Clinical trial NCT05618808
Conditions: Venous Thromboembolism
Keywords: Anti-factor XI (FXI) monoclonal antibody Deep Vein Thrombosis Unilateral total knee arthroplasty (TKA),
Sponsor: Regeneron Pharmaceuticals
Start date: 2023-05-24; Completion date: 2024-05-27
Enrollment: 373 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to evaluate the efficacy of REGN9933 for the prevention of venous thromboembolism (VTE) after unilateral total knee arthroplasty (TKA), compared to enoxaparin

The secondary objectives of the study are:

* To evaluate the bleeding risk (ie, major and clinically relevant non-major \[CRNM\] bleeding) of REGN9933 after unilateral TKA through time of venography, compared to enoxaparin
* To assess overall safety and tolerability of REGN9933 in participants undergoing TKA
* To evaluate the efficacy of REGN9933 in prevention of clinically relevant VTE, compared to enoxaparin
* To evaluate the efficacy of REGN9933 in prevention of deep venous thrombosis (DVT) detected by venography, compared to enoxaparin
* To evaluate the pharmacokinetics (PK) of REGN9933 after single intravenous (IV) administration
* To assess pharmacodynamic (PD) effects of REGN9933 on intrinsic and extrinsic coagulation pathways
* To assess immunogenicity following a single dose of REGN9933 over time
* To compare the efficacy of enoxaparin and apixaban in prevention of VTE after unilateral TKA

Detailed description:

Arms: arm 1: REGN9933 will be administered by intravenous (IV) infusion arm 2: Enoxaparin will be administered by subcutaneous (SC) administration arm 3: Apixaban will be administered orally twice a day
Interventions: intervention 1: REGN9933 intervention 2: Enoxaparin intervention 3: Apixiban
Intervention descriptions: intervention 1: Participants will receive a single dose of REGN9933 by IV infusion intervention 2: Participants will receive enoxaparin by SC administration daily through the time of venography (or day 12, whichever is earlier) intervention 3: Participants will receive apixaban orally twice a day through the time of venography (or day 12, whichever is earlier)

Protocol documents:
Prot_000.pdf: 
 
REGENERON CONFIDENTIAL 
Page 1 
EU CT: 2022-501470-18-00 
Regeneron Pharmaceuticals, Inc. 
 
 
Clinical Study Protocol 
A PHASE 2, MULTICENTER, RANDOMIZED, OPEN-LABEL, ACTIVE-CONTROL 
STUDY OF REGN9933, A FACTOR XI MONOCLONAL ANTIBODY, FOR 
PREVENTION OF VENOUS THROMBOEMBOLISM AFTER ELECTIVE, 
UNILATERAL, TOTAL KNEE ARTHROPLASTY 
 
 
 
Compound: 
REGN9933 
 
 
Clinical Phase: 
2 
Protocol Number: 
R9933-DVT-2230 
Protocol Version: 
R9933-DVT-2230-Amendment 1 
Amendment 1 Date of Issue: 
See appended electronic signature page 
Original Protocol Date of Issue: 
27 September 2022 
Medical /Study Director: 
 
 Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
Confidential: This submission contains confidential and proprietary commercial information 
and/or trade secrets which are subject to protection under laws and regulations worldwide 
including, but not limited to TRIPS Article 39 and regional, national or state laws whether by 
legislation or in equity.  For the purposes of compliance with all applicable freedom of information 
laws, and regulations, and their equivalents anywhere in the world including but not limited to the 
US Freedom of Information Act 5 U.S.C. §552, Regeneron expects that, prior to disclosure to third 
parties of any information and/or data related to, or contained within, this submission, it will be 
 
. 
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AMENDMENT HISTORY 
Overall Rationale for Amendment 1 
The purpose of this non-substantial amendment is to incorporate responses to Health Authority 
(HA) feedback. The table below provides a summary of changes made to the protocol and the 
affected sections: 
Description of Change 
Brief Rationale  
Section # and Name  
Updated text for consistency with the 
newly added Section 8.8.2 Permitted 
Medications. 
Added text to clarify that the use of 
anti-coagulants for VTE prophylaxis 
is prohibited for subjects randomized 
to REGN9933 and to provide a 
rationale for this. 
In response to HA feedback, updated 
text to clarify the permitted and 
prohibited medications. 
Section 3.2.1 Rationale for Study 
Design 
Added the italicized wording to the 
sentence: 
“If NovoSeven or another Factor VIIa 
formulation is available and selected 
for use at the discretion of the treating 
physician, the literature has commonly 
reported NovoSeven doses of 15 
μg/kg to 30 μg/kg administered as an 
IV bolus in FXI-deficient patients” 
In response to HA feedback, added 
text to clarify that the availability of 
Factor VII at study sites is not 
mandated by the protocol 
Section 8.2.2 Treatment of Bleeding 
Events 
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Description of Change 
Brief Rationale  
Section # and Name  
Created Section 8.8.2 Permitted 
Medications 
Text in Section 8.8.1 Prohibited 
Medications and Procedure 
reorganized for clarity and for 
consistency with the newly created 
Section 8.8.2 Permitted Medications 
Added statement that the use of 
standard-of-care medications not  
listed as prohibited will be allowed. 
Added text to clarify that, for subjects 
assigned to either the enoxaparin or 
apixaban treatment arm, continued 
VTE prophylaxis (after completion of 
protocol-defined treatment, ie through 
the day of venography [(or day 12, 
whichever is earlier]) is permitted, if 
deemed necessary by the site 
investigator based on local guidelines 
and/or clinical judgment.  
Moved the information on permitted 
vaccines from Section 8.8.1 
Prohibited Medications and 
Procedures to Section 8.8.2 Permitted 
Medication 
 
