies), 
positive hepatitis B (hepatitis B surface antigen [HBsAg]) or hepatitis C (anti-hepatitis C 
antibody [Anti-HCV]) at Screening; 
10. Uncontrolled hypertension as judged by the Investigator; 
11. Clinically significant abnormal ECG at Screening, as judged by the Investigator; 
12. Active infection; 
13. Unable to undergo venography due to a known allergy to the contrast agent, anticipated poor 
venous access, impaired renal function, or any other reason identified and specified by the PI; 
14. Hypersensitivity to enoxaparin or any contraindication listed in the local labeling of 
enoxaparin; 
15. Any underlying condition (e.g., atrial fibrillation, mechanical heart valve, or recent pulmonary 
embolism) that may lead to the required concomitant use of anticoagulants/antiplatelet agents 
(e.g., warfarin, dabigatran, rivaroxaban, apixaban, clopidogrel) that may affect study outcome 
or any other drug influencing coagulation (except low dose aspirin (100 mg or less)); 
16. Anticipated use of intermittent pneumatic compression devices and/or electrical/mechanical 
muscle stimulators post TKA procedure; 


 
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17. Anticipated use of indwelling intrathecal or epidural catheters; 
18. Participation in any other investigational study drug trial in which receipt of an investigational 
study drug occurred within 60 days prior to Day 1; 
19. History of alcoholism or drug addiction within 1 year prior to Screening; 
20. Any acute or chronic condition that, in the opinion of the Investigator, would limit the 
patient’s ability to complete and/or participate in this clinical study; or 
21. Unwillingness to comply with all study procedures including follow-up visits, as specified by 
this protocol, or unwillingness to cooperate fully with the Investigator. 
Duration of Treatment:   
During the Treatment Phase of this study each patient will receive either: 
1) A single 7.5 mg/kg dose of SelK2 administered intravenously 12 to 24 hours prior to the 
initiation of the TKA surgery, or  
2) 40 mg dose of enoxaparin (active comparator) administered SC 12 hours after TKA 
surgery followed by daily injections of 40 mg enoxaparin, SC for at least 9 additional 
days post-surgery and up to the day of the planned venography (with the option of giving 
an additional 40 mg enoxaparin, SC dose 12 hours prior to TKA surgery). 
 
Upon activation of the adaptive arm and discontinuation of the SelK2 only arm of the study, 
during the Treatment Phase each patient will receive either: 
1) A single 7.5 mg/kg dose of SelK2 administered intravenously 12 to 24 hours prior to the 
initiation of the TKA surgery AND 40 mg dose of enoxaparin administered SC 12 hours 
after TKA surgery followed by daily injections of 40 mg enoxaparin, SC for at least 9 
additional days post-surgery and up to the day of the planned venography, or 
2) 40 mg dose of enoxaparin (active comparator) administered SC 12 hours after TKA 
surgery followed by daily injections of 40 mg enoxaparin, SC for at least 9 additional 
days post-surgery and up to the day of the planned venography (with the option of giving 
an additional 40 mg enoxaparin, SC dose 12 hours prior to TKA surgery). 
 
Each randomized patient will undergo TKA surgery on the Day 2 of the study.  Patients must stay 
hospital for at least 2 nights after the TKA.  A mandatory venogram will be completed on Study 
Day 11 (± 2 days).  Completion of venography will conclude the Treatment Phase of the study.  
Patients will then enter a Follow-up Phase of the study which will consist of two clinic visits on 
Days 21 and 57 and follow-up telephone contacts on Days 29 and 43.  The final study visit occurs 
on Day 57 with a complete set of laboratory and safety assessments.  Prior to enrollment into the 
study, a Screening Phase consisting of clinical and laboratory evaluations will occur within 30 
days prior to randomization to assess patient’s eligibility for this study.  Each patient will 
participate in the study for up to approximately 13 weeks, including an up to 30-day Screening 
Phase, 11-day Treatment Phase, and a 45-day Follow-up Phase.   
Test Product, Dose Preparation, and Mode of Administration:   
Study Drug (SelK2): 
 
 
 
 Vials are stored refrigerated at 2 to 
8°C and protected from light. A pharmacist or designated personnel will compound individual 
doses of active study drug for patients on a milligram per kilogram basis in a 100 mL infusion 
bottle or bag of a sterile 0.9% sodium chloride solution (0.9% Sodium Chloride Injection, USP) in 
accordance with the Pharmacy Manual. Study drug will be administered over 30 minutes by IV 
infusion. 
 
Active Comparator (Enoxaparin):  Commercially available enoxaparin (40 mg in 0.4 mL water 


 
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in pre-filled disposable syringes for SC administration) will be provided to the study site 
pharmacies for use in this study, in accordance with local regulatory requirements.  Enoxaparin 
should be stored in a temperature-controlled environment which is maintained below 25°C; but 
should not be frozen.  
 
The Pharmacy Manual will provide further details about handling, storage, and mode of 
administration.   
Dose Rationale: 
 
 
 
 
 
  
 
 
 
 
 
 
 
Criteria for Evaluation:  
Primary Efficacy Endpoints:  The primary efficacy outcome is the composite of asymptomatic 
deep vein thrombosis (DVT) detected by mandatory unilateral venography of the operated leg or 
confirmed symptomatic DVT, confirmed symptomatic PE or unexplained death during the 
Treatment Phase.  All efficacy endpoint data will be adjudicated by a blinded Central Independent 
Adjudication Committee. 
 
Exploratory Efficacy Endpoints:  The exploratory efficacy outcomes will include measurements 
of markers of inflammation and thrombosis (hsCRP and D-dimer, respectively) and other possible 
PD markers of SelK2 efficacy. 
 
PK, PD, and Immunogenicity Evaluations:  Samples will be collected during Treatment and 
Follow-up Phases for evaluation of PK, PD, and immunogenicity. 
 
Safety: 
The primary safety outcome is a composite of major bleeding events or clinically relevant non-
major bleeding events during the Treatment Phase.  The secondary safety outcomes are the 
incidence of the composite of major, clinically relevant non-major, or minor bleeding events that 
occur during the Treatment and Follow-up Phases. 
 
Other safety evaluations will include assessment of adverse events, physical examinations, 12-
lead ECGs, vital signs (including  temperature, respiratory rate, and seated blood pressure and 
pulse), clinical chemistry laboratory evaluations, additional laboratory evaluations including 
prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time 
(aPTT), hematology panel, urinalysis, and pregnancy test (female patients of child bearing 
potential only). 
Statistical Methods: 
Demographic and other patient data will be summarized by treatment group using descriptive 
statistics. 
 


 
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The primary efficacy comparison will compare the SelK2 only-treated, SelK2 and enoxaparin-
treated, and enoxaparin only-treated arms.  The difference in the total VTE rate determined during 
the entire Treatment Phase will be estimated.  The 1-sided lower 90% CI of the difference 
between the SelK2 and enoxaparin groups only arms as well as the difference between the 
adaptive arm (SelK2 and enoxaparin) and enoxaparin only arms will be calculated and non-
inferiority will be concluded if the upper limit of the 90% CI is ≤ 15%.  Absolute changes from 
baseline in levels of high-sensitivity CRP and D-dimer will be assessed. A number of secondary 
analyses may be conducted to assess the robustness of the primary analysis finding. 
 
SelK2 concentrations will be summarized by descriptive statistics. 
 
Safety will be assessed by reported adverse events, changes from baseline during treatment in 
vital signs, ECGs, laboratory parameters, and physical examination and will be summarized using 
descriptive statistics.  Adverse events will be coded using the (Medical Dictionary for Regulatory 
Activities) MedDRA dictionary and summarized by system organ class, preferred term, 
Investigator causality assessment, and treatment group.  Incidence of bleeding events (as 
adjudicated by CIAC) will be tabulated by treatment group. 
 
Sample Size Considerations: 
  
Assuming that the rate of VTE for the active comparator (enoxaparin) arm of this study will be 
25%, it is estimated that a sample size of 76 evaluable patients per arm should give the study 80% 
power of declaring non-inferiority between the SelK2 only arm and the enoxaparin active 
comparator arm. This calculation uses a one-sided 90% CI with a non-inferiority margin of 
15%.  This calculation assumes that the underlying rate of VTE for the SelK2 and enoxaparin 
arms will be identical at 25% and with the non-inferiority margin set as the midpoint between the 
expected active therapy response compared with an assumed placebo event rate in this patient 
population of 55%.  Consequently, making the conservative estimate that up to 20% of 
randomized patients may not have evaluable endpoint data; a total of 95 patients will be enrolled 
per arm to provide at least 76 endpoint evaluable patients per arm.  
  
Sample Size Considerations for Adaptive Arm: 
  
With the same assumptions as above for the active comparator (enoxaparin) arm of the study 
event rate, it is estimated that a sample size of 76 evaluable patients in a combination therapy arm 
of SelK2 and enoxaparin should give the study 80% power of declaring superiority between the 
SelK2 and enoxaparin and the enoxaparin active comparator arm for an estimated SelK2 and 
enoxaparin VTE event rate of 6% (a 19% difference between combination treatment effect and 
active comparator treatment effect).  This calculation assumed a two-sided 0.1 alpha, a Pearson 
Chi-squared test, and a superiority comparison. 


 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .......................................................................................................................... iii 
1.0 
INTRODUCTION ............................................................................................................................. 1 
1.1 
Background .......................................................................................................................1 
1.2 
Preclinical Studies Supporting SelK2 Antithrombotic Activity ..............................................2 
1.2.1 
In Vivo Mechanism of Action ................................................................................................................. 2 
1.2.2 
Toxicology .............................................................................................................................................. 2 
1.2.3 
Absorption, Distribution, Metabolism, and Excretion ........................................................................... 3 
1.3 
Clinical Studies of SelK2 ......................................................................................................4 
1.4 
Study Rationale .................................................................................................................7 
1.5 
Rationale for the Dose Regimen .........................................................................................7 
2.0 
STUDY OBJECTIVES ..................................................................................................................... 8 
3.0 
STUDY DESIGN ............................................................................................................................... 9 
3.1 
Basic Design Characteristics................................................................................................9 
3.2 
Number of Patients ............................................................................................................9 
3.3 
Study Population ............................................................................................................. 10 
3.4 
Study Phases.................................................................................................................... 10 
3.4.1 
Screening Phase ................................................................................................................................... 10 
3.4.2 
Treatment Phase .................................................................................................................................. 10 
3.4.3 
Follow-Up Phase .................................................................................................................................. 11 
3.4.4 
Study Diagrams for SelK2 and Enoxaparin Arms ................................................................................. 11 
3.5 
Efficacy and Safety Assessments ....................................................................................... 12 
3.6 
Endpoints ........................................................................................................................ 13 
3.6.1 
Primary Efficacy Endpoint .................................................................................................................... 13 
3.6.2 
Exploratory Efficacy Endpoints ............................................................................................................ 13 
3.6.3 
Pharmacokinetic Assessments of SelK2 ............................................................................................... 13 
3.6.4 
Pharmacodynamic Assessments of SelK2 ............................................................................................ 14 
3.6.5 
Safety Endpoints .................................................................................................................................. 14 
4.0 
SELECTION OF STUDY POPULATION ................................................................................... 15 
4.1 
Inclusion Criteria .............................................................................................................. 15 
4.2 
Exclusion Criteria ............................................................................................................. 15 
5.0 
STUDY TREATMENTS ................................................................................................................. 17 
5.1 
Study Drug Information .................................................................................................... 17 
5.1.1 
Description of Study Drug .................................................................................................................... 17 
5.1.2 
Blinding, Packaging, and Labeling of Study Drug ................................................................................. 17 
5.1.3 
Randomization Methods and Procedures ........................................................................................... 17 
5.1.4 
Supply, Storage, Accountability, and Disposition of Study Drug ......................................................... 18 


 
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5.2 
Dosage Schedule .............................................................................................................. 19 
5.2.1 
Dosing of SelK2 .................................................................................................................................... 19 
5.2.2 
Dosing of Enoxaparin ........................................................................................................................... 19 
5.2.3 
Adaptive Arm: Dosing of SelK2 and Enoxaparin .................................................................................. 19 
5.3 
Prior and Concomitant Medications ................................................................................. 19 
6.0 
STUDY PROCEDURES ................................................................................................................. 21 
6.1 
Schedule of Events ........................................................................................................... 21 
6.2 
Screening Phase ............................................................................................................... 24 
6.3 
Treatment Phase.............................................................................................................. 25 
6.3.1 
Day 1 .................................................................................................................................................... 25 
6.3.2 
Day 2 .................................................................................................................................................... 26 
6.3.3 
Day 3 .................................................................................................................................................... 26 
6.3.4 
Day 4 .................................................................................................................................................... 26 
6.3.5 
Day 5 – Day 10 ..................................................................................................................................... 27 
6.3.6 
Day 11 .................................................................................................................................................. 27 
6.4 
Follow-Up Phase .............................................................................................................. 28 
6.4.1 
Day 21 .................................................................................................................................................. 28 
6.4.2 
Day 29 .................................................................................................................................................. 28 
6.4.3 
Day 43 .................................................................................................................................................. 28 
6.4.4 
Day 57 .................................................................................................................................................. 28 
6.4.5 
Early Discontinuation Visit ................................................................................................................... 29 
6.5 
Measurements and Assessments ...................................................................................... 29 
6.5.1 
Efficacy Assessments ........................................................................................................................... 29 
6.5.2 
Safety Assessments .............................................................................................................................. 31 
7.0 
ADVERSE EVENTS INCLUDING SPECIAL REPORTING REQUIREMENTS 
FOR POTENTIAL VTE AND BLEEDING ENDPOINT EVENTS ........................................ 35 
7.1 
Procedures for Handling and Reporting Adverse Events .................................................... 35 
7.1.1 
Adverse Event ...................................................................................................................................... 35 
7.1.2 
Serious Adverse Event ......................................................................................................................... 36 
7.1.3 
Safety Reporting to Health Authorities,Independent Ethics Committee/Institutional Review Board 37 
7.2 
Adverse Events that are Potential Study Endpoint Events.................................................. 38 
7.2.1 
Reporting Requirements for AE’s that are Potential Study Endpoints ................................................ 38 
7.3 
Monitoring of Subjects with Adverse Events ..................................................................... 39 
7.4 
Treatment Interruption or Discontinuation ....................................................................... 39 
8.0 
PATIENT WITHDRAWAL, REMOVAL OR SITE TERMINATION ..................................... 40 
8.1 
Withdrawal or Removal of Patient From Study ................................................................. 40 
8.2 
Termination of Study ....................................................................................................... 40 
9.0 
DATA HANDLING PROCEDURES ............................................................................................ 41 
9.1 
Electronic Case Report Form Completion .......................................................................... 41 
9.2 
Database Construction ..................................................................................................... 41 


 
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10.0 STATISTICAL METHODS AND PLANNED ANALYSES ....................................................... 42 
10.1 
Sample Size and Power .................................................................................................... 42 
10.2 
Analysis Populations ........................................................................................................ 42 
10.3 
Statistical Analysis ........................................................................................................... 42 
10.3.1 
General Considerations ................................................................................................................... 42 
10.3.2 
Background Characteristics ............................................................................................................. 43 
10.3.3 
Efficacy Analyses ............................................................................................................................. 44 
10.3.4 
Pharmacokinetics and Pharmacodynamics ..................................................................................... 44 
10.4 
Safety Analysis ................................................................................................................. 45 
10.4.1 
Adverse Events ................................................................................................................................ 45 
10.4.2 
Clinical Laboratory Assessments ..................................................................................................... 46 
10.4.3 
Electrocardiogram ........................................................................................................................... 46 
10.4.4 
Vital Signs ........................................................................................................................................ 47 
10.4.5 
Physical Examination ....................................................................................................................... 47 
10.5 
Steering and Safety Committee Data Reviews and Interim Analyses .................................. 47 
11.0 STUDY OPERATONS .................................................................................................................... 49 
11.1 
IQVIA - Contract Research Organization ............................................................................ 49 
11.2 
Itreas - Academic Research Organization .......................................................................... 49 
11.3 
Steering and Safety Committee ........................................................................................ 49 
11.4 
Central Independent Adjudication Committee .................................................................. 50 
12.0 ETHICAL ISSUES, LEGAL ASPECTS, AND ADMINISTRATIVE ISSUES ......................... 51 
12.1 
Good Clinical Practice ....................................................................................................... 51 
12.2 
Delegation of Investigator Responsibilities ....................................................................... 51 
12.3 
Patient Information and Informed Consent ....................................................................... 51 
12.4 
Confidentiality ................................................................................................................. 51 
12.5 
Protocol Amendments ..................................................................................................... 52 
12.6 
Approval of the Study Protocol and Amendments ............................................................. 52 
12.7 
Ongoing Information for Ethics Committee / Institutional Review Board ........................... 52 
12.8 
Premature Closure of the Study ........................................................................................ 53 
12.9 
Record Retention ............................................................................................................. 53 
12.10 
Liability and Insurance ................................................................................................. 53 
12.11 
Study Monitoring and Auditing .................................................................................... 54 
12.11.1 
Study monitoring ............................................................................................................................ 54 
12.11.2 
Source data verification and on-site audits .................................................................................... 54 
13.0 DOCUMENTATION AND USE OF STUDY FINDINGS .......................................................... 55 
13.1 
Documentation of Study Findings ..................................................................................... 55 