In response to HA feedback, added 
new Permitted Medications section, 
and updated text to clarify the 
permitted and prohibited medications. 
Section 8.8.1 Prohibited Medications 
and Procedures 
Section 8.8.2 Permitted Medications 
Reference to Regulation EU No 
536/2014 added 
In response to HA feedback, updated 
sections to refer to Regulation EU No 
536/2014 for:  
• 
expedited reporting of 
SUSARs in the EU  
• 
quality control and quality 
assurance requirements in the 
EU 
Section 10.4: Notifying Health 
Authorities, Institutional Review 
Board /Ethics Committee, and 
Investigators 
Section 12: Quality Control and 
Quality Assurance 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AC 
Adjudication Committee 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ASA 
Acetylsalicylic acid 
BID 
Twice daily 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CSR 
Clinical study report 
CT 
Computed tomography 
CTFG 
Clinical Trial Facilitation Group 
CRNM 
Clinically relevant non-major 
DOAC 
Direct oral anticoagulants 
DVT 
Deep venous thrombosis 
EU 
European Union 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOS 
End of study 
FAS 
Full analysis set 
FBR 
Future biomedical research 
FSH 
Follicle stimulating hormone 
FXI 
Factor XI 
FXIIa 
Factor XIIa 
FXI:C 
Factor XI functional activity 
GCP 
Good Clinical Practice 
HIT 
Heparin-induced thrombocytopenia 
HIV 
Human immunodeficiency virus 
IA 
Interim analysis 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
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IRB 
Institutional Review Board 
ISTH 
International Society on Thrombosis and Hemostasis 
INR 
International normalized ration 
IV 
Intravenous 
IVRS/IWRS 
Interactive voice response system/ interactive web response system 
LMWH 
Low molecular weight heparin 
MDRD 
Modification of Diet in Renal Disease 
mITT 
Modified intent to treat 
MR 
Magnetic resonance 
NOAEL 
No observed adverse effect level 
OR 
Odds ratio 
ORRA 
the odds ratio of confirmed VTE in participants administered REGN9933 as 
compared to that of apixaban  
ORRE 
the odds ratio of confirmed VTE in participants administered REGN9933 as 
compared to that of enoxaparin 
PD 
Pharmacodynamics  
PE 
Pulmonary embolism 
PK 
Pharmacokinetic 
PO 
Orally 
PRO 
Patient reported outcomes 
PT 
Prothrombin time 
RBQM 
Risk-Based Quality Monitoring 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SC 
Subcutaneous 
SmPC 
Summary of product characteristics 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TGA 
Thrombin generation assay 
TKA 
Total knee arthroplasty 
ULN 
Upper level of normal 
VTE 
Venous thromboembolism 
WBC 
White blood cell 
WOCBP 
Women of child-bearing potential 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................4 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................12 
1. 
INTRODUCTION ......................................................................................................17 
2. 
STUDY OBJECTIVES ..............................................................................................19 
2.1. 
Primary Objective .......................................................................................................19 
2.2. 
Secondary Objectives .................................................................................................19 
2.3. 
Exploratory Objectives ...............................................................................................19 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................21 
3.1. 
Hypotheses ..................................................................................................................21 
3.2. 
Rationale .....................................................................................................................21 
3.2.1. 
Rationale for Study Design .........................................................................................21 
3.2.2. 
Rationale for Dose Selection ......................................................................................23 
3.3. 
Risk-Benefit ................................................................................................................24 
3.3.1. 
Risk-Benefit for REGN9933 ......................................................................................25 
3.3.2. 
Risk-Benefit for Active Comparator and Calibrator ..................................................26 
3.3.2.1. 
Enoxaparin ..................................................................................................................26 
3.3.2.2. 
Apixaban .....................................................................................................................27 
4. 
ENDPOINTS ..............................................................................................................28 
4.1. 
Primary and Secondary Endpoints..............................................................................28 
4.1.1. 
Primary Endpoint ........................................................................................................28 
4.1.2. 
Secondary Endpoints ..................................................................................................28 
4.1.3. 
Exploratory Endpoints ................................................................................................28 
5. 
STUDY VARIABLES................................................................................................30 
5.1. 
Demographic and Baseline Characteristics ................................................................30 
5.2. 
Efficacy Variables ......................................................................................................30 
5.2.1. 
Confirmed VTE ..........................................................................................................30 
5.2.2. 
Major VTE ..................................................................................................................30 
5.3. 
Safety Variables ..........................................................................................................30 
5.3.1. 
Bleeding Events ..........................................................................................................30 
5.4. 
Pharmacokinetic Variables .........................................................................................31 
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5.4.1. 
Drug Target Variables ................................................................................................31 
5.5. 
Immunogenicity Variables ..........................................................................................31 
5.6. 
Pharmacodynamic and Other Biomarker Variables ...................................................31 
6. 
STUDY DESIGN .......................................................................................................32 
6.1. 
Study Description and Duration .................................................................................32 
6.1.1.1. 
Study Stopping Criteria ..............................................................................................33 
6.1.2. 
End of Study Definition ..............................................................................................33 
6.2. 
Planned Interim Analysis ............................................................................................33 
6.3. 
Study Committees .......................................................................................................34 
6.3.1. 
Independent Data Monitoring Committee ..................................................................34 
6.3.2. 
Steering Committee ....................................................................................................34 
6.3.3. 
Adjudication Committee .............................................................................................34 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PARTICIPANTS ........................................................................................................35 
7.1. 
Number of Participants Planned .................................................................................35 
7.2. 
Study Population .........................................................................................................35 
7.2.1. 
Inclusion Criteria ........................................................................................................35 
7.2.2. 
Exclusion Criteria .......................................................................................................35 
7.3. 
Premature Withdrawal from the Study .......................................................................37 
7.4. 
Replacement of Participants .......................................................................................37 
8. 
STUDY TREATMENTS............................................................................................38 
8.1. 
Investigational and Reference Treatments ..................................................................38 
8.2. 
Rescue Treatments ......................................................................................................39 
8.2.1. 
Treatment of VTE .......................................................................................................39 
8.2.2. 
Treatment of Bleeding Events ....................................................................................39 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................40 
8.3.1. 
Dose Modification ......................................................................................................40 
8.3.2. 
Study Intervention Discontinuation ............................................................................40 
8.3.2.1. 
REGN9933 Discontinuation .......................................................................................40 
8.3.2.2. 
Enoxaparin Discontinuation .......................................................................................40 
8.3.2.3. 
Apixaban Discontinuation ..........................................................................................40 
8.4. 
Management of Acute Reactions ................................................................................41 
8.4.1. 
Acute Intravenous Infusion Reactions ........................................................................41 
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8.4.1.1. 
Interruption of the Intravenous Infusion .....................................................................41 
8.4.1.2. 
Termination of the Intravenous Infusion ....................................................................41 
8.4.2. 
Acute Injection Reactions ...........................................................................................42 
8.4.2.1. 
Systemic Injection Reactions ......................................................................................42 
8.4.2.2. 
Local Injection Site Reactions ....................................................................................42 
8.5. 
Method of Treatment Assignment ..............................................................................42 
8.6. 
Blinding/Masking .......................................................................................................42 
8.7. 
Treatment Logistics and Accountability .....................................................................43 
8.7.1. 
Packaging, Labeling, and Storage ..............................................................................43 
8.7.2. 
Supply and Disposition of Treatment .........................................................................43 
8.7.3. 
Treatment Accountability ...........................................................................................43 
8.7.4. 
Treatment Compliance ................................................................................................43 
8.8. 
Concomitant Medications and Procedures .................................................................44 
8.8.1. 
Prohibited Medications and Procedures .....................................................................44 
8.8.2. 
Permitted Medications ................................................................................................44 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................45 
9.1. 
Schedule of Events .....................................................................................................45 
9.1.1. 
Footnotes for the Schedule of Events Table ...............................................................49 
9.1.1.1. 
Table 2 Schedule of Events ........................................................................................49 
9.1.1.2. 
Table 3 Schedule of Events: Visit 2 Blood Collection ...............................................50 
9.1.2. 
Early Termination Visit ..............................................................................................50 
9.1.3. 
Unscheduled Visits .....................................................................................................50 
9.2. 
Study Procedures ........................................................................................................50 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................50 
9.2.2. 
Efficacy Procedures ....................................................................................................51 
9.2.2.1. 
Venography of the Operated Leg ...............................................................................51 
9.2.2.2. 
Assessment of Symptomatic VTE ..............................................................................51 
9.2.3. 
Safety Procedures .......................................................................................................51 
9.2.3.1. 
Body Weight ...............................................................................................................51 
9.2.3.2. 
Height .........................................................................................................................52 
9.2.3.3. 
Vital Signs ..................................................................................................................52 
9.2.3.4. 
Physical Examination .................................................................................................52 
9.2.3.5. 
Electrocardiogram .......................................................................................................52 
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9.2.3.6. 
Assessment for Bleeding ............................................................................................52 
9.2.3.7. 
Laboratory Testing ......................................................................................................52 
9.2.4. 
Drug Concentration and Total Factor XI Measurements ...........................................54 
9.2.5. 
Immunogenicity Measurements and Samples ............................................................54 
9.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................54 
9.2.6.1. 
Activated Partial Thromboplastin Time and Prothrombin Time ................................54 
9.2.6.2. 
Factor XI Functional Activity Levels .........................................................................55 
9.2.6.3. 
Thrombin Generation Assay .......................................................................................55 
9.2.6.4. 
Exploratory Biomarkers ..............................................................................................55 
9.2.7. 
Future Biomedical Research (Optional) .....................................................................55 
9.2.8. 
Pharmacogenomic Analysis (Optional) ......................................................................55 
10. 
SAFETY EVALUATION AND REPORTING .........................................................57 
10.1. 
Recording and Reporting Adverse Events ..................................................................57 
10.1.1. 
General Guidelines .....................................................................................................57 
10.1.2. 
Reporting Procedure ...................................................................................................58 
10.1.2.1. 
Individual Case Safety Reporting (ICSR) ..................................................................58 
10.1.2.2. 
Aggregate Safety Reporting (Development Safety Update Report) ...........................58 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................58 
10.2. 
Definitions ..................................................................................................................59 
10.2.1. 
Adverse Event .............................................................................................................59 
10.2.2. 
Serious Adverse Event ................................................................................................59 
10.2.3. 
Adverse Events of Special Interest .............................................................................60 
10.2.4. 
Infusion Reactions ......................................................................................................60 
10.2.5. 
Severity .......................................................................................................................60 
10.2.6. 
Causality .....................................................................................................................61 
10.3. 
Safety Monitoring .......................................................................................................62 
10.4. 
Notifying Health Authorities, Institutional Review Board /Ethics Committee, 
and Investigators .........................................................................................................62 
11. 
STATISTICAL PLAN................................................................................................63 
11.1. 
Statistical Hypothesis ..................................................................................................63 
11.2. 
Justification of Sample Size........................................................................................63 
11.3. 
Analysis Sets ...............................................................................................................63 
11.3.1. 
Efficacy Analysis Sets ................................................................................................63 
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11.3.2. 
Safety Analysis Set .....................................................................................................64 
11.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................64 
11.3.4. 
Immunogenicity Analysis Sets ...................................................................................64 
11.3.5. 
Pharmacodynamic Analysis Set .................................................................................64 
11.4. 
Statistical Methods ......................................................................................................64 
11.4.1. 
Participant Disposition ................................................................................................64 
11.4.2. 
Demography and Baseline Characteristics .................................................................64 
11.4.3. 
Efficacy Analyses .......................................................................................................65 
11.4.3.1. 
Primary Efficacy Analysis ..........................................................................................65 
11.4.4. 
Control of Multiplicity ................................................................................................65 
11.4.5. 
Safety Analysis ...........................................................................................................65 
11.4.5.1. 
Adverse Events ...........................................................................................................65 
11.4.5.2. 
Other Safety ................................................................................................................66 
11.4.5.3. 
Treatment Exposure ....................................................................................................66 
11.4.5.4. 
Treatment Compliance ................................................................................................66 
11.4.6. 
Pharmacokinetics ........................................................................................................66 
11.4.6.1. 
Analysis of Drug Concentration Data .........................................................................66 
11.4.7. 
Analysis of Immunogenicity Data ..............................................................................67 
11.4.8. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ..............................67 
11.5. 
Interim Analysis ..........................................................................................................67 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........68 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................69 
12.1. 
Data Management and Electronic Systems ................................................................69 
12.1.1. 
Data Management .......................................................................................................69 
12.1.2. 
Electronic Systems ......................................................................................................69 
12.2. 
Study Monitoring ........................................................................................................69 
12.2.1. 
Monitoring of Study Sites ...........................................................................................69 
12.2.2. 
Source Document Requirements ................................................................................70 
12.2.3. 
Case Report Form Requirements ................................................................................70 
12.3. 
Audits and Inspections ................................................................................................70 
12.4. 
Study Documentation .................................................................................................71 
12.4.1. 
Certification of Accuracy of Data ...............................................................................71 
12.4.2. 
Retention of Records ..................................................................................................71 
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12.4.3. 
Recruitment Strategy ..................................................................................................71 
12.4.4. 
Data Protection ...........................................................................................................71 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................73 
13.1. 
Good Clinical Practice Statement ...............................................................................73 
13.2. 
Informed Consent .......................................................................................................73 
13.3. 
Participants Confidentiality and Data Protection .......................................................73 
13.4. 
Institutional Review Board/Ethics Committee ...........................................................74 
13.5. 
Clinical Study Data Transparency ..............................................................................74 
14. 
PROTOCOL AMENDMENTS ..................................................................................75 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSEOUT OF A 
SITE ............................................................................................................................76 
15.1. 
Premature Termination of the Study ...........................................................................76 
15.2. 
Close-out of a Site ......................................................................................................76 
16. 
CONFIDENTIALITY ................................................................................................76 
17. 
FINANCING AND INSURANCE .............................................................................76 
18. 
PUBLICATION POLICY ..........................................................................................76 
19. 
REFERENCES ...........................................................................................................77 
20. 
INVESTIGATOR’S AGREEMENT ..........................................................................80 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................81 
 
LIST OF TABLES 
Table 1: 
Study Interventions Administered ..............................................................................38 
Table 2: 
Schedule of Events .....................................................................................................46 
Table 3: 
Schedule of Events: Visit 2 Blood Collection ............................................................49 
 
LIST OF FIGURES 
Figure 1: 
Mean (+SD) Change from Baseline in a) Factor XI Activity and b) aPTT by 
Nominal Time and by Dose in Healthy Volunteers (0-63 Days, Linear Scale, 
Study R9933-HV-2107)..............................................................................................24 
Figure 2: 
Study Flow Diagram ...................................................................................................33 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 2, Multicenter, Randomized, Open-Label, Active-Control Study of 
REGN9933, a Factor XI Monoclonal Antibody, for Prevention of Venous 
Thromboembolism after Elective, Unilateral, Total Knee Arthroplasty 
Site Location(s) 
 
Principal Investigator 
Up to approximately 25 sites globally 
Principal investigator(s) will be identified and documented in the trial 
master file  
Objective(s) 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of REGN9933 
for the prevention of venous thromboembolism (VTE) after unilateral total 
knee arthroplasty (TKA), compared to enoxaparin 
Secondary Objectives 
The secondary objectives of the study are: 
• 
To evaluate the bleeding risk (ie, major and clinically 
relevant non-major [CRNM] bleeding) of REGN9933 after 
unilateral TKA through time of venography, compared to 
enoxaparin 
• 
To assess overall safety and tolerability of REGN9933 in 
participants undergoing TKA 
• 
To evaluate the efficacy of REGN9933 in prevention of 
clinically relevant VTE, compared to enoxaparin 
• 
To evaluate the efficacy of REGN9933 in prevention of DVT 
detected by venography, compared to enoxaparin 
• 
To evaluate the pharmacokinetics (PK) of REGN9933 after 
single intravenous (IV) administration 
• 
To assess pharmacodynamic (PD) effects of REGN9933 on 
intrinsic and extrinsic coagulation pathways (ie, aPTT, PT) 
• 
To assess immunogenicity following a single dose of 
REGN9933 over time 
• 
To compare the efficacy of enoxaparin and apixaban in 
prevention of VTE after unilateral TKA 
 
Study Design 
This is a phase 2 multicenter, multinational, randomized, open label, active-
control study of a single dose of IV REGN9933 for prevention of VTE in 
participants undergoing an elective, unilateral, TKA. 
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Participants who are at least 50 years of age and undergoing elective, 
unilateral TKA will be randomized after surgery to one of 3 treatment 
arms—REGN9933, enoxaparin, apixaban—in a ratio of 1:1:1, in a parallel 
manner. Participants will be stratified based on study site and age (<70 vs 
≥70 years of age). Approximately 120 participants will be enrolled in each 
arm, for a total of up to approximately 360 participants in the study. 
Participants will be randomized after completion of surgery to receive a 
single dose of REGN9933 300 mg IV, enoxaparin 40 mg subcutaneous (SC) 
daily through the time of venography, or apixaban 2.5 mg orally twice daily 
through the time of venography. 
Discharge from the hospital will be determined by the site investigator based 
on individual participant recovery and local practice. Participants will 
undergo unilateral venography of the operated leg performed on day 10 (±2 
days). While in the hospital after surgery and at subsequent study visits, 
participants will be assessed for signs and symptoms of symptomatic DVT 
and pulmonary embolism (PE). If DVT or PE is suspected, objective 
confirmatory testing should be obtained. 
Participants will be followed until the end-of-study visit on day 75. 
Assessments will include scheduled venography; adverse event (AE) 
monitoring; physical exams; clinical laboratory testing (hematology, 
chemistry, coagulation, and urinalysis); electrocardiogram (ECG); PK, PD, 
and biomarker sampling. 
 
Study Duration 
The duration of the study for a participant is approximately 75 days, 
excluding the screening period. 
 