 
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13.2 
Use of Study Findings ....................................................................................................... 55 
14.0 REFERENCES ................................................................................................................................ 56 
 
 
 


 
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LIST OF TABLES 
 
Table 1. Study Procedures Schedule of Events for SELK2-00005 ............................................................. 22 
Table 2. Listing of All Clinical Laboratory Assays Included in Clinical Chemistry, Hematology 
(CMC), Complete UA and Coagulation Parameters ........................................................................... 33 
 
 


 
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LIST OF ABBREVIATIONS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Transaminase 
AUC0-336 
Area Under the Concentration-Time Curve from Time 0 to 336 Hours 
Postdose 
AUC0-∞ 
Area Under the Concentration-Time Curve Extrapolated to Infinity 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CIAC 
Central Independent Adjudication Committee 
CL 
Clearance Rate 
Clast 
Last Observed Concentration 
Cmax 
Maximum Observed Concentration 
CO2 
Carbon Dioxide 
CRNMB 
Clinically Relevant Non-Major Bleeding event 
CRO 
Contract Research Organization 
DVT 
Deep Vein Thrombosis 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCFR 
Electronic Case Report Form 
EENT 
Eyes/ears/nose/throat 
FcRn 
Neonatal Fc Receptors 
gamma-GT 
Gamma Glutamyl Transpeptidase 
GCP 
Good Clinical Practice 
Hb 
Hemoglobin 
Hct 
Hematocrit 
HepB 
Hepatitis B 
HepC 
Hepatitis C 
HIV 
Human Immunodeficiency Virus 
hsCRP 
High Sensitivity C-Reactive Protein 
ICH 
International Conference on Harmonization 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT Analysis 
Intent-To-Treat Analysis 
IV 
Intravenous 
kDa 
Kilodalton 
kg 
Kilogram 
LDH 
Lactate Dehydrogenase 
Max 
Maximum 


 
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MB 
Major Bleeding event 
MCV 
Mean Corpuscular Volume 
MCH 
Mean Corpuscular Hemoglobin 
MedDRA 
Medical Dictionary for Regulatory Activities 
PAHA 
Primate Anti-Human Antibodies 
PD 
Pharmacodynamics 
PE 
Pulmonary Embolism 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PSGL-1 
P-Selectin Glycoprotein Ligand-1 
PT 
Prothrombin Time 
QTcB 
Bazett’s corrected QT interval 
QTcF 
Fridericia’s corrected QT interval 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SRM 
Study Reference Manual 
t1/2 
Terminal Phase Half-Life 
TEAE 
Treatment-Emergent Adverse Event 
TKA 
Total Knee Arthroplasty (Total Knee Replacement Surgery) 
UA 
Urinalysis 
VCAM 
Vascular Cell Adhesion Molecule 
V 
Volume of Distribution 
VTE 
Venous Thromboembolism 
V/V 
Volume to Volume Ratio 
WBC 
White Blood Cell 
WHO-DD 
World Health Organization Drug Dictionary 
 


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1.0 
INTRODUCTION  
1.1 
Background 
Deep vein thrombosis and pulmonary embolism are collectively referred to as venous 
thromboembolism (VTE).  Venous thromboembolism is a major medical burden affecting millions 
of people around the world, with approximately 300,000 deaths and 540,000 deaths annually in the 
United States and the European Union, respectively.  Current therapies available for venous 
thromboembolism include low-molecular-weight heparins (e.g., enoxaparin sodium), vitamin K 
antagonists (e.g., warfarin), and newer oral anticoagulants (e.g., rivaroxaban; a factor Xa inhibitor).  
These therapies target the coagulation system and can therefore result in the feared complication of 
hemorrhage, which can sometimes be fatal. 
 
VTE is one of the most serious complications experienced by patients undergoing joint 
replacement surgeries such as total knee arthroplasty (TKA).  Following elective TKA, objective 
venographic evidence of primarily asymptomatic deep vein thrombosis (DVT) occurs in 41-85% of 
patients without thromboprophylaxis.  Because of the strong concordance between asymptomatic 
DVT detected by venography and clinically important VTE, DVT detected by contrast venography 
is most often used in the early investigation of new antithrombotic agents (1).  
 
Considering the high incidence of VTE following TKA, the use of routine thromboprophylaxis is 
recommended in these patients.  However, agents available for use in this patient population block 
the coagulation system and can cause major bleeding events leading to significant morbidity and 
mortality.  There is a continuing medical need for the development of novel antithrombotic agents, 
especially those that may operate through a unique mechanism of action which is not associated 
with an increase in bleeding risk. 
 
The relationship between VTE and vein wall inflammation has been well established. PSGL-1 (P-
selectin glycoprotein ligand-1) and the selectin family of molecules (P-, E- and L-selectin) are cell 
adhesion molecules, regulating the interactions between leukocytes, the blood vessel wall, and 
activated platelets. The importance of PSGL-1/selectin interactions in the inflammatory process 
leading to VTE has been confirmed in several nonhuman primate studies. Collectively, these 
studies indicate that inhibition of PSGL-1 interactions with its selectin ligands results in a decrease 
in thrombosis, and importantly, in the absence of bleeding complications. The level of reduction in 
thrombosis resulting from PSGL-1/selectin inhibition is similar to that with the low-molecular-
weight-heparin, enoxaparin, which is associated with bleeding complications.  
 
During total hip and total knee replacement surgeries, endothelium injury and platelet activation 
result in the upregulation of selectins and disruption of the regulatory mechanisms of hemostasis. 
Platelets and the endothelium then participate in the formation of blood clots through receptor 
interactions with PSGL-1 found on multiple inflammatory cell types. The use of a tourniquet in 
total knee replacement surgery and immobilization following surgery also induces inflammation 
and increases the risk of thrombosis.  
 
SelK2 is a humanized monoclonal antibody that binds PSGL-1 with high affinity and specificity 
and blocks its ability to interact with selectins as well as with chemokines. Because of its ability to 
block the interactions of PSGL-1 with selectins and chemokines, SelK2 may be useful in the 
prevention of VTE in patients undergoing TKA. 
 


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1.2 
Preclinical Studies Supporting SelK2 Antithrombotic Activity 
1.2.1 
In Vivo Mechanism of Action 
The vascular anatomy and coagulation system of baboons are similar to those of humans. 
Therefore, baboon models of VTE and bleeding provide an excellent reflection of what might 
happen in humans. In one such model of DVT, baboons are subjected to either infrarenal inferior 
vena cava or iliac vein balloon occlusion with hypogastric vein ligation. In a meta-analysis of five 
different baboon studies using this model, PSGL-1/selectin inhibition reduced thrombosis to a 
similar degree as enoxaparin (2).  Selectin blockade also successfully reduced vein wall 
inflammation and fibrosis which has important implications for the prevention of postthrombotic 
syndrome. Importantly, bleeding was not reported in any study and coagulation parameters were 
not adversely affected.  
In a more recent study conducted in a baboon iliac vein stasis model of DVT, a P-selectin binding 
aptamer that inhibits PSGL-1/P-selectin interactions was shown to be effective in both prophylactic 
and treatment applications (3). Selectin inhibition resulted in increased iliac vein recanalization and 
valve competency equal to or greater than those observed with enoxaparin treatment. Importantly, 
selectin inhibition decreased intimal fibrosis while enoxaparin did not. There were no significant 
changes in fibrinogen or activated partial thromboplastin time and no bleeding events were 
observed in the study.  
 
 
 
 
 
 
 
Collectively, these studies indicate that inhibition of PSGL-1 interaction with its selectin ligands 
results in a decrease in thrombosis and improvements in both valve competency and vessel 
patency. The reduction in thrombosis with PSGL-1/selectin inhibition is similar to that with 
enoxaparin. Further, selectin inhibition results in a decrease in vein wall inflammation and fibrosis 
with no effect on inflammatory cell extravasation into the vein wall. Importantly, the 
antithrombotic activity with selectin inhibition occurs in the absence of potential bleeding 
complications characteristic of anticoagulants (4, 5). 
These data suggest that the inflammatory and procoagulant factors involved with thrombus 
initiation and resolution are associated with PSGL-1/selectin interactions on various cell types and 
that blockade of these interactions may be a novel therapeutic strategy in the prophylaxis and/or 
treatment of VTE. Further, intervention of the inflammatory response early in thrombogenesis may 
be beneficial for prevention of postthrombotic syndrome that often develops following DVT. 
1.2.2 
Toxicology 
 
 
 
 


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1.2.3 
Absorption, Distribution, Metabolism, and Excretion 
 
 
 
 
 
 


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1.3 
Clinical Studies of SelK2 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  


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1.4 
Study Rationale 
Venous thromboembolism is a major medical burden affecting millions of people around the 
world, with approximately one million cases and 300,000 deaths annually in the United States and 
approximately 1.5 million cases and 540,000 deaths annually in the European Union. 
 
Approved therapies and standard of care available for use in VTE target the coagulation system and 
can therefore result in major bleeding events leading to significant morbidity and mortality.  There 
is a continuing medical need for the development of novel antithrombotic agents, especially those 
that may operate through a unique mechanism of action which are not associated with an increase 
in bleeding risk. 
 
This randomized, active comparator-controlled, open-label study is being conducted to determine 
the efficacy and safety of SelK2 when administered once to patients undergoing primary unilateral 
total knee arthroplasty.  The study will compare the efficacy and safety of SelK2 to the standard of 
care, enoxaparin.  The primary endpoint to assess clinical efficacy will be the composite of 
asymptomatic DVT, detected by mandatory unilateral venography, and objectively confirmed 
symptomatic VTE during the treatment phase of the study.  The primary safety outcome is a 
combination of major bleeding events and clinically relevant non-major bleeding events during the 
treatment phase.  
 
This study includes an adaptive arm that investigates the efficacy and safety of SelK2 use in 
combination with enoxaparin.  This adaptive arm may be initiated if the Steering and Safety 
Committee determines that preliminary data suggests the potential of an additive effect in VTE 
reduction and that the combination does not pose an additional safety risk.  The data obtained from 
this Phase 2 study will be used to provide evidence to support the claim of efficacy and safety of 
SelK2 in this patient population. 
 
1.5 
Rationale for the Dose Regimen 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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2.0 
STUDY OBJECTIVES  
The objectives of this study are: 
Primary: 
• 
To investigate the efficacy of SelK2 as monotherapy for the prevention of VTE (composite 
of asymptomatic DVT detected by mandatory unilateral venography of the operated leg or 
confirmed symptomatic DVT, confirmed symptomatic PE or unexplained death) in patients 
undergoing primary unilateral TKA. 
• 
To assess the incidence of bleeding events (major bleeding events, clinically relevant non-
major bleeding events, and minor bleeding events) in patients administered SelK2 and 
undergoing primary unilateral TKA. 
• 
To assess the overall safety and tolerability of SelK2 in this patient population.  
 
 
Secondary: 
• 
To further describe the PK and PD of SelK2. 
• 
To evaluate the immunogenicity of single dose SelK2. 
• 
To evaluate exploratory efficacy endpoints of inflammation and thrombosis. 
 
Adaptive Arm (SelK2 given concomitantly with enoxaparin; SelK2, 7.5 mg/kg, IV and 
enoxaparin, 40 mg, SC, QD): 
• 
Assess the efficacy and safety of SelK2 when given in addition to enoxaparin for the 
prevention of VTE in patients undergoing primary unilateral TKA. 
 


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3.0 
STUDY DESIGN 
3.1 
Basic Design Characteristics 
This trial will be conducted at approximately 25 clinical centers as a multi-center, randomized, 
active-comparator controlled, open-label, adaptive design study to assess the safety and efficacy of 
intravenously-administered SelK2 in patients undergoing total knee arthroplasty.  A total of 
approximately 190 male or female patients between the ages of 18 and 80 years, inclusive, who 
meet all of the inclusion criteria and none of the exclusion criteria will be eligible for the study.  
After a complete assessment of inclusion and exclusion criteria and prior to the day of surgery, 
patients will be randomized into one of two arms with a 1:1 ratio (approximately 95 patients in 
each arm) as below: 
1. SelK2 (7.5 mg/kg, IV, single-dose)  
2. Active Comparator Enoxaparin (40 mg, SC, QD for up to 10 ± 2 days) 
 
For those randomized to receive SelK2, patients will receive a single dose of 7.5 mg/kg SelK2 via 
IV administration at least 12 hours but not longer than 24 hours prior to the start of the TKA 
surgery.   
 
For those randomized to receive enoxaparin, patients will receive their first dose of 40 mg 
enoxaparin administered SC 12 hours after TKA surgery followed by daily injections of 40 mg 
enoxaparin for at least 9 additional days post-surgery (with the option of giving an additional 40 
mg enoxaparin SC dose 12 hours prior to TKA surgery). 
 
Upon activation of the adaptive arm and discontinuation of the SelK2 only arm of the study, during 
the Treatment Phase each patient will receive either: 
 
1. A single 7.5 mg/kg dose of SelK2 (7.5 mg/kg, IV, single dose) and Enoxaparin (40 mg SC, 
QD for up to 10 ± 2 days) 
2. Active Comparator Enoxaparin (40 mg, SC, QD for up to 10 ± 2 days) 
 
 
The TKA will be conducted on Day 2 of the study.  All patients will be required to stay in the 
hospital after TKA and can be released from hospital on Study Day 4 (at the earliest).  On Study 
Day 4, a complete set of safety assessments will be completed on all patients.  At 10 ± 2 days post-
surgery (Study Day 11), a mandatory unilateral venography will be performed on the operated leg; 
at that visit a set of safety assessments will also be completed.  Upon completion of the 
venography, patients will continue in the Follow-up Phase for a total of 8 weeks.  The Follow-up 
Phase will consist of two phone call assessments and two safety visits in the clinic including a final 
safety visit occurring on Study Day 57.  The trial will conclude when the last study visit (Day 57) 
is completed for the last patient enrolled into this study. 
 
3.2 
Number of Patients 
Approximately 190 patients are planned to be enrolled in this clinical study as designed.  Based on 
adaptive design, if a third cohort of the study is added, an additional 95 patients may be added for a 
maximum of approximately 285 patients enrolled.   


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3.3 
Study Population 
Patients planning to undergo primary unilateral TKA who meet all of the inclusion criteria and 
none of the exclusion criteria will be eligible for the study.  Patients must be willing to undergo all 
study protocol assessments, tests and activities including unilateral venography of the operated leg 
approximately 10 days after TKA surgery. 
 
3.4 
Study Phases 
The study consists of Screening, Treatment and Follow-Up Phases.  Each patient will participate in 
this study for a total of up to 13 weeks, including an up to 30-day Screening Phase, followed by 
enrollment into the study, a 11-day (± 2 day) Treatment Phase, and a 45-day Follow-up Phase.   
3.4.1 
Screening Phase  
Once informed consent has been obtained, the screening assessments will be performed, and the 
eligibility of the patient will be determined.  During the Screening Phase, clinical and laboratory 
evaluations will occur within 30 days prior to randomization.  A screening log of all patients 
meeting the inclusion criteria will be maintained.  Patients who meet all of the inclusion criteria 
and none of the exclusion criteria will be eligible for the study.  At the Investigator’s discretion, 
patients that are excluded from the study may be rescreened for study inclusion at a later date that 
is at least two weeks following the initial study exclusion.  A patient may become a screen failure if 
they do not meet all of the inclusion criteria and/or meet one or more of the exclusion criteria. The 
primary reason for patient exclusions will be recorded for patients who are not randomized. 
3.4.2 
Treatment Phase  
After assessment that the patient has met all Inclusion Criteria and none of the Exclusion Criteria, 
on the day PRIOR to the scheduled TKA surgery, the patient will be randomized into this study.  
Prior to dosing of any study drug, baseline safety assessments will be taken.   
For those randomized to receive SelK2, patients will receive a single dose of 7.5 mg/kg SelK2 via 
IV administration at least 12 hours prior to but not longer than 24 hours prior to the start of the 
TKA surgery.  The Treatment Phase of the study consists of the period from the dosing of study 
drug (SelK2 or enoxaparin) or the TKA (for enoxaparin arm, if enoxaparin dosing is only done 
after TKA) up to the day of venography (Day 11 ± 2) or early study termination.  Note that for 
patients randomized to receive SelK2, study drug can be dosed either the day prior to TKA (Day 1) 
or on the day of TKA (Day 2) as long as the dosing occurs at least 12 hours prior to but not longer 
than 24 hours prior to the start of the TKA surgery. 
 
For those randomized to receive enoxaparin, patients will receive 40 mg enoxaparin administered 
via SC injection 12 hours after TKA surgery followed by daily SC injections of 40 mg enoxaparin 
for at least 9 additional days post-surgery (with the option of giving an additional 40 mg 
enoxaparin SC dose 12 hours prior to TKA surgery).  
 
For those randomized to receive SelK2 and enoxaparin, patients will receive a single dose of 7.5 
mg/kg SelK2 via IV administration at least 12 hours prior to but not longer than 24 hours prior to 


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the start of the TKA surgery and will receive 40 mg enoxaparin administered via SC injection 12 
hours after TKA surgery followed by daily SC injections of 40 mg enoxaparin for at least 9 
additional days post-surgery. 
 
For all patients, the Treatment Phase will be completed on the day the venography is completed. 
 
Patients will remain in the hospital for AT LEAST two overnights after TKA.  During the 
Treatment Phase, efficacy, safety and PK/PD/Immunogenicity assessments will be completed for 
each patient.  
3.4.3 
Follow-Up Phase 
After completion of the venography, each patient enters the Follow-Up Phase of the study which 
will last approximately 45 days.  During this Phase, each patient will return for safety assessment 
on Day 21 and Day 57 (Final Study Visit).  Patients will also be contacted on Day 29 and 43 by 
phone for assessment of any adverse events that have occurred since the last clinic visit.  
3.4.4 
Study Diagrams for SelK2 and Enoxaparin Arms 
The following diagram depicts the Screening, Treatment, and Follow-Up Phases of the study for 
patients randomized to receive SelK2:  
Screening 
Phase 
Treatment Phase 
Follow-Up  
Phase  
Screening 
(Maximum 
30 days 
prior to 
dosing) 
Day 1 
Baseline Assessments 
Randomization 
Single Dose of IV  
SelK2 7.5 mg/kg 
dosed 12 to 24 hours 
prior to TKA 
Day 2 
TKA 
Days 3 -11 
Assessment of 
Efficacy and Safety 
Day 11 
Venography 
Follow-Up 
Assessments 
Through  
Day 57 
 
The following diagram depicts the Screening, Treatment, and Follow-Up Phases of the study for 
patients randomized to receive Enoxaparin:  
Screening 
Phase 
Treatment Phase 
Follow-Up  
Phase  
Screening 
(Maximum 
30 days 
prior to 
dosing) 
Day 1 
Baseline Assessments 
Randomization 
Optional Enoxaparin  
40 mg SC at least 12 
hours pre-TKA 
Day 2 
TKA 
Enoxaparin 40 mg 
SC 12 hours post-
TKA 
Days 3-11 
Assessments of 
Efficacy and Safety 
Enoxaparin 40 mg 
SC, QD 
Day 11 
Venography 
Follow-Up 
Assessments 
Through  
Day 57 
 
IF Adaptive arm is activated: 
 
The following diagram depicts the Screening, Treatment, and Follow-Up Safety Phases of the 
study for Patients Randomized to Receive SelK2 and Enoxaparin:  


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Screening 
Phase 
Treatment Phase 
Follow-Up  
Phase  
Screening 
(Maximum 
30 days 
prior to 
dosing) 
Day 1 
Baseline Assessments 
Randomization 
Single Dose of IV 
SelK2 7.5 mg/kg 
dosed 12 to 24 hours 
prior to TKA 
Optional Enoxaparin  
40 mg SC at least 12 
hours pre-TKA 
Day 2 
TKA 
Enoxaparin 40 mg 
SC 12 hours post-
TKA 
Days 3-11 
Assessments of 
Efficacy and Safety 
Enoxaparin 40 mg 
SC, QD 
Day 11 
Venography 
Follow-Up 
Assessments 
Through  
Day 57 
3.5 
Efficacy and Safety Assessments 
Data for the assessment of efficacy will be collected during the Treatment and Follow-up Phases of 
this study.  A venography will be performed on Study Day 11 (± 2 days) to assess the potential for 
the occurrence of an asymptomatic DVT.  The venography as well as the reporting of any 
suspected venous thromboembolism will serve as the basis for efficacy assessments.  Blood 
samples at various times throughout conduct of the study will also be drawn to evaluate hsCRP and 
D-dimer which are exploratory markers for inflammation and thrombosis. 
Safety assessments will be performed throughout the study, at specified times prior to and 
following administration of study drug and active comparator during the Treatment and Follow-up 
Phases.  Safety assessments will include:  all adverse events including bleeding events or suspected 
bleeding events (e.g., suspicious reported AE), physical examinations, vital signs (blood pressure, 
pulse rate, respiratory rate, and body temperature), immunogenicity, clinical laboratory tests (Blood 
chemistry, Hematology panel, UA), additional laboratory evaluations (prothrombin 
time/international normalized ratio or PT/INR and activated partial thromboplastin time or aPTT), 
12-lead electrocardiograms, and reported or observed AEs.   
The Central Independent Adjudication Committee (CIAC) will evaluate in a blinded fashion all 
venograms, episodes of suspected VTE, and unexplained deaths and the outcome of the 
adjudication will be the basis for the final efficacy evaluations. The CIAC will also review all 
relevant data for each suspected bleeding event in a blinded fashion. Adjudicated data regarding 
efficacy and bleeding events will be used for both the interim and final analyses. The CIAC will 
also review any suspected arterial thrombotic events (e.g., myocardial infarction, ischemic stroke, 
etc.). 
A formal study Steering and Safety Committee will consist of at least 3 clinicians (with experience 
and expertise in venous thrombosis) and one or more representatives from the Sponsor. The 
Steering and Safety Committee will be charged with reviewing in an unblinded fashion all 
accumulating safety and efficacy data to assure overall patient safety in this study. Further details 
about the composition and conduct of the Steering and Safety Committee and the data to be 
presented to this Committee can be found in Section 11.3. Additional details will also be provided 
in the Steering and Safety Committee Charter. 
 


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3.6 
Endpoints 
3.6.1 
Primary Efficacy Endpoint 
3.6.1.1 
Incidence of Total Venous Thromboembolism 
The incidence of total venous thromboembolism will consist of a composite of: 
• 
Asymptomatic deep-vein thrombosis of the operated leg (detected by mandatory unilateral 
venography); 
• 
confirmed symptomatic DVT of the leg(s); 
• 
confirmed symptomatic pulmonary embolism; and 
• 
unexplained death for which pulmonary embolism could not be ruled out. 
 
A unilateral ascending venogram is to be performed on each study patient between Study Day 9 
and Study Day 13 of study conduct (approximately 10 days after completion of TKA).  The 
venogram will be obtained from the leg that underwent surgery.  Multiple views of each venous 
segment will be obtained per instructions provided in the Manual for Venography and Event 
Reporting.  The CIAC will review all venographic data in a blinded fashion for the adjudication of 
an endpoint event. 
Study patients will be evaluated for signs and symptoms of DVT (e.g., swelling, localized pain, 
redness, heat, localized warmth) and PE (e.g., unexplained shortness of breath, coughing up blood, 
chest pain that gets worse with a deep breath, unexplained coughing) during the post-surgery in 
hospital/clinic period and at all visits occurring throughout the Treatment and Follow-up Phases of 
the study. 
Every suspected episode of DVT or PE must be reported appropriately as an AE.  The underlying 
clinical data from any patient with a suspected DVT or PE events will be presented to the CIAC 
and adjudication as a possible study endpoint. 
 
3.6.2 
Exploratory Efficacy Endpoints 
3.6.2.1 
Laboratory Markers of Inflamation and Thrombosis 
Absolute changes from baseline in levels of high sensitivity C-reactive Protein (hsCRP) and D-
dimer will be assessed. 
3.6.3 
Pharmacokinetic Assessments of SelK2 
Pharmacokinetics will be assessed on all patients randomized to the SelK2 arm (and the adaptive 
arm of SelK2 and enoxaparin, if activated) by obtaining serum samples prior to receiving SelK2 
dosing, throughout the Treatment Phase after SelK2 dosing, and during the Follow-Up Phase 
Visits. 
Post-treamtent SelK2 concentrations for evaluable patients receiving SelK2 will be listed by study 
visit day and also summarized by descriptive statistics. 
 


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3.6.4 
Pharmacodynamic Assessments of SelK2 
Pharmacodynamics will be assessed on all patients randomized to the SelK2 arm (and the adaptive 
arm of SelK2 and enoxaparin, if activated) by obtaining serum samples prior to receiving SelK2 
dosing, throughout the Treatment Phase of the study, and during the Follow-Up Phase Visits. In 
this assay, patient serum will be added to a P-selectin/PSGL-1 binding assay. The amount of active 
SelK2 in the serum will be inversely proportional to the degree of interaction between P-selectin 
and PSGL-1 as SelK2 binding inhibits this interaction. The PD of SelK2 will be reported as the 
percentage of P-selectin/PSGL-1 interaction that is inhibited by a given serum sample.  Other 
markers of PD activity of SelK2 may be investigated. 
The percent inhibition (%) will be listed by study visit day and also summarized by descriptive 
statistics. 
 
 
3.6.5 
Safety Endpoints 
Safety parameters for this study include the following: 
• 
Bleeding Events 
• 
Other Adverse Events 
• 
Clinical laboratory measurements 
• 
Additional laboratory evaluations 
• 
Physical examination and vital signs 
• 
12-lead ECGs 
• 
Immunogenicity (anti-SelK2 antibodies) assessment 
• 
Transfusion(s) with blood products 
• 
Pregnancy test 
Suspected bleeding events will be adjudicated in a blinded fashion for categorization as a:  
1) Major Bleeding event (MB),  
2) Clinically Relevant Non-Major Bleeding event (CRNMB),  
3) Minor Bleeding, or  
4) No Bleed.  
The criteria for classification are specified in the CIAC charter and will include the classification 
for major bleeding in the surgical setting (8). 


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4.0 
SELECTION OF STUDY POPULATION 
A total of 190 patients will be enrolled, 95 patients in each of 2 arms of the study (Arm 1: 7.5 
mg/kg SelK2, IV or Arm 2: 40 mg enoxaparin, SC, QD).   
An additional adaptive arm of 95 patients may be added for the investigation of the combination of 
7.5 mg/kg SelK2, IV and 40 mg enoxaparin, SC, QD. 
4.1 
Inclusion Criteria 
Patients meeting all of the following criteria will be considered for admission to the study: 
1. Males or females, between 18 and 80 years of age, inclusive;  
2. Females must be non-pregnant and non-lactating, and either postmenopausal (>12 months 
since last menses) or using highly effective contraceptive measures as defined in the 
Clinical Trial Facilitation Group (CTFG) guidelines*; 
3. Males, if engaged in sexual relations with a partner of child-bearing potential, must 
use highly effective contraceptive measures as defined in the Clinical Trial Facilitation 
Group (CTFG) guidelines*; 
4. Planned to undergo elective, primary total unilateral TKA under general anesthesia; and 
5. Able to comprehend and willing to give written informed consent. 
4.2 
Exclusion Criteria 
Patients presenting with any of the following will not be included in the study: 
1. Body weight <50 kg at Screening; 
2. Previous deep vein thrombosis (DVT) of the leg or pulmonary embolism (PE) within the 
past year; 
3. Malignancy within 1 year, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated; 
4. Myocardial infarction, transient ischemic attack or stroke within the last 6 months;  
5. Patients at increased risk of bleeding because of history of increased bleeding tendency 
(i.e., history of bleeding diathesis) or any other condition that in the opinion of the 
Investigator increases risk of bleeding (e.g., recurrent gastrointestinal ulcer) or patients 
with a history of intracranial or intraocular bleeding; 
6. Brain, spinal, or ophthalmologic surgery within the past 3 months; 
7. Cockcroft-Gault calculated creatinine clearance <30 mL/min at Screening (central lab will 
calculate the Cockcroft-Gault value); 
8. Screening laboratory results as follows, or any other clinically significant abnormalities in 
screening laboratory values that, in the opinion of the PI, would render a patient unsuitable 
for inclusion: 
• ALT or AST >1.5x ULN 
• Total bilirubin >1.5x ULN 


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• Platelet count <150,000 or recent (over the last 3 months) history of 
thrombocytopenia (e.g. platelet count <150,000); 
9. Positive test for human immunodeficiency virus (HIV; by history of having HIV 
antibodies), positive hepatitis B (hepatitis B surface antigen [HBsAg]) or hepatitis C (anti-
hepatitis C antibody [Anti-HCV]) at Screening; 
10. Uncontrolled hypertension as judged by the Investigator; 
11. Clinically significant abnormal ECG at Screening, as judged by the Investigator; 
12. Active infection; 
13. Unable to undergo venography due to a known allergy to the contrast agent, anticipated 
poor venous access, impaired renal function, or any other reason identified and specified 
by the PI; 
14. Hypersensitivity to enoxaparin or any contraindication listed in the local labeling of 
enoxaparin; 
15. Any underlying condition (e.g., atrial fibrillation, mechanical heart valve, or recent 
pulmonary embolism) that may lead to the required concomitant use of 
anticoagulants/antiplatelet agents (e.g., warfarin, dabigatran, rivaroxaban, apixaban, 
clopidogrel) that may affect study outcome or any other drug influencing coagulation 
(except low dose aspirin (100 mg or less)); 
16. Anticipated use of intermittent pneumatic compression devices and/or 
electrical/mechanical muscle stimulators post TKA procedure; 
17. Anticipated use of indwelling intrathecal or epidural catheters; 
18. Participation in any other investigational study drug trial in which receipt of an 
investigational study drug occurred within 60 days prior to Day 1; 
19. History of alcoholism or drug addiction within 1 year prior to Screening; 
20. Any acute or chronic condition that, in the opinion of the Investigator, would limit the 
patient’s ability to complete and/or participate in this clinical study; or 
21. Unwillingness to comply with all study procedures including follow-up visits, as specified 
by this protocol, or unwillingness to cooperate fully with the Investigator. 
 
* Birth control methods which are considered as highly effective are listed in the Clinical Trial 
Facilitation Group (CTFG) Guidance, Final Version – 2014-09-15. 
One of these highly effective contraceptive methods must be used from the time of signing of 
the informed consent until 30 days after the Final Study Visit. 


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5.0 
STUDY TREATMENTS  
5.1 
Study Drug Information 
5.1.1 
Description of Study Drug  
 
 
 
 
 
 
 
 
 
SelK2 vials will be shipped in temperature-controlled shippers for delivery to site study personnel.  
A pharmacist or designated personnel will compound individual doses of active drug for study 
patients on a milligram per kilogram basis in a 100 mL infusion bag or bottle of a sterile 0.9% 
sodium chloride solution (0.9% Sodium Chloride Injection, USP) in accordance with the Pharmacy 
Manual.  Study drug will be administered over 30 minutes by IV infusion. Patients will be 
monitored for 60 minutes following the infusion.  
The active comparator is commercially available enoxaparin and will be provided by the Sponsor.  
Enoxaparin (enoxaparin sodium) will be provided as pre-filled syringes of 40 mg/0.4 mL (100 
mg/mL concentration) of enoxaparin for SC injection.  Sites may also use local supplies of 
commercially available enoxaparin if necessary. 
5.1.2 
Blinding, Packaging, and Labeling of Study Drug 
This is a randomized and unblinded study, consequently no effort is required to blind study drug or 
active comparator from any of the study personnel at the clinical site.  A pharmacist will be 
responsible for the compounding of individual doses of study drug (SelK2) for patients randomized 
to receive SelK2.  
Each SelK2 vial is labeled in accordance with specific country regulatory requirements as well as 
with the study number, specific drug contents, and unique vial number. 
Enoxaparin pre-filled syringes will be labeled in accordance with specific country regulatory 
requirements.  
5.1.3 
Randomization Methods and Procedures 
Patients will be screened prior to randomization and assigned a Subject ID number by IRT. After 
patient’s eligibility is confirmed, treatment assignment will be determined by a validated central 
randomization schedule using IRT (Interactive Response Technology).  If a patient meets all of the 
inclusion criteria and none of the exclusion criteria, delegated and approved site personnel, trained 
on the use of the IRT, will randomize the patient.  The IRT system will assign the patient a 
treatment group based on the next available slot in the randomization scheme.  It is important to 
note that the randomization web entry should only be made after eligibility has been established.  
Prior to randomization, baseline efficacy and safety assessments will be taken. 