End of Study Definition 
The definition for end of study (trial) is the date of global last participant’s 
last visit, or the date of withdrawal from the study, or lost to follow-up (ie, 
the study participant can no longer be contacted by the investigator).  
Population 
 
 
Sample Size: 
Up to approximately 360 participants will be enrolled in the study  
 
Target Population: 
The study population will consist of adults who are at least 50 years of age 
and undergoing an elective, unilateral TKA. 
Treatment(s) 
 
 
Study Drug 
 
Dose/Route/Schedule: 
REGN9933 
300 mg IV, single dose administered as 0.5-hour infusion  
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Reference Drug 
 
Dose/Route/Schedule: 
Enoxaparin 
40 mg SC, daily through the time of venography (or day 12, whichever is 
earlier) 
 
Reference Drug 
 
Route/Schedule: 
Apixaban 
2.5 mg orally, twice daily through the time of venography (or day 12, 
whichever is earlier) 
Endpoint(s) 
 
 
Primary: 
The primary endpoint is the incidence of confirmed, adjudicated VTE 
through day 12 (REGN9933 vs enoxaparin).  
 
Secondary: 
The secondary endpoints are: 
• 
Incidence of major bleeding and clinically relevant non-
major bleeding through time of venography (or day 12, 
whichever is earlier). 
• 
Incidence of treatment-emergent adverse events (TEAE) 
through the end of study 
• 
Incidence of major VTE through day 12 (REGN9933 vs 
enoxaparin) 
• 
Incidence of DVT as measured by venography of the 
operated leg on day 10 ± 2 days (REGN9933 vs enoxaparin) 
• 
Concentrations of REGN9933 in serum through end of study 
• 
Change in activated partial thromboplastin time from 
baseline through end of study 
• 
Change in prothrombin time from baseline through end of 
study 
• 
Incidence and titer of anti-drug antibodies (ADA) to 
REGN9933 through end of study 
• 
Incidence of confirmed, adjudicated VTE through day 12 
(enoxaparin vs apixaban) 
 
Procedures and Assessments 
Efficacy Procedures: Venography of the operated leg will be performed on 
day 10 (±2 days). If DVT or PE is suspected at any point during the study, 
objective confirmatory testing should be carried out. 
Safety Procedures: Safety assessments will include body weight, height, 
monitoring of vital signs, physical examination, ECG, assessment for 
bleeding, laboratory testing, and the monitoring and reporting of AEs. 
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Blood samples will be collected for drug concentration, total Factor XI 
concentration, ADA, and exploratory biomarker and research measurements 
and assessments. 
 
Statistical Plan 
Statistical Hypothesis: The clinical hypothesis comparing the efficacy of 
REGN9933 to enoxaparin will be assessed through a Bayesian estimation 
framework. Bayesian posterior probabilities will be reported to estimate the 
incidence of confirmed VTE for participants treated with REGN9933 and 
enoxaparin, as well as the odds ratio (OR) of confirmed VTE in participants 
administered REGN9933 as compared to that of enoxaparin (ORRE). The 
statistical hypothesis ORRE <1. 
Justification of Sample Size: Up to a total of approximately 
360 participants will be randomized in a 1:1:1 allocation ratio to 
REGN9933, apixaban or enoxaparin. Each arm will have an approximate 
number of 120 participants. 
The sample size was determined using the following assumptions: 
• 
The event rate of VTE for REGN9933 was assumed to be 
13% and was set to be 22.4% for enoxaparin  
• 
The prior distribution of the treatment difference was 
assumed to be log(OR)~N(0,0.843), which was expressed as 
the log(OR). The prior distribution follows a normal 
distribution centered around no treatment difference and with 
a variance such that extreme treatment differences are 
expected to be unlikely, ie the probability that OR is between 
0.25 and 4 is 90%. 
Using these assumptions, and for the purpose of choosing a sample size, the 
following quantities were simulated: 
• 
The probability of any beneficial effect of REGN9933 over 
enoxaparin, ie, the posterior distribution of the odds ratio 
comparing REGN9933 to enoxaparin of confirmed VTE. A 
beneficial effect is where ORRE < 1, and thus the study will 
estimate P(ORRE < 1 | data). 
• 
In 75% of the simulated trials, in studies where the P(ORRE < 
1 | data) > 0.95, the sample size was 120 participants or less. 
Therefore, a sample size of 120 subjects per group was 
chosen. 
Statistical Methods: The clinical objectives will be estimated using the 
posterior distribution of ORRE. For comparison of REGN9933 vs 
enoxaparin, different posterior probabilities will be provided, such as 
P(OR<0.5, 0.9, 1.0, 1.1, 1.2 etc|data). 
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The entire posterior density function for the treatment effect (ORRE and the 
OR of confirmed VTE in participants administered REGN9933 as compared 
to that of apixaban) will be computed, along with the cumulative posterior 
distribution, which quantifies evidence for all possible treatment effects. A 
prior for treatment difference log(OR)~N(0,0.843) will be used. Bayesian 
summary statistics including two-sided 95% Highest Density Interval, 
posterior mean, and median will be reported. Summary statistics based on 
the raw data including the number of participants reflected in the calculation 
(n), mean, standard deviation, Q1, median, Q3, minimum, and maximum 
will be reported. 
The Kaplan-Meier plot for cumulative incidence of confirmed VTE over 
time will be provided by treatment groups. Subjects dropped out before the 
venogram or with missing venograms are considered as censored.  
Safety will be assessed by clinical and statistical review of all relevant 
parameters, including vital signs, physical examinations, ECGs, laboratory 
evaluations, and AEs.  
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1. 
INTRODUCTION  
Anticoagulants are medications used to treat and prevent venous and arterial thrombotic and 
embolic events by interfering with components of the coagulation cascade. The major 
complication of anticoagulants in clinical usage (such as warfarin, heparins, direct oral 
anticoagulants [DOAC]) is bleeding, since these drugs not only reduce thrombus formation, but 
also impair hemostasis. Furthermore, the bleeding liability of current anticoagulants has been 
associated with their blockade of the extrinsic and common pathways of the coagulation system 
(Harter, 2015). A major goal in the development of novel anticoagulants is to minimize bleeding 
risk while maintaining efficacy; targeting the intrinsic pathway is hypothesized to preserve normal 
hemostatic mechanisms and therefore carry less bleeding risk.  
Inhibition of Factor XI (FXI), a component of the intrinsic pathway, has emerged as a promising 
approach for effective anticoagulation (ie, prevention of thrombus) with minimal effect on 
hemostasis. Patients with FXI deficiency (Hemophilia C) have well documented reductions in 
thromboembolic disease with a relatively mild bleeding phenotype and no other obvious 
deleterious effects. In addition, a retrospective study including more than 10,000 patients observed 
that FXI activity <50% of normal was associated with a decreased incidence of cardiovascular 
events (eg, stroke, transient ischemic attack, and myocardial infarction) and a reduced risk of 
venous thromboembolism (Preis, 2017). Preclinical studies using either genetic or pharmacologic 
reduction of FXI support the anti-thrombotic activity of FXI inhibition (Wang, 2005) (Yau, 2014). 
Finally, several therapeutics aimed at reducing FXI levels and/or activity have demonstrated 
promising antithrombotic activity, without evidence of increased bleeding risk, as compared to 
enoxaparin, in clinical studies (Büller, 2015) (Verhamme, 2021) (Weitz, 2020) (Weitz, 2021). In 
summary, blockade of FXI activity may prevent thromboembolic events without increasing 
bleeding risk (Hsu, 2021). 
Factor XI can be activated by Factor XIIa (FXIIa). Factor XIIa activation is the initial step in the 
intrinsic pathway of coagulation and can be triggered by contact with negatively charged 
molecules, including polyphosphates from bacteria or platelets, free nucleic acids, misfolded 
proteins, or nonbiological surfaces (Al-Horani, 2018). 
 