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Patients will be randomly placed into one of two treatment arms: 
1) 7.5 mg/kg SelK2, IV or  
2) 40 mg enoxaparin, SC, QD.  
 
Patients will be randomized to these two treatment arms in a 1:1 ratio. Randomization will be 
stratified by site. 
For patients randomized into the 7.5 mg/kg SelK2 arm, the IRT system will calculate the number 
of vials required based on the patient weight and will provide the user the appropriate vial numbers 
to use. 
Changes in Randomization Procedure when Adaptive arm is activated and enrollment into the 
SelK2 only arm is discontinued: 
When the adaptive arm is activated and the SelK2 only arm is closed, the central randomization 
process will allow for placing patients randomly into one of the below two treatment arms and 
randomization will continue to be stratified by site. 
Patients will be randomly placed into one of two treatment arms: 
1) 40 mg enoxaparin, SC, QD, or 
2) 7.5 mg/kg SelK2, IV and 40 mg enoxaparin, SC, QD. 
 
The randomization ratio will be altered to a 2:1 ratio (2 patients receiving 7.5 mg/kg SelK2 and 
enoxaparin to every 1 patient receiving Enoxaparin only) so that the total number of patients in 
each of the two remaining arms will be approximately equivalent at the end of the study. This 
modified randomization ratio will be controlled by the centralized IRT system. 
 
5.1.4 
Supply, Storage, Accountability, and Disposition of Study Drug 
The pharmacist will inventory and acknowledge receipt of all shipments of study drug.  All study 
drug must be kept in a locked area with access restricted to designated study personnel.  The study 
drug must be stored in accordance with the package instructions.  All storage records (i.e 
temperature logs) must be maintained.  The pharmacist will also keep accurate records of the 
quantities of study drug dispensed and used by each patient.  A monitor will ensure accountability 
of all study drug used.  Refer to the Pharmacy Manual for further detailed instruction on study drug 
(both SelK2 and enoxaparin) storage and accountability. 
At the conclusion of the study, after final drug reconciliation is completed by the monitor, all 
unused study drug can be destroyed at site (with appropriate documentation) or can be returned to a 
designee as instructed by Sponsor.   IQVIA will assure that a final report of drug accountability is 
prepared and maintained by the Investigator. 
Neither SelK2 nor enoxaparin will be provided to study participants after their participation in this 
study is completed.  Neither SelK2 nor enoxaparin will be made available to any participants at the 
conclusion of this study. 
 
 


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5.2 
Dosage Schedule 
5.2.1 
Dosing of SelK2 
For those randomized to receive SelK2, patients will receive a single dose of 7.5 mg/kg SelK2 via 
IV administration at least 12 hours prior to but not longer than 24 hours prior to the start of the 
TKA surgery.  SelK2 will be given as an approximately 100 mL IV infusion over approximately 30 
minutes (± 15 minutes). 
 
5.2.2 
Dosing of Enoxaparin 
For those randomized to receive enoxaparin, patients will receive 40 mg enoxaparin administered 
via SC injection 12 hours after TKA surgery followed by daily SC injections of 40 mg enoxaparin 
through and including Day 11 (± 2 days).  Daily dosing of enoxaparin should continue until the 
venogram is completed.  At the discretion of the PI, sites also have the option of giving an 
additional 40 mg enoxaparin SC dose 12 hours PRIOR to TKA surgery.  
 
5.2.3 
Adaptive Arm: Dosing of SelK2 and Enoxaparin 
When the adaptive arm is activated, for those randomized to receive SelK2 and enoxaparin in 
combination, patients will receive a single dose of 7.5 mg/kg SelK2 via IV administration at least 
12 hours prior to but not longer than 24 hours prior to the start of the TKA surgery.  SelK2 will be 
given as an approximately 100 mL IV infusion over approximately 30 minutes (± 15 minutes). 
Additionally, patients will receive 40 mg enoxaparin administered via SC injection 12 hours after 
TKA surgery followed by daily SC injections of 40 mg enoxaparin through and including Day 11 
(± 2 days).   
5.3 
Prior and Concomitant Medications 
In general, medications consistent with the standard care of patients undergoing TKA (e.g., 
tranexamic acid, etc.) will be allowed during this study. 
Except for the protocol prescribed SelK2 or enoxaparin, all efforts should be made to exclude the 
concomitant use of anticoagulants/antiplatelet agents (e.g., warfarin, dabigatran, rivaroxaban, 
apixaban, clopidogrel, phenprocoumon, acenocoumarol, edoxaban, prasugrel, ticagrelor, 
sulodexide, aspirin+dipyridamole, cilostazol, etc.) throughout the duration of the study, from Day 1 
through Day 57 UNLESS medically necessary (i.e., patient experiences a VTE, myocardial 
infarction, etc.).  Use of NSAIDs is discouraged and should only be used when unavoidable.  
NSAIDS should be used in the lowest dose and for the shortest period of time possible.  Any 
concomitant use of aspirin should be avoided (except for low dose aspirin, 100 mg or less). 
 
Any medication or non-pharmacological therapy (in addition to the study drug) that is taken by or 
administered to the patient at any point during the course of this study must be recorded in the 
eCRF. The entry must include the dose, regimen, route, indication, and dates of use. The collection 
of prior medications will include medications used within the past 6 months from the estimated 
Day 1 date. 
 


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Patients may not participate in any other interventional drug study for at least 60 days prior to 
starting this study (Study Day 1) and may not participate in any other interventional drug study 
throughout the study period. 


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6.0 
STUDY PROCEDURES 
6.1 
Schedule of Events 
The procedures and assessments to be performed during each phase of the study are outlined in the 
Study Schedule of Events (see Table 1).  
 


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Table 1. Study Procedures Schedule of Events for SELK2-00005 
Study Procedures 
Screening 
Phase 
Treatment Phase 
Day 21 
Day 29 
Phone 
Call 
Day 43 
Phone 
Call 
Day 57 
Final Study Visit/ 
Early 
Discontinuation 
Visit 
Day 1a 
(Randomization) 
Day 2 
(TKA) 
Day 3 
Day 4 
Day 5 to 
Day 10 
Day 11 
Visit Window (days) 
30 days to 1 
day prior to 
Randomization 
N/A 
N/A 
N/A 
N/A 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xb 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
Xc 
 
 
Xc 
 
Xc 
Xc 
 
 
X 
12-Lead ECG 
X 
 
 
 
X 
 
 
 
 
 
X 
Vital Signs, Body Weight 
Xd 
Xd 
Xe 
 
X 
 
X 
X 
 
 
X 
Chemistry, Hematology 
(CBC), and Urinalysis 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
PT/INR and aPTT 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
Samples for hsCRP,  
D-dimer analysis 
X 
X 
 
 
X 
Xf  
(Day 6 
Only) 
X 
X 
 
 
X 
HIV, Hepatitis B and C 
X 
 
 
 
 
 
 
 
 
 
 
TKA Surgery 
 
 
X 
 
 
 
 
 
 
 
 
Venography 
 
 
 
 
 
 
X 
 
 
 
 
PK/PD Blood Samples 
(only SelK2 or adapt. arm) 
 
Xg 
Xh 
 
X 
Xf   
(Day 6 
Only) 
X 
X 
 
 
X 
Immunogenicity  
(only SelK2 or adapt. arm) 
 
Xg 
 
 
 
 
X 
X 
 
 
X 
Pregnancy Test 
Xi 
Xi 
 
 
 
 
 
 
 
 
 
Record Concomitant 
Medications and 
Transfusions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IRT Randomization 
 
X 
 
 
 
 
 
 
 
 
 
SelK2 Dosing 
(only SelK2 or adapt. arm) 
 
Xj 
 
 
 
 
 
 
 
 
 
Enoxaparin Dosing 
(only enoxaparin or adapt. 
arm) 
 
Xk 
Xl 
X 
X 
X 
X 
 
 
 
 


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a All Day 1 assessments and activities need to be completed PRIOR to randomization. 
b Interim medical history only to confirm no change in patient eligibility to be done prior to patient 
randomization. 
c Abbreviated physical examination only (refer to Section 6.5.2.3). 
d Body weight to be recorded only at Screening and on Day 1. 
e Vital signs (temperature, respiration rate, blood pressure, and pulse) should be collected on Day 2 prior to 
TKA procedure. 
f If patients remain in the hospital through Study Day 6, blood samples should be collected for PK/PD and 
Inflammatory and Thrombosis Markers of hsCRP and D-dimer. 
g PK, PD and immunogenicity blood sampling to occur on Day 1 prior to SelK2 dosing. 
h PK and PD blood sampling to occur on Day 2 prior to TKA approximately 12-24 hours after SelK2 dosing. 
i For all females of child bearing potential, a serum pregnancy test will be conducted during Screening and, 
for women of child-bearing potential, a urine pregnancy test must be completed prior to randomization on 
Day 1.  Both tests must be NEGATIVE prior to randomization on Day 1. 
j SelK2 dosing should ONLY occur after randomization of patient to SelK2 arm (or those randomized to   
adaptive arm of SelK2 and enoxaparin). 
k If PI/site plans to dose enoxaparin prior to TKA procedure, dosing can ONLY occur after randomization of 
patient to enoxaparin arm and should be dosed 12 hours prior to TKA surgery. 
l Enoxaparin dosing on Day 2 should be administered SC 12 hours after TKA surgery. 
 
N/A = Not Applicable; ECG=electrocardiogram; AE=adverse event; PD=pharmacodynamics; 
PK=pharmacokinetics; CBC=complete blood count; UA=urinalysis; PT/INR=prothrombin time/international 
normalized ratio; aPTT=activated partial thromboplastin time; HIV= human immunodeficiency virus; IRT= 
Interactive Response Technology; TKA= Total Knee Arthroplasty (Total Knee Replacement Surgery) 
 
 


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6.2 
Screening Phase 
This screening process will be conducted to confirm the patient’s eligibility to participate in this 
study based on a review of all inclusion and exclusion criteria.  The following procedures are to be 
performed within 30 days prior to Day 1 of the Treatment Phase (note, medical history can be used 
to confirm criteria as long as data was collected/verified within the 30-day screening phase):   
1. Signed the Informed Consent; 
2. Demographics including age, gender, race; 
3. Medical history; 
4. Complete physical examination (refer to section 6.5.2.3); 
5. 12-lead ECG;  
6. Vital signs including sitting blood pressure, pulse rate, respiratory rate, and temperature 
after sitting for 3-5 minutes, and body weight; 
7. Collection of clinical laboratory samples (blood and urine) to be shipped to the central lab 
for evaluation of hematology, blood chemistry, coagulation parameters and urinalysis (See 
Section 6.5.2.2 for complete listing of analyses); 
8. HIV antibody testing, Hepatitis B and C testing; 
9. High Sensitivity C-reactive Protein (hsCRP) and D-dimer sample collection; 
10. In female patients of child bearing potential perform serum pregnancy test; and 
11. Record concomitant medications and transfusions.  
 
Patients who meet all of the inclusion criteria and none of the exclusion criteria during the 
Screening Phase will be eligible for the study. At the Investigator’s discretion, patients that are 
excluded from the study may be rescreened for study inclusion at a later date that is at least two 
weeks following the initial study exclusion. The primary reason for patient exclusions will be 
recorded in a screening log for patients who are not randomized.  
No study-specific procedures will be performed prior to completion of informed consent by patient.   
 
 


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6.3 
Treatment Phase 
The schedule of assessments and procedures to be performed during the Treatment Phase are 
outlined below by Study Day and in the “Study Schedule of Events” (see Table 1). 
6.3.1 
Day 1 
The following procedures are to be performed on Day 1.  Day 1 can also serve as the day of Check-
in to the hospital facility as an inpatient and serve as the beginning of the patient’s stay at the 
hospital study site. (Day 1 activities could be conducted as an outpatient if assurance that patient 
will return to facility early on Day 2 for TKA). 
IMPORTANT NOTE:  All the listed assessments (1-8) are to be completed PRIOR to 
randomization. 
1. Medical history (update any additional medical history or any changes in medical history 
that has occurred since the time of the Screening Visit); 
2. Abbreviated physical examination (refer to section 6.5.2.3); 
3. Vital signs including sitting blood pressure, pulse rate, respiratory rate, and temperature 
after sitting for 3-5 minutes, and body weight; 
4. Collection of clinical laboratory samples (blood and urine) to be shipped to the central lab 
for evaluation of hematology, blood chemistry, coagulation parameters and urinalysis; 
5. Collection of blood samples for hsCRP and D-dimer assessments; 
6. Collection of blood samples for PK, PD, and immunogenicity assessments prior to study 
drug dosing; 
7. In female patients of child-bearing potential, perform urine pregnancy test. The urine 
pregnancy test must be negative before randomization and dosing of study drug; and 
8. Record any new or changes to concomitant medications and transfusions.  
 
It is preferred that procedures are performed in following order:  ECG and vital signs followed by 
blood draws. 
 
If all of the inclusion criteria and none of the exclusion criteria (that are immediately evaluable) are 
met, patients can be enrolled in the study and the following activities can be completed on Day 1. 
 
9. RANDOMIZATION of patient using IRT. 
10. If patient is randomized to the SelK2 arm or SelK2 + enoxaparin arm, SelK2 dosing should 
be completed on Day 1 at least 12 hours but not more than 24 hours prior to beginning of 
TKA procedure. Patients MUST remain in the clinic for at least 1 hour after dosing with 
SelK2. 
11. If patient is randomized to the enoxaparin arm or SelK2 + enoxaparin arm, site may choose 
to give a pre-surgery dose of enoxaparin 12 hours prior to TKA surgery. 
12. Assessment of AE’s. 
 
 
 


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6.3.2 
Day 2 
The following need to be completed prior to the start of the TKA procedure. 
1. Vital signs including sitting blood pressure, pulse rate, respiratory rate, and temperature 
after sitting for 3-5 minutes; 
2. Assessment of AEs; and 
3. For patients in the SelK2 arm or SelK2 + enoxaparin arm, collection of blood samples for 
PK and PD assessments prior to start of TKA surgery but between 12 to 24 hours after 
SelK2 dosing. 
Once these activities have been completed, patient can be prepared for the TKA procedure. 
4. TKA procedure to be completed. 
Once TKA is completed: 
5. For patients randomized to the enoxaparin arm or SelK2 + enoxaparin arm, dosing of 
enoxaparin to occur 12 hours after TKA. 
6. Recording of concomitant medications and transfusions; and 
7. Assessment of AEs. 
 
6.3.3 
Day 3 
Patients will remain in hospital facility during Day 3 and undergoing the following procedures. 
1. For patients randomized to the enoxaparin arm or SelK2 + enoxaparin arm, dosing of 
enoxaparin; 
2. Recording of concomitant medications and transfusions; and 
3. Assessment of AEs. 
 
6.3.4 
Day 4 
Patients will undergo the following procedures on Day 4. 
1. Abbreviated physical examination; 
2. 12-lead ECG;  
3. Vital signs including sitting blood pressure, pulse rate, respiratory, and temperature after 
sitting for 3-5 minutes; 
4. Collection of clinical laboratory samples (blood and urine) to be shipped to the central lab 
for evaluation of hematology, blood chemistry, coagulation parameters and urinalysis; 
5. Collection of blood samples for hsCRP and D-dimer assessments; 
6. For patients randomized to the SelK2 arm or SelK2 + enoxaparin arm, collection of blood 
samples for PK and PD assessments; 
7. For patients randomized to the enoxaparin arm or SelK2 + enoxaparin arm, enoxaparin 
dosing; 
8. Record any new concomitant medications and transfusions; and 
9. Assessment of AEs.  


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Patients can be released from the hospital research site following completion of all assessments on 
Day 4. 
6.3.5 
Day 5 – Day 10 
Patients can remain in the hospital site throughout Day 5 – Day 10 OR may be discharged from the 
hospital at any point during this time frame at the discretion of the site and their standard practices.  
Site personnel will be charged with collecting data on concomitant medications, transfusions, and 
assessment of AEs for each patient throughout this period.   
For Days 5-10 regardless of whether or not patient is in hospital or discharged to home, patients 
will undergo the following procedures. 
1. For patients randomized to the enoxaparin arm or SelK2 + enoxaparin arm, enoxaparin 
dosing. 
 