 
 
REGN9933 is a monoclonal antibody which binds to FXI 
. 
Thus, REGN9933 may prevent pathologic thrombosis due to activation of the intrinsic pathway of 
coagulation, while potentially maintaining hemostatic mechanisms distal to FXIIa activation of 
FXI. 
REGN9933 is being evaluated in an ongoing randomized, double-blind, placebo-controlled 
phase 1 clinical study in healthy volunteers (study R9933-HV-2107). As of 01 Aug 2022, this 
ongoing study has randomized and dosed 40 subjects across 5 intravenous (IV) cohorts. Each 
cohort contained 8 subjects (6 randomized to REGN9933 and 2 randomized to placebo) at the 
following REGN9933 dose levels: 3 mg, 10 mg, 30 mg, 100 mg, and 300 mg. As of 01 Aug 2022, 
no adverse events (AEs) considered by the investigator to be related to study drug, no severe AEs, 
and no serious adverse events (SAEs) or clinically significant bleeding have reported in this 
ongoing study.  
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A dose-dependent prolongation of the activated partial thromboplastin time (aPTT) was observed 
across these 5 cohorts with an aPTT mean change from baseline of approximately 2.5-fold at the 
100 mg IV and 300 mg IV dose levels (see Section 3.2.2). No dose-dependent trends have been 
observed in the prothrombin time (PT), and no safety concerns have been identified to date. 
Refer to the Investigator’s Brochure (IB) for additional background information on REGN9933 
and the development program to date. 
This study is assessing the occurrence of VTE after TKA, which is a commonly used clinical 
setting to demonstrate proof-of-concept of the antithrombotic effects of novel anticoagulants. 
Venous thromboembolism includes deep venous thrombosis (DVT) of the lower extremities and 
pulmonary embolism (PE). Patients undergoing TKA are at high risk of developing VTE in the 
post-operative period, due to local tissue trauma, immobility, and inflammation. Venous 
thrombosis (most of which is asymptomatic) is extremely common in the days following TKA, 
with rates reported on placebo of >50% (Agnelli, 2004). Even with approved therapies that reduce 
the rates of symptomatic VTE, the incidence of asymptomatic VTE is substantial 
(Verhamme, 2021) (Warwick, 2010) (Weitz, 2020), allowing for detection of relative efficacy 
compared to approved agents. Thrombosis may be reliably detected with protocol venography 
performed 8 to 12 days after surgery. Many anticoagulants have established proof-of-concept using 
this model, and subsequently shown clinical efficacy in other clinical settings, such as prevention 
of stroke in patients with atrial fibrillation. As a result, use of this model allows for benchmarking 
of REGN9933 against many other comparable drugs, and can also potentially serve as a proof-of-
concept to help inform further development in other clinical settings. 
 