For patient remaining in the hospital on Study Day 6, the following assessments should be done on 
Day 6 ONLY: 
2. Collection of blood samples for hsCRP and D-dimer sample collection; and 
3. For patients randomized to the SelK2 arm or SelK2 + enoxaparin arm, collection of blood 
samples for PK and PD assessments. 
 
6.3.6 
Day 11 
Patients will undergo the following procedures on Day 11: 
1. Abbreviated physical examination;  
2. Vital signs including sitting blood pressure, pulse rate, respiratory, and temperature after 
sitting for 3-5 minutes; 
3. Collection of clinical laboratory samples (blood and urine) to be shipped to the central lab 
for evaluation of hematology, blood chemistry, coagulation parameters and urinalysis; 
4. Collection of blood samples for hsCRP and D-dimer assessments; 
5. For patients randomized to the SelK2 arm or SelK2 + enoxaparin arm, collection of blood 
samples for PK, PD, and immunogenicity assessments; 
6. For patients randomized to the enoxaparin arm or SelK2 + enoxaparin arm, enoxaparin 
dosing; 
7. Venography; 
8. Record concomitant medications and transfusions; and 
9. Assessment of AEs. 
 
Patients can be released from the hospital or clinic following completion of all assessments on Day 
11. 
 


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6.4 
Follow-Up Phase 
The schedule of assessments and procedures to be performed during the Follow-up Phase are 
outlined below by Study Day and in the “Study Schedule of Events” (see Table 1). 
 
6.4.1 
Day 21 
Patients will undergo the following procedures on Day 21. 
1. Abbreviated physical examination;  
2. Vital signs including sitting blood pressure, pulse rate, respiratory, and temperature after 
sitting for 3-5 minutes; 
3. Collection of clinical laboratory samples (blood and urine) to be shipped to the central lab 
for evaluation of hematology, blood chemistry, coagulation parameters and urinalysis; 
4. Collection of blood samples for hsCRP and D-dimer assessments; 
5. For patients randomized to the SelK2 arm or SelK2 + enoxaparin arm, collection of blood 
samples for PK, PD, and immunogenicity assessments; 
6. Record concomitant medications and transfusion; and 
7. Assessment of AEs. 
 
6.4.2 
Day 29 
Phone contact to assess the following: 
1. Record concomitant medications and transfusions; and 
2. Assessment of AEs. 
 
6.4.3 
Day 43 
Phone contact to assess the following: 
1. Record concomitant medications and transfusions; and 
2. Assessment of AEs. 
 
6.4.4 
Day 57 
Patients will undergo the following procedures on Day 57. 
1. Complete physical examination;  
2. 12-lead ECG; 
3. Vital signs including sitting blood pressure, pulse rate, respiratory, and temperature after 
sitting for 3-5 minutes; 
4. Collection of clinical laboratory samples (blood and urine) to be shipped to the central lab 
for evaluation of hematology, blood chemistry, coagulation parameters and urinalysis; 
5. Collection of blood samples for hsCRP and D-dimer assessments; 


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6. For patients randomized to the SelK2 arm or SelK2 + enoxaparin arm, collection of blood 
samples for PK, PD, and immunogenicity assessments; 
7. Record concomitant medications and transfusions; and 
8. Assessment of AEs. 
 
The completion of assessments listed above on Day 57 marks the completion of each patient in this 
study. 
 
Patients should be reminded that they must remain on a highly effective contraceptive 
method until 30 days after their Final Study Visit. 
 
 
6.4.5 
Early Discontinuation Visit 
IMPORTANT NOTE:  For patients that are early terminating from the study, site personnel 
should make every effort to have patients undergo an Early Discontinuation Visit which has 
assessments identical to those done for the final safety visit on Day 57. 
Patients will undergo the following procedures at their Early Discontinuation Visit 
1. Complete physical examination;  
2. 12-lead ECG; 
3. Vital signs including sitting blood pressure, pulse rate, respiratory, and temperature after 
sitting for 3-5 minutes; 
4. Collection of clinical laboratory samples (blood and urine) to be shipped to the central lab 
for evaluation of hematology, blood chemistry, coagulation parameters and urinalysis; 
5. Collection of blood samples for hsCRP and D-dimer assessments; 
6. For patients randomized to the SelK2 arm or SelK2 + enoxaparin arm, collection of blood 
samples for PK, PD, and immunogenicity assessments; 
7. Record concomitant medications; and 
8. Assessment of AEs. 
 
6.5 
Measurements and Assessments 
Details of specific efficacy, safety, PK, and PD assessments are provided in this section.  
Additional details are provided in the Laboratory Manual. 
6.5.1 
Efficacy Assessments 
6.5.1.1 
Venography 
A unilateral ascending venogram of the operated leg is to be performed for each study patient 
between Day 9 and Day 13 of the study, approximately 10 days after completion of TKA.  The 
Manual for Venography and Event Reporting describes instructions for the venography and image 
acquisition.  A venography will be evaluable when images with multiple views of all the deep veins 
of the leg can be evaluated (only exception is the deep femoral vein which sometimes difficult to 
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6.5.1.2 
Suspected Symptomatic VTE  
Patients will be evaluated for signs and symptoms of DVT (e.g., swelling, localized pain, redness, 
heat, localized warmth) and PE (e.g., unexplained shortness of breath, coughing up blood, chest 
pain that gets worse with a deep breath, unexplained coughing) during the post-surgery in 
hospital/clinic period and at all visits occurring throughout the Treatment and Follow-up Phases of 
the study. Patients with suspected DVT and or PE should undergo further diagnostic testing per 
hospital routine (e.g compression ultrasound for suspected DVT and spiral CT scan for patients 
with PE). Every suspected episode of DVT or PE must be reported appropriately as an AE and the 
underlying supportive data (e.g images and reports of diagnostic tests, hospital reports) will be 
submitted for adjudication by the CIAC. The Study Site Manual for Venography and Event 
Reporting provides instruction on the documentation, data collection, and reporting required for 
each suspected episode of DVT or PE.  
If patients would have a PE or DVT confirmed by diagnostic testing during the Treatment Phase, 
the planned venography of the operated leg is not required.   
If a patient would have an event that requires therapeutic anticoagulant treatment, the prophylactic 
dosing of enoxaparin will need to be discontinued.  The anticoagulant treatment undertaken will be 
at the discretion of the treating physician and any question regarding SelK2 should be referred to 
the medical monitor by contacting the medical help line. 
 
6.5.1.3 
Laboratory Markers of Inflammation and Thrombosis 
Blood sampling will be collected on Screening, Day 1, Day 4, Day 6 (optional), Day 11, Day 21, 
and Day 57 for assessment of hsCRP and D-dimer. 
 
6.5.1.4 
Pharmacokinetic and Pharmacodynamic Assessments of 
SelK2 
Blood sampling will be performed to supply 2 mL of serum for PK evaluations and 2 mL of serum 
for PD evaluations in patients randomized to SelK2 arm or adaptive arm. Blood samples will be 
collected via an indwelling catheter and/or via direct venipuncture. Please note that since the PK 
and PD samples will generally be collected at the same time points, one tube will be used to collect 
both samples and then samples aliquoted accordingly. 
 
Blood sampling will be collected on Day 1 (pre-dose SelK2), Day 2 (prior to TKA), Day 4, Day 6 
(optional), Day 11, Day 21, and Day 57 for assessment of PK and PD. 
 
The exact date and sampling time will be recorded on the appropriate eCRF page.  Please refer to 
the Laboratory Manual for details of collection, storage, and shipping of samples.  
 
The PK and PD assays will be performed at Cytovance Biologics, 840 Research Parkway, Suite 
400, Oklahoma City, Oklahoma, USA 73104. 
 


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6.5.2 
Safety Assessments 
Safety assessments for this study include the following: 
6.5.2.1 
Adverse Events 
Adverse events will be assessed by standard non-leading questions. All clinical AEs occurring 
from Randomization on Day 1 and up until the Day 57 visit whether observed by the investigator 
or reported by the patient will be assessed, documented, and reported in accordance with ICH GCP 
guidelines.  Section 7.0 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs.  A separate document that details AE eCRF completion 
guidelines for Investigators as well as training will be provided. 
6.5.2.1.1 
Bleeding  
All suspected bleeding events are to be reported and additional examination will be done if deemed 
necessary by the investigator depending on the type of bleeding (e.g. hematology blood sample, 
endoscopy).  If a patient has a hemorrhagic stroke both stroke and bleeding will be reviewed.  
Narratives of bleeding events should be detailed and contain the following elements at the 
minimum:  
• 
Location of the bleeding  
• 
Size (in case of hematoma) 
• 
Duration   
• 
Provocation e.g. associated with any procedure 
• 
Hemoglobin values prior and after bleeding if available  
• 
Any transfusion or medication given  
Other bleeding related parameters should be recorded during the trial: 
• 
Hb level, HCT and red cell count changes during the treatment period 
• 
Blood loss (peri-, post-operative) quantified by the routine method in each hospital 
• 
Number of transfusions of packed red cells and transfused quantities until follow-up 
(e.g., 30 days after surgery; homologous and autologous transfusions need to be 
distinguished) 
If a decrease in hemoglobin, blood loss or more transfusions are given than expected following 
TKA a suspect bleeding event needs to be reported and the narrative as specified above needs to be 
completed. 
The data of all reported bleeding events or potential bleeding event must be submitted to the CIAC. 
The Study Site Manual for Venography and Event Reporting provides instruction for sites on the 
documentation, data collection, and reporting required for each suspected bleeding event.  
Approach to Patients With Acute Bleeding  


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The following steps are recommended for patients with ongoing life-threatening bleeding (bleeding 
resulting in hemodynamic compromise requiring intervention or any intracranial hemorrhage): 
• 
Withhold enoxaparin and all other anticoagulant/antiplatelets; 
• 
Institute standard of care for life-threatening bleeding (large bore IV or central venous 
line, type and crossmatch blood, admit to the intensive care unit, provide 
hemodynamic and respiratory support); 
• 
Administer antidotes if applicable (e.g., administer protamine if the patient had 
recently received heparin); and 
• 
Administer packed red blood cells (or whole blood) as needed. 
Use of prothrombin complex concentrates (PCCs), recombinant Factor VIIa, other factor 
procoagulants, or antifibrinolytics (depending upon the clinical situation and local availability) 
should be considered in consultation with a local available hematology expert. The SelK2 Medical 
Support Line (+32 495 54 74 51) can be contacted to discuss patient management (English 
language only). 
6.5.2.1.2 
Stroke 
If a patient has a suspected stroke, the diagnostic work-up should be performed according to the 
hospital routine (it is expected that CT scans/MRI of the brain are done).  Stroke will be reviewed 
by the CIAC to evaluate whether hemorrhagic stroke was present which will be considered as a 
major bleeding event. 
6.5.2.1.3 
Death 
For patients who died, the adjudication committee will need to classify cause of death and will 
attribute death to PE if no other cause can be identified. 
It is therefore crucial to provide a detailed description including the sequence of events preceding 
death (e.g. “patient gradually deteriorated and was found dead, or patient became suddenly short of 
breath and collapsed). 
6.5.2.2 
Clinical laboratory measurements 
Blood (for hematology/CBC and clinical chemistry panel) and urine samples (for urinalysis) will 
be collected according to the Study Schedule of Events and analyzed at a central laboratory. All 
blood samples will be collected while patients are in a seated or supine position. Specific 
instructions for the collection, processing, and shipment of samples will be provided in the 
Laboratory Manual. Laboratory test results that are abnormal and considered clinically significant 
must be reported as AEs. Screening laboratory results must be available before randomization. 
All of the major clinical laboratory assessments (including Clinical Chemistries, Hematology/CBC, 
complete Urinalysis (UA), coagulation parameters (PT/INR and aPTT) will be conducted at the 
central laboratory.  In addition, at screening, samples for HIV (HIV antibody), Hepatitis B 
(HBsAg), Hepatitis C (Anti-HCV antibody) and serum pregnancy (women only) will be collected 
for analysis at central laboratory.  All supplies for clinical laboratory sample collection will be 
provided in the form of kits from the central laboratory.   


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The samples for laboratory assays and the visits at which these samples will be collected 
are indicated in Table 1 (Study Procedures Schedule of Events). 
 
Table 2 provides an exhaustive and complete listing of all the clinical laboratory assessments that 
will be included in this study. 
 
 
 
Table 2. Listing of All Clinical Laboratory Assays Included in Clinical Chemistry, 
Hematology (CMC), Complete UA and Coagulation Parameters 
Chemistry: 
Hematology (CBC): 
Complete UA: 
Albumin 
Hematocrit 
pH and Specific Gravity 
Alkaline Phosphatase 
Hemoglobin 
Glucose 
Alanine Transaminase (ALT) 
MCH 
Protein 
Aspartate Transaminase (AST) 
MCHC 
Blood 
Blood urea nitrogen (BUN) 
MCV 
Ketones 
Calcium 
MPV 
Reflexive Microscopic analysis 
(including RBCs 
 and WBCs per high power 
field) 
Chloride 
Platelet count 
 
Bicarbonate/Carbon Dioxide 
(CO2) 
Red blood cell distribution width 
(RDW) 
Coagulation Parameters: 
Creatinine 
Red blood cell (RBC) count 
Prothrombin Time/International 
Normalized Ratio (PT/INR) 
Direct Bilirubin 
White blood cell (WBC) count 
activated Partial 
Thromboplastin Time (aPTT) 
Gamma glutamyl transferase 
(GGT) 
White blood cell differential 
 
Glucose 
 (% & Absolute): 
 
Lactate Dehydrogenase (LDH) 
 Basophils 
 
Phosphorus 
 Eosinophils 
 
Potassium 
 Lymphocytes 
 
Sodium 
 Monocytes 
 
Total Bilirubin 
 Neutrophils 
 
Total Protein 
 
 
Uric acid 
 
 
 
6.5.2.3 
Physical examination and vital signs 
A complete physical examination and vital signs assessment will be performed at select study 
visits, as listed in the study schedule of events. A complete physical examination includes a review 
of the following systems: general appearance, head/eyes/ears/nose/throat (HEENT); neck; 
respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and neurological. At all 
other scheduled visits, an abbreviated physical examination including exam of general appearance, 
skin, respiratory, cardiovascular, and abdomen will be conducted. 
Vital signs including sitting blood pressure (systolic and diastolic), pulse rate, respiratory rate, and 
temperature will be collected after sitting for 3-5 minutes.  Body weight will also be measured.  


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After Screening, any clinically significant abnormal findings in physical exams or clinically 
significant vital signs should be reported as AEs. 
6.5.2.4 
12-lead ECGs 
Standard, digital, 12-lead ECGs will be performed at all time points as indicated in the Study 
Schedule of Events. Additional 12-lead ECGs should be performed at any other time if clinically 
indicated. The performance of all ECGs must adhere to the following guidelines: 
• 
All standard digital ECGs will be performed after the patient has been supine for at least 5 
minutes. 
• 
The ECG will be performed before any other procedures that may affect heart rate (e.g., 
blood draws). 
• 
The ECG will be performed prior to dosing. 
• 
When ECG time points coincide with PK blood sampling time points, the ECG must be 
performed before blood sampling so that any patient’s response to the blood sampling does 
not cause a change in ECG interval durations.   
 
A hard copy of the ECG will be printed at the site. To ensure safety of the patients, the Investigator 
or designee at the Investigator site will make comparisons to baseline measurements, which is 
defined as the most recent non-missing (scheduled or unscheduled) measurement collected prior to 
the initial administration of study drug. If a clinically significant finding is noted at any time on 
ECG, site will follow-up with a cardiology consult to verify initial ECG findings and further 
evaluate safety of patient. 
See Study Procedures or Study Schedule of Events (Table 1) for assessment days. 
6.5.2.5 
Immunogenicity (anti-SelK2 antibodies) assessment 
Serum samples will be collected according to the procedure described below: 
Blood sampling will be performed to supply at least 1 mL of serum for immunogenicity 
assessments in patients randomized to the SelK2 arm or adaptive arm.  Blood samples will be 
collected via an indwelling catheter and/or via direct venipuncture.  
The exact date and sampling time will be recorded on the appropriate eCRF page.  Please refer to 
the Laboratory Manual for details of collection, storage, and shipping of samples. 
Immunogenicity evaluations will be performed at Cytovance Biologics, 840 Research Parkway, 
Suite 400, Oklahoma City, Oklahoma, USA 73104. 
6.5.2.6 
Urine Pregnancy test 
A urine pregnancy tests will be performed on all woman of child-bearing potential at the site on the 
Day 1 prior to randomization.  If the urine pregnancy test is positive and confirmed as correct, 
patient will not be allowed to be randomized into this clinical study. 
 
 


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7.0 
ADVERSE EVENTS INCLUDING SPECIAL REPORTING 
REQUIREMENTS FOR POTENTIAL VTE AND BLEEDING 
ENDPOINT EVENTS 
7.1 
Procedures for Handling and Reporting Adverse Events 
7.1.1 
Adverse Event 
An adverse event (AE) is any undesirable medical event affecting a patient during a clinical trial.  
An AE can therefore be defined as any sign, symptom, syndrome, or new illness that appears while 
a patient is participating in this clinical study (from Randomization to final study visit (either Day 
57 Visit or Early Discontinuation Visit)) or, if present at baseline, worsens in a patient during the 
period of observation in the clinical study and that may impair the well-being of the patient.  The 
term also covers laboratory findings or results of other diagnostic procedures that are considered to 
be medically important (e.g., that require unscheduled diagnostic procedures, treatment measures, 
or result in withdrawal from the study).  An AE may or may not have a causal relationship with the 
study drug.  The period of observation for AEs is defined as from the point at which the patient is 
randomized into the study to the completion of the Follow-Up Phase assessments at Day 57 (or the 
Early Discontinuation Visit, if patient early discontinues).  
An AE may be: 
• 
A new illness; 
• 
Worsening of a sign or symptom of the condition under treatment or of a concomitant 
illness; 
• 
An effect of the study drug; 
• 
Unrelated to participation in the clinical study; or 
• 
A combination of one or more of these factors. 
 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery.  However, the condition for which the surgery is required may be an AE.  Planned 
surgical measures permitted by the study protocol and the condition(s) leading to these measures 
are not AEs. 
Each AE is to be recorded only once on the “Adverse Event” eCRF page with seriousness and 
maximum intensity that occurred over the duration of the event.  Each event also should be 
evaluated with respect to causality and actions taken.  All AEs are to be monitored and recorded 
from the point of study Randomization through Day 57 (or earlier if patient discontinues from the 
study).  For all AEs that require the patient to be discontinued from the study, the event(s) will be 
followed until final resolution or stabilization of the event(s).  Note that unexpected SAEs should 
be reported as outlined in Section 7.1.2.  Adverse events may be identified by spontaneous patient 
report or from standardized open-ended verbal probes.  
The Investigator will classify and evaluate each AE as follows: 
• 
Seriousness (see definition of SAEs in Section 7.1.2); 
• 
Intensity (“Mild” [does not interfere with daily activities]; “Moderate” [interferes with 
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• 
Relationship to study drug (Not Related [clearly not related to study drug], Unlikely 
Related [doubtfully related to the study drug], Possibly Related [may be related to study 
drug], Probably Related [likely related to study drug] or Definitely Related [clearly related 
to study drug]);   
• 
Action taken (None, Required concomitant medication, Other [explain]); and 
• 
Outcome (Recovered without sequelae, Resolved with sequelae, Ongoing, Unknown, 
Death). 
 
Procedures Regarding Pregnancy 
Pregnancy is considered an AE. Should a female patient become pregnant (must be confirmed by 
the serum pregnancy test) during the study, the medical monitor should be immediately notified, 
and the patient followed to term.  Should the female partner of a male patient become pregnant 
during the male patient’s enrollment in this study, the medical monitor should be immediately 
notified, and the male patient’s partner should be followed to term, if consent is received by her. 
 
7.1.2 
Serious Adverse Event 
A serious adverse event (SAE) is any AE that, at any dose of study drug or at any time during the 
period of observation: 
• 
Results in death; 
• 
Is immediately life-threatening; 
• 
Requires or prolongs in-patient hospitalization; 
• 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions; 
• 
Involves congenital anomaly or malignancy; 
• 
Is medically important; or 
• 
Requires medical intervention to prevent permanent impairment or damage. 
 
Hospital admissions and/or surgical operations planned before or during a study are not considered 
AEs/SAEs if the illness or disease existed before the patient was enrolled in the study, provided 
that it did not deteriorate in an unexpected way during the study. 
“Medically important events” are events that may not be immediately life threatening or result in 
death or hospitalization, but may jeopardize the patient or require intervention to prevent one of the 
other outcomes listed in the definition above.  Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or the development of drug dependency or drug abuse.  Such events 
should be documented and reported as SAEs via data entry into the appropriate eCRF (see 
Reporting Requirements below). 
“Events requiring medical intervention to prevent permanent impairment or damage” are events 
where the Investigator believes that medical or surgical intervention is necessary to preclude 
permanent impairment of a body function or to prevent permanent damage to a body structure.  As 
there is an overlap between the terms "medically important event" and "events requiring medical 


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intervention to prevent permanent impairment or damage", it is left to the discretion of the 
Investigator to select the more applicable of the two criteria when entering data on the eCRF about 
the SAE. 
Reporting Requirements for Serious Adverse Events Are As Follows: 
All serious adverse events (SAEs) that occur from the time of randomization through the end of the 
study (Day 57 Visit), whether or not considered related to study drug, must be reported via data 
entry into the appropriate eCRF or fax within 24 hours of occurrence. 
Sites will be provided with phone and faxline numbers for each country, on the paper SAE back up 
form. 
All SAEs should be reported immediately to the sponsor except for those SAEs that the protocol or 
other document (e.g., Investigator's Brochure) identifies as not needing immediate reporting. The 
immediate reports should be followed promptly by detailed, written reports. The immediate and 
follow-up reports should identify subjects by unique code numbers assigned to the trial subjects 
rather than by the subjects' names, personal identification numbers, and/or addresses. The 
investigator should also comply with the applicable regulatory requirement(s) related to the 
reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the 
IRB/IEC. 
The Sponsor or its designated Contract Research Organization (CRO) will ensure that all 
regulatory reporting requirements are met. 
 
7.1.3 
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards 
The sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations. The investigator must comply with any applicable site-specific 
requirements related to the reporting of SAEs (and in particular deaths) involving his/her subjects 
to the IEC/IRB that approved the trial. In accordance with ICH GCP guidelines, the sponsor will 
inform the investigator of “findings that could adversely affect the safety of subjects, impact the 
conduct of the trial, or alter the IEC’s/IRB’s approval/favorable opinion to continue the trial.” In 
particular and in line with respective regulations, the sponsor will inform the investigator of AEs 
that are both serious and unexpected and are considered to be related to the administered product 
(“suspected unexpected serious adverse reactions” [SUSARs]). The investigator should place 
copies of Safety reports in the Investigator Site File. National regulations with regard to Safety 
report notifications to investigators will be taken into account. When specifically required by 
regulations and guidelines, the sponsor will provide appropriate Safety reports directly to the 
concerned lead IEC/IRB and will maintain records of these notifications. When direct reporting by 
the sponsor is not clearly defined by national or site-specific regulations, the investigator will be 
responsible for promptly notifying the concerned IEC/IRB of any Safety reports provided by the 
sponsor and of filing copies of all related correspondence in the Investigator Site File. For trials 
covered by the European Directive 2001/20/EC, the sponsor’s responsibilities regarding the 
reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with that Directive and 
with the related Detailed Guidances. 
 


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7.2 
Adverse Events that are Potential Study Endpoint Events 
Please note that AEs and SAEs that are listed below are being captured as events defined as 
endpoints for this clinical study (both efficacy and safety endpoints).    
Symptomatic events that will be adjudicated include the following: 
 
• 
Suspected symptomatic DVT 
• 
Suspected symptomatic PE 
• 
Suspected bleed 
• 
Suspected stroke 
• 
Death 
• 
Suspected arterial thrombotic events (e.g., myocardial infarction, ischemic stroke, etc.) 
 
Whenever the site becomes aware of one of these clinical events, it is crucial that the event is 
reported as soon as possible, preferably within 24 hours. These events must be reported following the 
rules as outlined for all adverse events in Section 7.1. 
 
An appropriate event adjudication dossier will need to be submitted even if a suspected event is 
not confirmed by tests locally, for example if imaging did not confirm a new clinical event. 
 
7.2.1 
Reporting Requirements for AE’s that are Potential Study 
Endpoints 
The Study Site Manual for Venography and Event Reporting provides instruction for sites on the 
documentation, data collection, and reporting required for events considered (suspected) endpoints.  
Typically for the above clinical events of suspected symptomatic DVT, suspected symptomatic PE, 
bleeding, stroke, or death, data will be collected in order to generate an adjudication dossier which 
will consist of eCRF data and supportive documentation which is assembled for review by the 
CIAC. 
All suspected clinical outcomes must be reported as adverse events. Reporting a suspected outcome 
as an adverse event on the AE page in eCRF will automatically trigger an event specific form (refer 
also to eCRF completion guidelines). The eCRF triggered event forms contain a narrative section. 
In this narrative, a short clinical description should be provided: e.g. including symptom 
description and duration, eventually performed diagnostic tests or intervention with dates and 
description.  
The supportive documentation (adjudication dossier) will depend on the type of clinical event and 
will typically consist of images and reports of the diagnostic tests done to explore the suspected 
clinical event, and other reports that could be relevant to the CIAC (e.g. medical records and/or 
hospital letters, discharge summaries, laboratory tests). 


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7.3 
Monitoring of Subjects with Adverse Events 
Any AE that occurs during the course of a clinical trial and is considered to be possibly related to 
the study drug must be monitored and followed up by the investigator until stabilization or until the 
outcome is known, unless the subject is documented as “lost to follow-up”. Reasonable attempts to 
obtain this information must be made and documented. It is also the responsibility of the 
investigator to ensure that any necessary additional therapeutic measures and follow-up procedures 
are performed. The sponsor will actively follow-up and collect information on any AE that occurs 
during the course of a clinical trial, however while this activity will continue for any serious AEs 
until stabilization or until the outcome is known, it will be discontinued at the time of database lock 
for non-serious AEs. 
 
7.4 
Treatment Interruption or Discontinuation 
If an adverse reaction occurs during the administration of study drug, the infusion rate may be 
slowed or interrupted and the appropriate supportive measures instituted at the discretion of the 
physician. If the infusion is slowed, the total infusion time should not exceed two hours. Monitor 
the patient for at least one hour following completion of the infusion for signs or symptoms of an 
infusion reaction. 
 
As with all protein products, administration of study drug may result in infusion reactions, 
including anaphylaxis or other hypersensitivity reactions. The infusion should be discontinued 
immediately if the patient experiences a serious infusion reaction such as signs of cardiovascular 
instability or respiratory compromise, and the appropriate supportive measures instituted. Patients 
should be evaluated and carefully monitored until complete resolution of signs and symptoms.  
 
 
 
 
 
 
 
 


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8.0 
PATIENT WITHDRAWAL, REMOVAL OR SITE 
TERMINATION  
8.1 
Withdrawal or Removal of Patient From Study 
Patients may withdraw from the study (withdraw consent) or be withdrawn by PI under the 
following circumstances: 
• 
At their own request or at the request of their legally authorized representative; 
• 
Patient is lost to follow-up;  
• 
Investigator deems it necessary to stop study drug administration (e.g., for safety or for 
non-compliance to protocol); or 
• 
At the specific request of the Sponsor. 
 
In all cases, the reason for withdrawal must be recorded in the eCRF and in the patient's 
medical records.  The patient must be evaluated to establish whether the reason was an AE, 
and, if so, this must be reported in accordance with the procedures outlined in Data Handling 
Procedures (see Section 9.0). 
Even if the patient has decided to discontinue from the other study procedures, the Early 
Discontinuation Visit assessments should be performed approximately eight weeks after the 
patient’s Day 1 (randomization) visit, if possible.  In addition, those female patients required 
to use acceptable birth control during the study must be reminded that they should continue 
this form of birth control for a total of 10 weeks after receiving a dose of SelK2. The 
Investigator must make every effort to contact patients lost to follow-up on at least 
2 occasions, including sending the patient a letter by certified mail (return receipt). 
Occasionally patients may also withdraw consent to allow further data collection.  Under such 
conditions, completion of the scheduled events, procedures, and assessments as specified in the 
protocol will not be possible.  A record of the reason for discontinuation of data collection should 
be made on the appropriate eCRF page. 
8.2 
Termination of Study 
The study may be terminated at any time for the following reasons:  1) Investigator/IRB/EC at a 
specific site after consultation with the Sponsor stops study for safety reasons; 2) Sponsor may also 
stop the study at one or more sites due to safety, site noncompliance, loss or lack of data quality, or 
project termination; 3) if the governing Regulatory Agency mandates study stop; or 4) for safety if 
recommended by the Steering Committee with Sponsor agreement.  If the study is stopped at a site 
due to the action of the Investigator/IRB/EC, IQVIA and the Sponsor should be informed 
immediately.  See Section 12.8 for further instructions on premature closure of the study.   
 


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9.0 
DATA HANDLING PROCEDURES 
9.1 
Electronic Case Report Form Completion 
Access to the eCRF will be granted to Investigator and/or delegated staff after completion of proper 
training.  Data from source documents will be entered directly onto the eCRF by the Investigator or 
designated representative.  The eCRF must be reviewed by the Investigator.  The eCRF should be 
kept current to allow the clinical monitor to be able to review the patient’s current status.  Once the 
patient has completed the study and all data have been entered onto the eCRF, the eCRFs will be 
electronically signed by the Investigator.   
9.2 
Database Construction 
Missing data and inconsistencies will be identified through an extensive computerized editing 
procedure.  The accuracy of the clinical database will be verified through a series of reviews of data 
listings and other pertinent data processing reports.  As a final quality control measure, the database 
will be proofread and the data listings will be reviewed to ensure that they are understandable, 
complete, and reliable.   
 


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10.0 
STATISTICAL METHODS AND PLANNED ANALYSES 
10.1 
Sample Size and Power 
Assuming that the rate of VTE for the active comparator (enoxaparin) arm of this study will be 
25%, it is estimated that a sample size of 76 evaluable patients per arm should give the study 80% 
power of declaring non-inferiority between the SelK2 arm and the enoxaparin active comparator 
arm.  This calculation uses a one-sided 90% CI with a non-inferiority margin of 15%.  This 
calculation assumes that the underlying rate of VTE for the SelK2 and enoxaparin arms will be 
identical at 25% and with the non-inferiority margin set as at the midpoint between the expected 
active therapy response compared to an assumed placebo event rate in this patient population of 
55%.  Consequently, making the conservative estimate that up to 20% of randomized patients may 
not yield evaluable endpoint data, a total of 95 patients will be enrolled per arm to provide at least 
76 endpoint evaluable patients per arm.  
  
Sample Size Considerations for Adaptive Arm: 
 
With the same assumptions as above the for active comparator (enoxaparin) arm of the study event 
rate, it is estimated that a sample size of 76 evaluable patients in a combination therapy arm of 
SelK2 and enoxaparin should give the study 80% power of declaring superiority between the 
SelK2 and enoxaparin arm and the enoxaparin active comparator arm for an estimated SelK2 and 
enoxaparin VTE event rate of 6% (an 19% difference between combination treatment effect and 
active comparator treatment effect).  This calculation assumes a two-sided 0.1 alpha, a Pearson 
Chi-squared test, and a superiority comparison. 
10.2 
Analysis Populations 
Assignment of patients to analysis populations will be done prior to clinical data lock for the study. 
The following populations will be defined: Intent-to-Treat (ITT), modified Intent-to-Treat (mITT), 
Per-Protocol (PP), and Safety. 
Intent-to-Treat (ITT): All patients who are randomized. The ITT population will be analyzed by 
randomized treatment group. 
Modified Intent-to-Treat (mITT): All patients in the ITT population who also have a successful 
venogram or symptomatic VTE event which allow for assessment of the primary efficacy outcome.   
Per-Protocol (PP): All mITT patients who complete the study and have no major protocol 
violations that will impact the efficacy assessments.   
Safety: All patients who received at least 1 dose of study drug. Safety population will be analyzed 
by actual treatment received. 
 
10.3 
Statistical Analysis 
10.3.1 
General Considerations 
Descriptive summary statistics include mean, median, standard deviation, interquartile range, and 
range (minimum, maximum) for continuous variables, and counts and percentages for categorical 


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variables.  Unless otherwise specified, continuous variables will be analyzed using two-sample t-
test or Wilcoxon-Mann-Whitney test, whichever is appropriate; and categorical variables will be 
analyzed using chi-squared test or Fisher’s exact test, whichever is appropriate. 
 
SAS 9.3 or later will be used to perform statistical analysis.  Unless otherwise specified, a two-
sided p-value less than 0.05 will be considered statistically significant.  No multiplicity adjustment 
will be made.  
 