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2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of REGN9933 for the prevention of 
VTE after unilateral TKA, compared to enoxaparin. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the bleeding risk (ie, major and clinically relevant non-major [CRNM] 
bleeding) of REGN9933 after unilateral TKA through time of venography, compared 
to enoxaparin 
• To assess overall safety and tolerability of REGN9933 in participants undergoing 
TKA 
• To evaluate the efficacy of REGN9933 in prevention of clinically relevant VTE, 
compared to enoxaparin 
• To evaluate the efficacy of REGN9933 in prevention of DVT detected by 
venography, compared to enoxaparin 
• To evaluate the pharmacokinetics (PK) of REGN9933 after single IV administration 
• To assess PD effects of REGN9933 on intrinsic and extrinsic coagulation pathways 
(ie, aPTT, PT) 
• To assess immunogenicity following a single dose of REGN9933 over time 
• To compare the efficacy of enoxaparin and apixaban in prevention of VTE after 
unilateral TKA 
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• Explore the efficacy of REGN9933 in prevention of VTE after unilateral TKA 
through the end of study, compared to enoxaparin and apixaban  
• Explore the efficacy of REGN9933 in prevention of symptomatic, clinical 
thrombosis, compared to enoxaparin and apixaban 
• Explore the efficacy of REGN9933 in prevention of DVT detected by venography, 
compared to apixaban 
• Explore the extent of DVT burden on venography in participants receiving 
REGN9933 compared to enoxaparin and apixaban 
• Explore the bleeding risk (ie, major bleeds and CRNM) of REGN9933 after unilateral 
TKA through end of study compared to enoxaparin and apixaban 
• Explore the occurrence of minor bleeding compared to enoxaparin and apixaban 
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• Explore biomarkers related to FXI inhibition by REGN9933 
• Develop a molecular understanding of venous thromboembolism, and related diseases  
• Explore relationships between PK, biomarkers of anticoagulant activity, and efficacy 
• To study REGN9933 mechanism of action the coagulation cascade, VTE, and related 
diseases  
• Explore whether potential differences in participant efficacy and safety are associated 
with genotype and gene expression and further study FXI and coagulation-related 
diseases, using optional whole blood DNA and RNA collected from consented 
subjects 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypotheses 
REGN9933 will reduce the incidence of VTE after elective unilateral TKA as compared to 
enoxaparin. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
The population for this study is adults undergoing elective, unilateral TKA. Participants less than 
50 years of age are excluded, due to a significantly lower incidence of symptomatic VTE relative 
to older participants (Lee, 2015). Weight greater than 130 kg is exclusionary to limit the variability 
in exposure and PD effect of the fixed dosing regimen of the antibody. Since venography will 
provide most of the events that make up the primary endpoint, those with or at high risk of contrast 
allergy will be excluded. Participants with contraindications to enoxaparin, such as a history of 
heparin-induced thrombocytopenia (HIT), or apixaban will not be enrolled. Several risk factors for 
abnormal bleeding or clotting are also exclusionary. Finally, women of child-bearing potential 
(WOCBP) are excluded, since the risk of bleeding in the setting of FXI inhibition in this 
subpopulation is not yet characterized; further, the age cutoff of > 50 years of age already precludes 
nearly all WOCBP. 
Participants will be stratified by two factors: age (< 70 vs ≥ 70 years of age), based on the higher 
incidence of DVT in the ≥ 70 years age group (Lee, 2015); and site, to account for local variation 
in surgical and anesthesia practices. 
Several medications are approved in the countries in which the trial will be conducted for the 
prevention of VTE after TKA; therefore, a placebo-treated group would not be appropriate. 
Enoxaparin, a low molecular weight heparin (LMWH), is approved for the prevention of VTE 
after orthopedic surgery. In European Union (EU) countries, the approved dose is 40 mg SC once 
daily (Inhixa [Summary of Product Characteristics], 2021). Refer to Section 3.3.2.1 for discussion 
on enoxaparin dosing in Canada. Dosing will start 12 to 24 hours after surgery in this study, per 
the label. The duration of treatment is a minimum of 7 to 14 days per the label, and this can be 
extended up to 35 days (Inhixa [Summary of Product Characteristics], 2021) (Lovenox [Product 
Monograph], 2021), although the benefit of longer duration treatment is more pronounced after 
total hip replacement relative to TKA (Comp, 2001) (Eikelboom, 2001). In this study, study drug 
treatment will occur through the time of venography (or day 12, whichever is earlier). Several 
recent studies using this paradigm have utilized enoxaparin as an active comparator (Büller, 2015) 
(Verhamme, 2021) (Weitz, 2020) (Weitz, 2021), allowing for benchmarking of results from this 
study to other agents in development.  
Apixaban, a DOAC, is approved for the prevention of VTE after orthopedic surgery 
(Eliquis [Summary of Product Characteristics], 2021), and has also shown efficacy in prevention 
of VTE after TKA. In these studies, the regimen of apixaban evaluated was 2.5 mg twice daily 
(BID), initiated 12 to 24 hours after surgery, and continued for 10 to 14 days after surgery 
(Lassen, 2010) (Lassen, 2009). Apixaban serves as a calibrator in this study; a difference between 
apixaban and enoxaparin is expected and will be descriptively evaluated as a positive control. In 
addition, it will be useful to gain an early understanding of how REGN9933 compares to apixaban. 
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Timing of initiation of anticoagulants for prophylaxis of thrombosis following total knee 
replacement is a balance between safety and efficacy. Dosing closer to the time of surgery may 
confer additional efficacy but at the expense of increased bleeding risk.  Apixaban and enoxaparin 
will be started at 12 to 24 hours post-operatively, consistent with labeled dosing regimens and 
REGN9933 will also be dosed at 12 to 24 hours post-surgery, to allow a direct comparison. Dosing 
of FXI inhibitors in this time range, as well as pre-operatively, has been shown to well-tolerated 
in published trials of FXI inhibitors (Büller, 2015) (Verhamme, 2021) (Weitz, 2020). 
Regarding duration of treatment, for subjects assigned to study drug treatment with enoxaparin or 
apixaban, subsequent VTE prophylaxis (beyond day 12 or day of venography) may be determined 
by the site investigator as guided by local standard of care (see Permitted Medications, 
Section 8.8.2). However, for subjects assigned to REGN9933, use of anti-coagulants for VTE 
prophylaxis is prohibited, because REGN9933 elevates aPTT through at least day 35 (see 
Figure 1). 
Treatment is administered in an open-label manner because enoxaparin is packaged in pre-filled 
syringes, making blinding operationally challenging. In addition, performing the study in a blinded 
manner would require most (two thirds) of the participants to take placebo injections, which would 
have increased participant burden. To mitigate bias, participants will be randomized to treatment 
assignment. To further mitigate bias in outcome assessment, adjudication of outcomes related to 
VTE and bleeding (ie, results of venograms and any confirmatory study for symptomatic VTE; 
categorization of bleeding events) will be performed by a centralized adjudication committee (AC) 
that is blinded to treatment assignment (Section 6.3.3).  
The primary efficacy endpoint, which is a composite of confirmed asymptomatic DVT, confirmed 
symptomatic VTE (symptomatic DVT of the leg or non-fatal pulmonary embolism [PE]), and 
unexplained death for which PE cannot be ruled out, was designed to comprehensively capture 
VTE events and has been used in prior post-TKA VTE studies (Verhamme, 2021) (Weitz, 2020) 
(Weitz, 2021). Asymptomatic DVT is best detected with venography because of its high sensitivity 
relative to other modalities. In a study that directly compared venography to ultrasound for 
detection of asymptomatic DVT following hip or knee replacement surgery in patients receiving 
anticoagulant prophylaxis, the overall incidence of DVT detected by venography was 18.9%, 
compared to 11.5% with ultrasound (Schellong, 2007). Unilateral venography of the operated leg 
detects more than 80% of DVTs in patients undergoing unilateral TKA. Relative to bilateral 
procedure, unilateral venography reduces discomfort and improves compliance with the procedure 
with relatively limited loss of event detection. Venography is performed at day 10 (± 2 days), based 
on early studies suggesting that most DVTs form prior to day 12 after surgery (Gallus, 1976). 
The safety secondary endpoint was chosen to capture clinically relevant bleeding events. The 
International Society on Thrombosis and Hemostasis (ISTH) criteria will be used for both major 
(Schulman, 2010) and CRNM (Kaatz, 2015) bleeds. Both have clear, consensus definitions that 
will allow for robust adjudication.  
Minimal bleeds are not included in the secondary safety endpoint due to lack of clear criteria, 
which are crucial due to unblinded assignment of treatment. As minimal bleeding occurs more 
frequently and might therefore be of interest, incidence of minimal bleeding will be tabulated 
separately as an exploratory endpoint.  Minimal bleeding comprises any bleeding AE that does not 
qualify as either major bleeding or CRNM. 
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The length of study follow-up is 75 days. Data from study R9933-HV-2107 showed that aPTT had 
returned within 10% of normal values by Day 64 following a single 300 mg IV dose, which is the 
dose used in this trial (Section 3.2.2). Both enoxaparin and apixaban will be dosed through the 
time of venography (or day 12, whichever is earlier); based on their half-lives (enoxaparin 4.5 to 
7 hours, apixaban 12 hours), pharmacologically relevant levels are not present a few days after the 
last dose. 
3.2.2. 
Rationale for Dose Selection  
A single 300 mg IV dose of REGN9933 has been chosen based on data from a single ascending 
dose study with REGN9933 in healthy volunteers (study R9933-HV-2107) which explored the 
safety, PK, and PD effects, of single IV doses of REGN9933 up to 300 mg. Study participants 
each received a single 0.5 hour IV infusion of REGN9933 or matching placebo and blood samples 
for measurement of concentrations of REGN9933 in serum and PD assays (including Factor XI 
activity, PT and aPTT) were collected at intervals. REGN9933 pharmacokinetics were non-linear 
across the 3 to 300 mg dose range in a manner consistent with target-mediated drug disposition. 
REGN9933 treatment had no apparent effect on PT, but produced a rapid, dose-dependent decrease 
in Factor XI activity and a rapid, dose-dependent increase in aPTT without significant safety, 
tolerability, or bleeding findings. Preliminary analyses of available data are summarized in 
Section 5.2 of the IB. 
Single doses of REGN9933 ≥100 mg produced sustained inhibition of FXI activity and increases 
in aPTT in all treated individuals (Figure 1). Based on these observed data it is expected that a 
REGN9933 dose of 300 mg will maintain maximal inhibition of FXI activity and maximal effects 
on aPTT (~2.8-fold change from baseline, corresponding to absolute aPTT values of 
approximately 60 to 80 sec) in all individuals for ≥14 days. Pharmacodynamic data from study 
R9933-HV-2107 showed that aPTT values had returned to within 10% of normal values 64 days 
following the 300 mg dose. 
REGN9933 exposures from a 300 mg IV dose are substantially lower than corresponding 
exposures at the non-clinical toxicology no observed adverse effect level (NOAEL). Observed 
average total REGN9933 exposures from a 300 mg dose in study R9933-HV-2107 were >60× 
lower than average exposures at the NOAEL dose (100 mg/kg IV) in the 5-week REGN9933 GLP 
monkey toxicology study (R9933-TX-20070). 
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Figure 1: 
Mean (+SD) Change from Baseline in a) Factor XI Activity and b) aPTT by 
Nominal Time and by Dose in Healthy Volunteers (0-63 Days, Linear Scale, 
Study R9933-HV-2107) 
 
Arithmetic means, error bars represent standard deviation. 
Previous studies investigating the use of FXI inhibitors for prevention of post-operative VTE have 
shown that efficacy correlates with the magnitude of treatment effects on aPTT; maximum efficacy 
was achieved at doses which maintained near-maximal increases in aPTT (ie 2 to 3x increase from 
baseline) throughout the assessment period eg (Verhamme, 2021). It is therefore anticipated that a 
300 mg dose of REGN9933 will produce maximal efficacy for prevention of VTE in this clinical 
setting. 
 