10.3.2 
Background Characteristics 
10.3.2.1 
Patient Disposition 
Both number and percentage of patients in the following categories will be summarized as 
appropriate:  
• 
Randomized; 
• 
Safety Population; 
• 
ITT Population; 
• 
mITT Population 
• 
PP Population; 
• 
Completed treatment visits; and 
• 
Prematurely discontinued the study and the reasons for discontinuations. 
Reasons for discontinuation and major protocol violations will be summarized by treatment groups 
for the ITT and mITT populations. 
 
10.3.2.2 
Demographics, Background, and Baseline Characteristics 
Demographics, background (e.g., medical history), and baseline characteristics will be 
summarized. Protocol deviations/violations will be provided as a patient data listing only. Major 
protocol deviations/violations will be identified for analysis purposes. 
The demographics and baseline characteristics summary will be presented for the ITT, mITT, PP, 
and safety populations to allow review of the characteristics of those included in the efficacy and 
safety analyses, which will be based on these analysis populations. Background (e.g., medical 
history) summary will be presented for the ITT population only. 
 
10.3.2.3 
Prior and Concomitant Medications 
Medications used in this study will be coded by the World Health Organization Drug Dictionary 
(WHODD), and summarized as frequency tables for the preferred terms in 2 parts: 
• 
Prior medication: any medication that started prior to the first dose of study drug, regardless 
of when it ended (collected for medications given up to 6 months prior to Day 1). 


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• 
Concomitant medication: medication received at or after dosing of study drug, or 
medication that was received prior to dosing with study drug and continued after dosing of 
study drug.   
If medication start date is on the day of or after the first dose of study drug, then medication will be 
summarized as concomitant medication regardless of whether the medication end date is missing or 
not. If the medication end date is before the date of first dosing of study drug, then the medication 
will be summarized as prior medication regardless of whether the medication start date is missing 
or not. Note that medication that started prior to first dosing of study drug and continued after 
dosing will be summarized as prior medication and separately as concomitant medication. Both 
prior and concomitant medications will be based on the ITT population. For medications with 
partial start dates, missing month will be imputed with January and missing day will be imputed 
with 1. For medications with partial stop dates, missing month will be imputed with December and 
missing day will be imputed with the last day of the month. 
 
10.3.3 
Efficacy Analyses 
For all efficacy analyses, the main analysis will be based on the mITT population.  Both primary 
and secondary endpoint analyses will also be performed on the PP population; these analyses will 
be supportive only.  Comparisons will be made between the SelK2 treated patients SelK2 and 
enoxaparin treated patients, and the enoxaparin group.  The difference of the total VTE rate during 
the Treatment Phase (from time of randomization up until the day of completion of venogram) 
between the SelK2, SelK2 and enoxaparin, and enoxaparin treatment groups will be estimated.  
The lower 1-sided 90% CI of the difference will be calculated and non-inferiority will be 
concluded if the upper limit of the 90% CI is ≤ 15%. The same analysis will be completed on the 
PP population. 
 
The following secondary analyses will be performed on the mITT and PP populations: 
 
- 
Comparison of the rates of the individual components of the primary efficacy outcome 
between the SelK2, SelK2 and enoxaparin, and enoxaparin treatment groups through 
Treatment Period. 
 
- 
Conduct primary efficacy analysis of the total VTE rate between the SelK2 treatment, 
SelK2 and enoxaparin treatment, and enoxaparin treatment with the inclusion of events 
through Study Day 57. 
 
- 
Complete comparison of the rates of the indivudal components of the primary efficacy 
outcome between the SelK2, SelK2 and enoxaparin, and enoxaparing treatment groups 
with the inclusion of events through Study Day 57. 
 
Absolute changes from baseline in hsCRP and D-dimer will be summarized by treatment group at 
each post-baseline visit.   Change from baseline in each parameter will be analyzed and compared 
between treatment groups using a mixed linear model with repeated measures (MMRM).  
 
 
10.3.4 
Pharmacokinetics and Pharmacodynamics 
Serum pre- and post-treatment SelK2 concentrations for evaluable patients receiving SelK2 will be 
listed by dose, day and patient and also summarized by descriptive statistics. 
 


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Potential relationships between selected pharmacodynamics and plasma exposure measures may be 
explored, where deemed appropriate. 
10.4 
Safety Analysis 
All treatment-emergent AEs and SAEs will be summarized by treatment using the MedDRA 
coding system, by system organ class, preferred term, relationship to Study Drug and severity (See 
Section 10.4.1).   
Incidence of bleeding events (as adjudicated by the CIAC) including the following will be 
tabulated by treatment: 
1) Major Bleeding event (MB),  
2) Clinically Relevant Non-Major Bleeding event (CRNMB),  
3) Minor Bleeding event, or  
4) Combination of MB and CRNMB  
 
Additionally, the overall safety profile of study drug will be assessed in terms of the following 
safety and tolerability endpoints:  
• 
Incidence of treatment-emergent adverse events (TEAEs), 
• 
Clinical laboratory values (hematology, serum chemistries, urinalysis, and coagulation 
parameters), 
• 
ECGs, 
• 
Vital signs. 
 
These safety endpoint measures will be tabulated by treatment arm and study visit (and timepoint, 
where appropriate) and may also be presented as change and percent change from baseline, as 
appropriate. 
Safety analysis will be based on the set of data associated with the period from randomization 
through the final Follow-Up Phase visit (Day 57). All Safety analyses will be performed on the 
safety population. Descriptive analysis of the above safety parameters will be performed.   
10.4.1 
Adverse Events 
For analyses purposes, adverse events will be classified as pre-treatment emergent, treatment 
emergent, or post-treatment emergent. Adverse events which start (or increase in severity) during 
the period from the signing of informed consent up to, but not including, the first dose of study 
drug will be considered pre-treatment emergent. Adverse events which start (or increase in 
severity) during the period from the first dose of study drug through completion of the final 
Follow-up Visit (Day 57) will be considered treatment emergent. Adverse events which start (or 
increase in severity) after the completion of the Follow-Up Visit will be considered post-treatment 
emergent. For AEs with partial start dates, missing month will be imputed with January and 
missing day will be imputed with 1. 


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Adverse event summary tables will be presented for AEs only and will include the following: 
• 
All treatment-emergent adverse events (TEAEs) or by severity or by relationship, 
• 
Related (defined as possibly related or related) TEAEs, 
• 
TEAEs leading to treatment discontinuation, 
• 
Serious TEAEs, and 
• 
Frequently reported TEAEs. 
 
Summaries will be presented by Medical Dictionary for Regulatory Activities (MedDRA) system 
organ class and preferred term using frequency counts and percentages (i.e., number and 
percentage of patients with an event as well as total number of events). Patients with multiple 
occurrences of the same adverse event or a continuing adverse event will be counted once; only the 
maximum severity level of this AE will be presented in the severity summaries; and only the 
worst/highest relationship level of this AE will be presented in the relationship summaries. A 
separate table will summarize all TEAEs when each of them is considered unique, hereafter 
referred as adverse event count table. In addition, a listing containing individual patient adverse 
event data for all deaths and other serious and significant adverse events will be provided, 
separately. All adverse events including pre- and post-treatment adverse events will be presented in 
individual patient data listings. 
Narratives of deaths, serious and significant adverse events, including early withdrawals due to 
adverse events, will also be provided. 
10.4.2 
Clinical Laboratory Assessments 
For results reported by the central laboratory, continuous hematology and chemistry results will be 
summarized in SI units by treatment group at each scheduled time point. Visits summarized will 
include baseline and post baseline visits, including early termination and Follow-Up. Changes from 
baseline will also be summarized at each time point. The number and percentage of patients with 
shift changes from baseline based on the laboratory normal ranges will be tabulated by treatment 
group and scheduled time point.  
Urinalysis results and serum pregnancy test results will be listed in individual patient data listings 
only. In addition, a listing containing individual patient hematology, chemistry, and coagulation 
values outside the reference ranges will be provided. This listing will include data from scheduled 
and unscheduled time points.  
10.4.3 
Electrocardiogram 
Standard digital ECG assessments will be conducted at baseline and post-baseline visits.  A 
summary of raw values and change from baseline values will be provided by treatment group at 
each scheduled time point for the following standard digital ECG measurements: PR, QT, and QT 
corrected for HR (QTc) intervals (Fridericia correction [QTcF = QT/RR0.33] and Bazett correction 
[QTcB = QT/RR0.50]), QRS duration, and HR. The number and percentage of patients with shift 
changes from baseline based on the overall ECG evaluation will be tabulated by treatment group 
and visit. In addition, the number and percentage of patients will be tabulated by maximum on-
treatment value of QT/QTc intervals, categorized as ≤450 msec, >450 msec and ≤480 msec, >480 


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msec and ≤500 msec, and >500 msec, as well as maximum on-treatment change from baseline 
value of QT/QTc intervals, categorized as ≤30 msec, >30 msec and ≤60 msec, and >60 msec. 
10.4.4 
Vital Signs 
The following vital signs will be summarized by treatment group at each scheduled time point: 
systolic and diastolic blood pressure (mmHg), body temperature (oC), heart rate (beats per minute 
[bpm]), respiratory rate (breaths per minute), and body weight (kg). Absolute changes from 
baseline will also be summarized. 
10.4.5 
Physical Examination 
Findings of the physical examination will be presented as a data listing only. 
10.5 
Steering and Safety Committee Data Reviews and Interim Analyses  
A formal study Steering and Safety Committee will consist of at least 3 clinicians (with experience 
and expertise in venous thrombosis). The Steering and Safety Committee will be charged with 
reviewing in an unblinded fashion all accumulating safety and efficacy data to assure overall 
patient safety in this study.  
The following efficacy and safety data will be provided to the Steering and Safety Committee by 
treatment group, and where appropriate by study visit day and time: 
• 
Overall VTE event rate (as adjudicated);  
• 
Individual component event rate (individual components of the composite VTE event rate);  
• 
Incidence of bleeding events (as adjudicated) including the following will be tabulated by 
treatment: 
1) Major Bleeding event (MB),  
2) Clinically Relevant Non-Major Bleeding event (CRNMB),  
3) Minor Bleeding even, or  
4) Combination of MB and CRNMB  
• 
Incidence of AEs (including SAEs) ; 
• 
Clinical laboratory values (hematology, serum chemistries, urinalysis, and coagulation 
parameters); 
• 
ECGs; and 
• 
Vital signs. 
The Steering and Safety Committee will use all of the above accumulating data to assess the safety 
of continuing each aspect of this study. 
 
Interim Analyses to support decision on whether or not to recommend activation of Adaptive Arm: 
 
The Steering and Safety Committee is also charged with making recommendations to the Sponsor 
with regards to the activation of the adaptive arm that investigates the efficacy and safety of SelK2 
use in combination with enoxaparin.  At certain enrollment milestones, the Steering and Safety 
Committee will be presented with interim analysis tables which will include VTE event rates by 
treatment group with 80% confidence intervals and the calculated risk difference (the difference 


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between the cumulative incidence in the SelK2 arm to that of the cumulative incidence the 
enoxaparin arm) with 80% confidence intervals.  The conditional powers for demonstrating non-
inferiority at the end of the trial based upon accumulated data at interim may also be computed.  
These interim analyses will be part of the data set used by the Committee as they determine 
whether or not to recommend activation of adaptive arm.  This adaptive arm may be initiated if the 
Steering and Safety Committee determines that preliminary data suggests the potential for an 
additive effect in VTE reduction and that the combination does not pose an additional safety risk.   


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11.0 
STUDY OPERATONS  
The overall clinical operations of the study will be managed by IQVIA, a Contract Research 
Organization (CRO), Itreas, an Academic Research Organization (ARO), and the Sponsor.  Other 
formal study committees include:  Steering and Safety Committee and the Central Independent 
Adjudication Committee (CIAC). 
11.1 
IQVIA - Contract Research Organization 
Day to day operations of this study will be conducted by IQVIA (4820 Emperor Blvd, Durham, 
NC 27703 USA), which will ensure the study is conducted with the highest ethical, legal, and 
regulatory standards, according to Good Clinical Practice/ICH Guidelines.  All site selection, 
initiation, periodic monitoring, and closeout activities will be handled by this organization.  
11.2 
Itreas - Academic Research Organization 
Itreas (Honthorststraat 2A, 1071 DD Amsterdam, the Netherlands) will perform medical 
monitoring responsibilities for this study.  This will include the review of all accumulating safety 
and efficacy data for this study.  Itreas will also be responsible for overseeing the Medical Monitor 
Telephone Support Line.  The Medical Monitor Telephone Support Line is a 24 hour-a-day/7 days-
a-week support telephone line for this study that can be contacted by any site personnel when study 
specific questions or issues arise.  In addition, Itreas will coordinate and manage the collection and 
adjudication of all study endpoint events.  This will include coordinating data collection from the 
clinical sites, assembling of adjudication dossiers for each event, and managing the adjudication 
process as completed by the CIAC. 
11.3 
Steering and Safety Committee 
The Steering and Safety Committee is responsible for the overall clinical and scientific oversight of 
this trial.  The scope of its responsibilities include the ongoing review of accumulating safety and 
efficacy data in an unblinded fashion. These reviews will include review of (a) venography results, 
(b) symptomatic venous thromboembolism [DVT/PE], bleeding and death, (c) all other SAEs, (d) 
clinical laboratory values, ECGs, and vital sign assessments to assure overall patient safety in this 
study.  The Steering and Safety Committee will review all efficacy and safety data in an unblinded 
fashion and provide guidance and recommendations to the Sponsor regarding any needed study 
modifications.  This Committee will also make recommendations to the Sponsor regarding 
activation of the adaptive arm of the study when sufficient data has accumulated to make such 
recommendation. 
 
Further details about the presentation of data to the Steering and Safety Committee will be 
contained in the Steering and Safety Committee Charter.  
After completing their unblinded reviews of accumulating safety and efficacy data, the Steering 
and Safety Committee will make a global assessment of safety and risk and will be empowered to 
make the following study recommendations: 
1) Continue the study without modification; 
2) Continue the study contingent upon making recommended study design changes 
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3) Continue study but pause enrollment, pending resolution of a specified issue; 
4) Terminate the study.   
11.4 
Central Independent Adjudication Committee 
The scheduled unilateral venography, all episodes of suspected venous thrombosis [DVT/PE], 
bleedings, stroke and deaths will be reviewed by the CIAC in a blinded fashion, i.e., not aware of 
the treatment assignment.  The procedures followed by the CIAC are described in the adjudication 
charter.  Adjudication results will be the basis for the final endpoint and safety analyses. 
 


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12.0 
ETHICAL ISSUES, LEGAL ASPECTS, AND 
ADMINISTRATIVE ISSUES 
12.1 
Good Clinical Practice 
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigator abide by 
good clinical practice (GCP).  Compliance with these regulations also constitutes compliance with 
the ethical principles described in the current revision of the Declaration of Helsinki. 
12.2 
Delegation of Investigator Responsibilities 
The Investigator should ensure that all persons assisting with the trial are adequately informed 
about the protocol, any amendments to the protocol, the study treatments, and their trial-related 
duties and functions.  The Investigator should maintain a list of Sub-Investigators and other 
appropriately qualified persons to whom he or she has delegated significant trial-related duties. 
12.3 
Patient Information and Informed Consent 
Before being admitted to the clinical research study, the patient must consent to participate after the 
nature, scope, and possible consequences of the clinical study have been explained in a form 
understandable to him.  An informed consent document that includes both information about the 
study and the consent form will be prepared and given to the patient.  The ICF must contain the 
20 elements of informed consent described in ICH E6, Section 4.8. The document must be in a 
language understandable to the patient and must specify who informed the patient. 
After reading the informed consent document, the patient must give consent in writing.  The 
patient's consent must be confirmed at the time of consent by the personally dated signature of the 
person conducting the informed consent discussions.  A copy of the signed consent document must 
be given to the patient or the patient's legally authorized representative.  “Legally authorized 
representative” means an individual or judicial or other body authorized under applicable law to 
consent on behalf of a prospective patient to the patient’s participation in the procedure(s) involved 
in the research.  The original signed consent document will be retained by the Investigator.  The 
Investigator will not undertake any measures specifically required only for the clinical study until 
valid consent has been obtained.   
The Investigator should inform the patient’s primary physician about the patient’s participation in 
the trial if the patient has a primary physician and if the patient agrees to the primary physician 
being informed. 
For patients who require a parent or legal guardian’s permission to participate, two consent 
documents will be used.  One for obtaining the parent or guardian’s permission and one, which 
outlines the study in simplified language, for obtaining the assent of the patient.  The process will 
be the same as outlined above.  
12.4 
Confidentiality 
Patient names will not be supplied to the Sponsor.  Only the randomization number and patient 
initials will be recorded in the eCRF, and if the patient name appears on any other document (e.g., 
pathologist report), it must be redacted before a copy of the document is supplied to the Sponsor.  