3.3. 
Risk-Benefit 
Recognizing that the “Coronavirus Disease 2019” (COVID-19) pandemic will have an impact on 
the conduct of clinical trials, the Sponsor does not intend to screen any participants in this study 
until the impact of the COVID-19 pandemic is deemed manageable and no longer interfering with 
the conduct of trials at individual sites, and participants can safely participate in this study. Until 
then, the Sponsor plans to obtain approvals from Health Authorities/Ethics Committees to enable 
initiation of study sites for this study, as allowed by local laws and regulations. 
For information regarding the permitted timing of COVID-19 vaccinations, see Section 7.2.2 
Exclusion Criteria, criterion #22, and Section 8.8.1 Prohibited Concomitant Medications and 
Procedures. 
A risk-benefit statement with respect to the overall development program is provided in Section 7 
of the IB. 
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3.3.1. 
Risk-Benefit for REGN9933 
REGN9933 is a monoclonal antibody that binds to FXI and inhibits activation by the intrinsic 
pathway of the coagulation cascade. 
There is no clinical evidence that REGN9933 prevents VTE in post-surgical patients, including 
TKA. However, several lines of evidence suggest that inhibition of the intrinsic pathway, and FXI 
specifically, may reduce the incidence of VTE. As discussed in Section 1, FXI deficiency is 
associated with reduced risk of VTE in humans. Furthermore, clinical studies with other FXI 
blockers have shown reduced incidence of VTE after TKA relative to enoxaparin (Büller, 2015) 
(Verhamme, 2021) (Weitz, 2020) (Weitz, 2021). Extrapolation of these data to REGN9933 may 
be limited since it has a distinct mode of binding to FXI. Single doses of REGN9933 have been 
studied in healthy volunteers (study R9933-HV-2107) and REGN9933 treatment produced a rapid, 
dose-dependent decrease in FXI activity and a corresponding rapid, dose-dependent increase in 
aPTT, indicating inhibition of the intrinsic pathway (refer the Section 5.2 of the IB for preliminary 
analyses of available data). The magnitude of FXI inhibition and PTT elevation are comparable to 
those seen with other FXI blockers at doses that reduced VTE after TKA. Furthermore, the key 
design elements of this study are similar to those in the previous FXI inhibitor trials referenced 
above. 
Post-TKA VTE are generally asymptomatic. In the aforementioned studies comparing FXI 
targeted therapy versus enoxaparin in post-TKA VTE, <2% of participants experienced a 
symptomatic VTE. In addition, of all of the participant who experienced a VTE, <15% were 
symptomatic.  Even with placebo, only 13% of patients experienced a proximal DVT after TKA 
(Lovenox [Package Insert], 2022) . 
Mitigation and monitoring for VTE risk include: 
• Participant selection will exclude those with history of thromboembolic disease or 
thrombophilia 
• Routine, protocol-specified monitoring for clinical signs of VTE 
• Scheduled venogram can identify subclinical DVTs that may be treated with 
therapeutic anticoagulation 
Bleeding is an important potential risk of treatment with any anticoagulant, including REGN9933. 
As discussed in Section 1, genetic FXI deficiency is not associated with spontaneous bleeding. 
Clinical studies with other FXI inhibitors have not shown increased risk of bleeding, even when 
dosed prior to TKA surgery.  
To date, no study drug-related AEs or SAEs have been observed with REGN9933 in the healthy 
volunteer study R9933-HV-2107 (as discussed in Section 1).  
In preclinical toxicology studies with cynomolgus monkeys, REGN9933 was administered at 
doses up to 100 mg/kg via SC injection and 100 mg/kg via IV infusion (once weekly for 5 weeks). 
There were no significant increases in PT, and bleeding events were similar between treated and 
non-treated animals. 
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Mitigation and monitoring for bleeding risk include the following: 
• Participant selection will exclude participants with identified bleeding disorders or 
risk factors for significant bleeding.  
• During the trial, participants will be monitored for bleeding events.  
• Coagulation parameters will be followed for all participants.  
• Moderate to severe bleeding (both spontaneous and non-spontaneous) will be 
considered adverse events of special interest (AESI) with expedited reporting. 
• In the event participants need to seek medical attention during the follow-up period, 
they are provided a card that details that they are enrolled in a study of a novel 
anticoagulant targeting FXI upon clinic discharge following surgery. 
As described in the Study Stopping Rules (Section 6.1.1.1), the Independent Data Monitoring 
Committee (IDMC) will monitor the overall rates of both VTE and bleeding, and can recommend 
pausing of REGN9933 dosing if there are concerns of increased VTE or bleeding risk relative to 
enoxaparin. 
Other important potential safety risks include systemic hypersensitivity reactions, embryofetal 
toxicity, and immunogenicity. With regard to potential embryofetal toxicity, WOCBP and men 
whose sexual partners are not willing to practice highly effective contraception are excluded from 
this study. For more information on mitigation and monitoring for these potential risks, please 
refer to Section 6 of the IB. 
3.3.2. 
Risk-Benefit for Active Comparator and Calibrator 
As with other anticoagulants, participants taking apixaban or enoxaparin are to be carefully 
observed for signs of bleeding. In countries where enoxaparin and apixaban have been granted 
marketing authorization, the regulatory bodies have considered that the benefit of therapy has 
outweighed the risk for the indications granted, including VTE prophylaxis after TKA. All 
investigators must comply with and satisfy all requirements for the local risk management plan or 
equivalent for apixaban and enoxaparin where applicable and before dosing participants. In this 
study, participants will be closely monitored for bleeding, with oversight of the study by the IDMC 
(Section 6.3.1). Emergent evaluation and management of bleeding should be conducted according 
to standard local protocols aligned with bleeding management guidelines, as described in 
Section 8.2.  
3.3.2.1. 
Enoxaparin 
Enoxaparin is approved for the prevention of VTE after TKA in the countries in which the trial 
will be conducted (Inhixa [Summary of Product Characteristics], 2021) (Lovenox [Product 
Monograph], 2021) In this study, enoxaparin is being administered at the dose recommended by 
the EU summary of product characteristics (SmPC). While the 40 mg once daily dose is not 
approved in Canada, it is included as an acceptable regimen in a clinical guide issued by a Canadian 
vascular medicine professional organization (Thrombosis Canada, 2013) and has been used in 
several recent similar trials (Weitz, 2020) (Weitz, 2021). Once daily dosing is also expected to 
improve compliance with dosing. There are no additional benefits and risks to participants apart 
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from those described in the approved prescribing information for enoxaparin. See Section 3.2.1 
for information on the rationale for inclusion of enoxaparin. 
3.3.2.2. 
Apixaban 
Apixaban is approved for the prevention of VTE after TKA in the countries in which the trial will 
be conducted (Eliquis [Summary of Product Characteristics], 2021) (Eliquis [Product Monograph], 
2019). In this study, apixaban is being administered at the recommended dose within the approved 
indication. There are no additional benefits and risks to participants apart from those described in 
the approved prescribing information for apixaban. See Section 3.2.1 for information on the 
rationale for inclusion of apixaban. 
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4. 
ENDPOINTS  
4.1. 
Primary and Secondary Endpoints 
4.1.1. 
Primary Endpoint 
The primary endpoint is the incidence of confirmed, adjudicated VTE (defined in Section 5.2.1) 
through day 12 (REGN9933 vs enoxaparin).  
4.1.2. 
Secondary Endpoints 
The secondary endpoints are: 
• Incidence of major bleeding and CRNM bleeding (defined in Section 5.3.1) through 
time of venography (or day 12, whichever is earlier) 
• Incidence of treatment-emergent adverse events (TEAEs) through the end of study 
• Incidence of major VTE (defined in Section 5.2.2) through day 12 (REGN9933 
versus enoxaparin) 
• Incidence of DVT as measured by venography of the operated leg on day 10 ±2 days 
(REGN9933 vs enoxaparin) 
• Concentrations of REGN9933 in serum through end of study 
• Change in aPTT from baseline through end of study 
• Change in PT from baseline through end of study 
• Incidence and titer of anti-drug antibodies (ADA) to REGN9933 through end of study 
• Incidence of confirmed, adjudicated VTE through day 12 (enoxaparin vs apixaban) 
4.1.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
• Incidence of confirmed VTE (defined in Section 5.2.1) through day 12 (REGN9933 
vs apixaban) and through the end of study 
• Incidence of major VTE (defined in Section 5.2.2) through the end of study 
• Incidence of confirmed symptomatic DVT in either leg through day 12 and through 
the end of the study 
• Incidence of confirmed PE through day 12 and through the end of study 
• Incidence of fatal PE, which includes sudden death for which PE cannot be ruled out, 
through day 12 and through the end of study 
• Incidence of DVT as measured by venography of the operated leg on day 10 ±2 days 
(REGN9933 vs apixaban) 
• In participants with DVT detected on venogram: 
− distribution of DVT (proximal versus distal) 
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− for proximal DVT, size of VTE 
− for distal DVT, the number of veins affected 
• Incidence of major bleeding and CRNM bleeding (defined in Section 5.3.1) through 
end of study 
• Incidence of minimal bleeding through time of venography and through the end of 
study 
• Change in measures of coagulation pathway function compared to baseline, 
including, but not limited to: 
− FXI:C ([Factor XI functional activity] FXI coagulant activity assay) 
− Total FXI concentration 
− Thrombin generation assay (TGA) for extrinsic and intrinsic pathways 
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5. 
STUDY VARIABLES  
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc), 
disease characteristics, medical history, medication history, baseline aPTT and FXI level, and 
information on TKA surgery for each participant. 
5.2. 
Efficacy Variables 
5.2.1. 
Confirmed VTE 
The primary efficacy variable is adjudicated, confirmed VTE. This is a composite endpoint that 
includes: asymptomatic deep DVT detected by unilateral venography of the operated leg; 
confirmed symptomatic DVT of either leg; confirmed fatal or nonfatal PE including unexplained 
death for which PE cannot be ruled out. 
5.2.2. 
Major VTE 
This is a composite endpoint that includes: proximal DVT; confirmed symptomatic DVT of either 
leg; confirmed fatal or nonfatal PE including unexplained death for which PE cannot be ruled out. 
5.3. 
Safety Variables 
The safety variables include physical examination (including weight, temperature, and other vital 
signs), electrocardiograms (ECGs), laboratory evaluations (hematology, chemistry, urinalysis, 
other laboratory tests), concomitant medications, bleeding events (major bleeding and CRNM 
bleeding), and AEs. 
5.3.1. 
Bleeding Events 
The ISTH criteria will be used for both major bleeding events and CRNM events as described 
below. Minimal bleeding will be captured separately as an exploratory endpoint. 
Major Bleeding (ISTH): 
• Fatal bleeding and/or  
• Bleeding that is symptomatic and occurs in a critical area or organ, such as 
intracranial, intraspinal, intraocular, retroperitoneal, pericardial, in a non-operated 
joint, or intramuscular with compartment syndrome, assessed in consultation with the 
surgeon, and/or  
• Overt extrasurgical site bleeding causing a fall in hemoglobin level of 20 g/L 
(1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood 
or packed red cells, with temporal association within 24 to 48 hours to the bleeding, 
and/or  
• Surgical site bleeding that requires a second intervention (open, arthroscopic, 
endovascular) or a hemarthrosis of sufficient size as to interfere with rehabilitation by 
delay in mobilization or delayed wound healing, resulting in prolonged 
hospitalization or a deep wound infection, and/or  
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• Surgical site bleeding that is unexpected and prolonged and/or is sufficiently large to 
cause hemodynamic instability, as assessed by the surgeon. There should be an 
associated fall in hemoglobin level of at least 20 g/L (1.24 mmol/L), or transfusion 
indicated by the bleeding, of at least two units of whole blood or red cells, with 
temporal association within 24 hours to the bleeding.  
Clinically Relevant Non-Major Bleeding (ISTH): 
• Any sign or symptom of hemorrhage (eg, more bleeding than would be expected for a 
clinical circumstance, including bleeding found by imaging alone) that does not fit 
the criteria for the ISTH definition of major bleeding but does meet at least one of the 
following criteria: 
− requiring medical intervention by a healthcare professional 
− leading to hospitalization or increased level of care 
− prompting a face to face (ie, not just a telephone or electronic communication) 
evaluation 
Minimal Bleeding 
Any overt bleeding event that does not meet the criteria for either major or CRNM bleeding will 
be categorized as a minor bleeding event. 
5.4. 
Pharmacokinetic Variables 
The PK variable is the concentration of total REGN9933 at each time point. These sampling 
timepoints are specified in Table 2 and Table 3.  
5.4.1. 
Drug Target Variables 
The drug target variable is the concentration of total FXI in plasma at each time point. These 
sampling timepoints are specified in Table 2 and Table 3. 
5.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, and time-point/visit. Samples in this study 
will be collected at the clinic visits specified in Table 2 and Table 3. 
5.6. 
Pharmacodynamic and Other Biomarker Variables 
Activated partial thromboplastin time and PT are the variables for the secondary PD endpoints. 
Additional PD and biomarker variables include FXI:C, intrinsic-pathway-triggered thrombin 
generation, and extrinsic-pathway-triggered thrombin generation. Samples in this study will be 
collected at the clinic visits specified in Table 2 and Table 3.  
The list may be altered or expanded, as it is recognized that more relevant or novel biomarkers 
may be discovered during the study. The biomarkers studied will be ones believed to be relevant 
to the understanding of efficacy, pathophysiology of indication, target engagement, mechanism of 
action, and possible toxicities of REGN9933. 
 