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Study findings stored on a computer will be stored in accordance with local data protection laws.  
The patients will be told that representatives of the Sponsor, EC/IRB, or regulatory authorities may 
inspect their medical records to verify the information collected, and that all personal information 
made available for inspection will be handled in strictest confidence and in accordance with local 
data protection law.  The Investigator will maintain a personal patient identification list (patient 
numbers with the corresponding patient names) to enable records to be identified. 
12.5 
Protocol Amendments 
Neither the Investigators nor the Sponsor will alter this study protocol without obtaining the written 
agreement of the other.  Substantive changes in the protocol include changes that affect the safety 
of patients or changes that alter the scope of the investigation, the scientific quality of the study, the 
experimental design, dosages, assessment variable(s), the number of patients treated, or the patient 
selection criteria must be prepared as a protocol amendment by the Sponsor and implemented only 
upon joint approval of the Sponsor and the Investigator. Once the study has started, amendments 
should be made only in exceptional cases.  The changes then become part of the study protocol. 
12.6 
Approval of the Study Protocol and Amendments 
Before the start of the study, the study protocol, informed consent documents, and any other 
appropriate documents will be submitted to the Ethics Committee (EC) / Institutional Review 
Board (IRB) with a cover letter or a form listing the documents submitted, their dates of issue, and 
the site (or region or area of jurisdiction, as applicable) for which approval is sought.  
Study drug can only be supplied to the Investigator after documentation on all ethical and legal 
requirements for starting the study has been received by the Sponsor.  This documentation must 
also include a list of the members of the EC/IRB and their occupation and qualifications.  If the 
EC/IRB will not disclose the names of the committee members, it should be asked to issue a 
statement confirming that the composition of the committee is in accordance with GCP.  The 
EC/IRB General Assurance Number may be accepted as a substitute for this list.  Formal approval 
by the EC/IRB should preferably mention the study title, study code, study site (or region or area of 
jurisdiction, as applicable), and any other documents reviewed.  It must mention the date on which 
the decision was made and must be officially signed by a committee member. 
Before the first patient is enrolled in the study, all ethical and legal requirements must be met. 
The EC/IRB must be informed of all subsequent protocol amendments, in accordance with local 
legal requirements.  Amendments must be evaluated to determine whether formal approval must be 
sought and whether the informed consent documents should also be revised. 
The Investigator must keep a record of all communication with the EC/IRB and, if applicable, 
between a coordinating Investigator and the EC/IRB.  This also applies to any communication 
between the Investigator (or coordinating Investigator, if applicable) and the authorities. 
12.7 
Ongoing Information for Ethics Committee / Institutional Review 
Board 
If required by legislation or the EC/IRB, the Investigator must submit to the EC/IRB: 
• 
Information on unexpected SAEs as soon as possible; and 


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• 
Periodic reports on the progress of the study. 
12.8 
Premature Closure of the Study 
The Sponsor or the Investigator has the right to close this study at any time.  As far as possible, this 
should occur after mutual consultation.  The EC/IRB must be informed, if required by legislation. 
Should the study be closed prematurely, all study materials (completed, partially completed and 
blank eCRFs, study drug, etc.) must be returned to the Sponsor or its designate, as if the study had 
been completed. 
12.9 
Record Retention 
The following records must be retained by the Investigator for at least 2-years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2-years have elapsed since 
the formal discontinuation of clinical development of the investigational product:  
• 
Signed informed consent documents for all patients; 
• 
Patient identification code list, screening log (if applicable), and enrollment log; 
• 
Record of all communications between the Investigator and the EC/IRB; 
• 
Composition of the EC/IRB; 
• 
Record of all communications between the Investigator and Sponsor (or CRO); 
• 
List of Subinvestigators and other appropriately qualified persons to whom the Investigator 
has delegated significant trial-related duties, together with their roles in the study and their 
signatures; 
• 
Copies of CRFs and of documentation of corrections for all patients; 
• 
Drug accountability records; 
• 
Record of any body fluids or tissue samples retained; 
• 
All other source documents (patient records, hospital records, laboratory records, etc.); and 
• 
All other documents as listed in Section 8 of the ICH (step 4) consolidated guideline on 
GCP (Essential Documents for the Conduct of a Clinical Trial). 
However, because of international regulatory requirements, the Sponsor may request retention for a 
longer period of time.  The Investigator must therefore obtain approval in writing from the Sponsor 
prior to destruction of any records.  Normally, these records will be held in the Investigator's 
archives.  If the Investigator is unable to meet this obligation, he must ask the Sponsor for 
permission to make alternative arrangements.  Details of these arrangements should be 
documented. 
12.10 
Liability and Insurance 
The Sponsor provides insurance for study patients to make available compensation in 
case of study-related injury.  Liability and insurance provisions for this study are given in the 
Investigator's contract. 


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12.11 
Study Monitoring and Auditing 
Monitoring and auditing procedures compliant with ICH GCP guidelines will be followed.  On-site 
checking of the eCRFs for completeness and clarity, cross-checking with source documents, and 
clarification of administrative matters will be performed. 
12.11.1 
Study monitoring 
The study will be monitored by a CRO.  Monitoring will be done by on-site visits from a clinical 
monitor who will review the eCRFs and source documents.  By frequent communications (email, 
letter, telephone, and/or fax) and site visits, the clinical monitor will ensure that the investigation is 
conducted according to protocol design and regulatory requirements. 
12.11.2 
Source data verification and on-site audits 
Regulatory authorities, the EC/IRB and/or the Sponsor’s clinical quality assurance group may 
request access to all source documents, eCRFs, and other study documentation for on-site audits or 
inspections.  Direct access to these documents must be guaranteed by the Investigator, who must 
provide support at all times for these activities.  Study CRO will be completing on-site source data 
verification (monitoring) of selected data fields entered into eCRF. 


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13.0 
DOCUMENTATION AND USE OF STUDY FINDINGS 
13.1 
Documentation of Study Findings 
An electronic CRF (eCRF) will be completed for each patient. All protocol-required information 
collected during the study must be recorded by the Investigator, or designated representative, in the 
source documents and transcribed to the eCRF.  If the Investigator authorizes other personnel to 
make changes to the eCRF, the names, positions, signatures, and initials of these persons must be 
supplied to the Sponsor.  Any changes to the eCRF are to be verified by the authorized individual.  
The eCRF must be reviewed and signed by the Investigator or by a designated Sub-Investigator.  
The site will receive a CD with all the site’s eCRFs after database is locked. 
13.2 
Use of Study Findings 
All information concerning the product as well as any matter concerning the operation of Tetherex 
Pharmaceuticals, such as clinical indications for the drug, its formula, methods of manufacture and 
other scientific data relating to it, that have been provided by Tetherex Pharmaceuticals and are 
unpublished, are confidential and must remain the sole property of Tetherex Pharmaceuticals.  The 
Investigator will agree to use the information only for the purposes of carrying out this study and 
for no other purpose unless prior written permission from Tetherex Pharmaceuticals is obtained.  
Tetherex Pharmaceuticals has full ownership of the eCRFs completed as part of the study. 
By signing the study protocol, the Investigator agrees that the results of the study may be used for 
the purposes of national and international registrations, publications, and information for medical 
and pharmaceutical professionals by Tetherex Pharmaceuticals.  If necessary, the authorities will 
be notified of the Investigator's name, address, qualifications, and extent of involvement. 
The Investigator may not publish or present any information on this study without the express 
written approval of Tetherex Pharmaceuticals.  Additionally, Tetherex Pharmaceuticals may, for 
any reason, withhold approval for publication or presentation. 


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14.0 
REFERENCES  
1. 
Quinlan, D. J., Eikelboom, J. W., Dahl, O. E., Eriksson, B. I., Sidhu, P. S., and Hirsh, J. (2007) 
Association between asymptomatic deep vein thrombosis detected by venography and 
symptomatic venous thromboembolism in patients undergoing elective hip or knee surgery. J 
Thromb Haemost 5, 1438-1443 
2. 
Ramacciotti, E., Myers, D. D., Jr., Wrobleski, S. K., Deatrick, K. B., Londy, F. J., Rectenwald, J. 
E., Henke, P. K., Schaub, R. G., and Wakefield, T. W. (2010) P-selectin/ PSGL-1 inhibitors 
versus enoxaparin in the resolution of venous thrombosis: a meta-analysis. Thromb Res 125, 
e138-142 
3. 
Diaz, J. A., Wrobleski, S. K., Alvarado, C. M., Hawley, A. E., Doornbos, N. K., Lester, P. A., 
Lowe, S. E., Gabriel, J. E., Roelofs, K. J., Henke, P. K., Schaub, R. G., Wakefield, T. W., and 
Myers, D. D., Jr. (2015) P-selectin inhibition therapeutically promotes thrombus resolution and 
prevents vein wall fibrosis better than enoxaparin and an inhibitor to von Willebrand factor. 
Arterioscler Thromb Vasc Biol 35, 829-837 
4. 
Yeh, C. H., Gross, P. L., and Weitz, J. I. (2014) Evolving use of new oral anticoagulants for 
treatment of venous thromboembolism. Blood 124, 1020-1028 
5. 
Crowther, M. A., and Warkentin, T. E. (2008) Bleeding risk and the management of bleeding 
complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents. 
Blood 111, 4871-4879 
6. 
Lobo, E. D., Hansen, R. J., and Balthasar, J. P. (2004) Antibody pharmacokinetics and 
pharmacodynamics. J Pharm Sci 93, 2645-2668 
7. 
Dall'Acqua, W. F., Woods, R. M., Ward, E. S., Palaszynski, S. R., Patel, N. K., Brewah, Y. A., 
Wu, H., Kiener, P. A., and Langermann, S. (2002) Increasing the affinity of a human IgG1 for the 
neonatal Fc receptor: biological consequences. J Immunol 169, 5171-5180 
8. 
Schulman, S., Angeras, U., Bergqvist, D., Eriksson, B., Lassen, M. R., Fisher, W., Subcommittee 
on Control of Anticoagulation of the, S., Standardization Committee of the International Society 
on, T., and Haemostasis. (2010) Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in surgical patients. J Thromb Haemost 8, 202-204 
 


 
 
 
CONFIDENTIAL 
 
Listing of Significant Protocol Modifications 
 
Section 
Description of Changes 
Synopsis, Study Design 
Section 
and 
Section 3.1 Basic Design 
Characteristics 
Synopsis Revised Text 
 
Previously: Adaptive Design:  The Steering and Safety Committee will 
review the accumulating efficacy and safety data and based upon the 
safety and efficacy profile of SelK2 may decide to modify enrollment, 
potentially adding a third study arm testing 7.5 mg/kg SelK2 given in 
addition to enoxaparin (40 mg, SC, QD). 
 
Now: Adaptive Design:  The Steering and Safety Committee and 
Sponsor will review the accumulating efficacy and safety data at planned 
intervals, and based upon the safety and efficacy profile of SelK2 may 
decide to modify enrollment by adding a third study arm testing 7.5 
mg/kg SelK2 given in addition to enoxaparin (40 mg, SC, QD) and 
removal of the SelK2 only arm. The two remaining arms will enroll 
patients in a 2:1 ratio with two patients receiving SelK2 and Enoxaparin 
for every one patient receiving Enoxaparin only at doses shown below: 
 
1.) 7.5 mg/kg SelK2 (IV, single-dose) and 40 mg Enoxaparin, SC, 
QD 
2.) Active Comparator (40 mg Enoxaparin, SC, QD) 
 
Section 3.1 Text Added: 
Upon activation of the adaptive arm and discontinuation of the SelK2 
only arm of the study, during the Treatment Phase each patient will 
receive either: 
 
1. A single 7.5 mg/kg dose of SelK2 (7.5 mg/kg, IV, single dose) 
and Enoxaparin (40 mg SC, QD for up to 10 ± 2 days) 
2. Active Comparator Enoxaparin (40 mg, SC, QD for up to 10 ± 2 
days) 
Synopsis, Duration of 
Treatment 
and 
Section 3.4.2 Treatment 
Phase 
Synopsis Add Text: 
Upon activation of the adaptive arm and discontinuation of the SelK2 
only arm of the study, during the Treatment Phase each patient will 
receive either: 
1) A single 7.5 mg/kg dose of SelK2 administered intravenously 12 
to 24 hours prior to the initiation of the TKA surgery AND 40 
mg dose of enoxaparin administered SC 12 hours after TKA 
surgery followed by daily injections of 40 mg enoxaparin, SC for 
at least 9 additional days post-surgery and up to the day of the 
planned venography, or 
2) 40 mg dose of enoxaparin (active comparator) administered SC 
12 hours after TKA surgery followed by daily injections of 40 
mg enoxaparin, SC for at least 9 additional days post-surgery 
and up to the day of the planned venography (with the option of 
giving an additional 40 mg enoxaparin, SC dose 12 hours prior 
to TKA surgery). 
 


 
 
 
CONFIDENTIAL 
 
Section 
Description of Changes 
Section 3.4.2 Text Added: 
For those randomize to receive SelK2 and enoxaparin, patients will 
receive a single dose of 7.5 mg/kg SelK2 via IV administration at least 
12 hours prior to but not longer than 24 hours prior to the start of the 
TKA surgery and will receive 40 mg enoxaparin administered via SC 
injection 12 hours after TKA surgery followed by daily SC injections of 
40 mg enoxaparin for at least 9 additional days post-surgery. 
Section 5.1.3 
Randomization Methods 
and Procedures 
Section 5.1.3 Text Change: 
 
Previously:  Changes in Randomization Procedure if Adaptive arm is 
activated: 
If the adaptive arm is activated, a third arm will be added to the study 
and the central randomization process will then allow for placing patients 
randomly into one of three treatment arms.  Randomization will continue 
to be stratified by site. 
Patients will be randomly placed into one of three treatment arms: 
1) 7.5 mg/kg SelK2, IV or  
2) 40 mg enoxaparin, SC, QD, or 
3) 7.5 mg/kg SelK2, IV and 40 mg enoxaparin, SC, QD. 
 
The activation of the adaptive arm, if it occurs, is planned at a time in the 
study conduct when a significant portion (ranging between 33%-50%) of 
patients will have already been randomized to one of the two previously 
opened arms (7.5 mg/kg SelK2, IV or 40 mg enoxaparin, SC, QD).  
Consequently, the randomization ratio will be altered after addition of 
the third arm to allow for the total number of patients to be enrolled in 
each of the three arms to be equivalent.  This modified randomization 
ratio will be controlled by the centralized IRT system. 
 
Now: Changes in Randomization Procedure when Adaptive arm is 
activated and enrollment into the SelK2 only arm is discontinued: 
When the adaptive arm is activated and the SeLK2 only arm is closed, 
the central randomization process will allow for placing patients 
randomly into one of the below two treatment arms and randomization 
will continue to be stratified by site. 
Patients will be randomly placed into one of two treatment arms: 
1) 40 mg enoxaparin, SC, QD, or 
2) 7.5 mg/kg SelK2, IV and 40 mg enoxaparin, SC, QD. 
 
The randomization ratio will be altered to a 2:1 ratio (2 patients receiving 
7.5 mg/kg SelK2 and enoxaparin to every 1 patient receiving Enoxaparin 
only) so that the total number of patients in each of the two remaining 
arms will be approximately equivalent at the end of the study. This 
modified randomization ratio will be controlled by the centralized IRT 
system. 


 
 
 
CONFIDENTIAL 
 
Section 
Description of Changes 
Synopsis, Safety Section 
and 
Section 3.5 Safety and 
Efficacy Assessments 
and 
Section 6.0 Study 
Procedures 
Remove “oral” as the only manner in which to measure body 
temperature 
Synopsis Safety Section 
And 
Section 3.5 Safety and 
efficacy Assessments 
And  
Section 6.0 Study 
Procedures 
Add “of child bearing potential” to description of women for which 
serum pregnancy test should be completed 
Section 5.2.3. Adaptive 
Arm: Dosing of SelK2 and 
Enoxaparin 
Section 5.2.3 Delete: At the discretion of the PI, sites also have the 
option of giving an additional 40 mg enoxaparin SC dose 12 hours 
PRIOR to TKA surgery.  If both SelK2 and enoxaparin dosing are 
planned for prior to the start of the TKA surgery, SelK2 should be given 
prior to the enoxaparin dosing. 
Synopsis, Statistical 
Methods 
and 
Section 10.3.3 Efficacy 
Analysis 
 
Clarify that all primary and secondary analyses will compare SelK2 only, 
SelK2 and Enoxaparin, and Enoxaparin only arms