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6. 
STUDY DESIGN  
6.1. 
Study Description and Duration 
This is a phase 2 multicenter, multinational, randomized, open label, active-control study of a 
single dose of IV REGN9933 for prevention of VTE in participants undergoing an elective, 
unilateral, TKA. An overview of study design is provided in Figure 2. 
Participants who are at least 50 years of age and undergoing elective, unilateral TKA will be 
randomized after surgery to one of 3 treatment arms—REGN9933, enoxaparin, apixaban—in a 
ratio of 1:1:1, in a parallel manner. Randomization will be stratified based on study site and age 
(<70 vs ≥ 70 years of age). Approximately 120 participants will be enrolled in each arm, for a total 
of up to approximately 360 participants in the study.  
After providing informed consent, participants will undergo screening, which can occur from 
approximately day -30 to -1 (day 1 is defined as the day of TKA surgery). Participants will be 
randomized after completion of surgery to treatment in one of the following groups: 
• REGN9933 300 mg IV, once 
• Enoxaparin 40 mg subcutaneous (SC), daily 
• Apixaban 2.5 mg orally (PO), BID 
Dosing with REGN9933 will occur 12 to 24 hours after the end of surgery. 
Dosing with enoxaparin or apixaban will begin 12 to 24 hours after the end of surgery and will 
continue through the day of venography (or day 12, whichever is earlier). Administration of 
enoxaparin prior to TKA surgery is not permitted in this study (Section 7.2.2 Exclusion criterion 
10 and Section 8.8.1). All investigators must comply and satisfy all requirements for the local risk 
management plan or equivalent for apixaban and enoxaparin where applicable and before dosing 
participants. 
Discharge from the hospital will be determined by the site investigator based on individual 
participant recovery and local practice. If required, the participant will return to the site for the 
scheduled assessments, including the mandatory unilateral venography of the operated leg 
performed on day 10 (±2 days). Prior to site discharge, participants are provided a card detailing 
that they are enrolled in this study and may be on an FXI inhibitor in the event they need to seek 
medical attention during the outpatient period. 
While in the hospital after surgery and at subsequent study visits, participants will be assessed for 
signs and symptoms of: symptomatic DVT, including lower extremity swelling, warmth, redness, 
and pain; PE, including shortness of breath, chest pain exacerbated by inspiration, and hemoptysis; 
bleeding, either at the surgical site or elsewhere. If DVT is suspected, objective confirmatory 
testing should be obtained using either lower extremity ultrasound, conventional venography, CT 
venography, or magnetic resonance (MR) venography, with the choice of modality at the discretion 
of the investigator. If PE is suspected, objective confirmatory testing should be obtained using 
spiral CT, ventilation/perfusion scan, or pulmonary angiography, with the choice of modality at 
the discretion of the investigator. If the confirmatory tests do not demonstrate DVT/PE, or if a 
distal DVT is demonstrated by ultrasound, then venography should be performed as specified in 
the protocol. On the other hand, if the presence of DVT (if diagnosed by ultrasound, then DVT 
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must be proximal) or PE is confirmed prior to the protocol-defined venogram on day 10 (±2 days), 
then the venogram is not performed.  
Participants will continue to be followed until the end-of-study visit on day 75. Assessments will 
include venography as described above; AE monitoring; physical exams; clinical laboratory testing 
(hematology, chemistry, coagulation, and urinalysis); ECG; PK, PD and biomarker sampling. 
Figure 2: 
Study Flow Diagram 
 
6.1.1.1. 
Study Stopping Criteria 
The IDMC will monitor unblinded data on an ongoing basis to assess the risk/benefit profile of 
REGN9933. If at any time the IDMC has significant concerns regarding a meaningful imbalance 
in VTE incidence, TEAEs, treatment-emergent SAEs, or treatment-emergent AESIs, they may 
make a recommendation to the sponsor to halt dosing with REGN9933 or make other changes in 
the study conduct. This will prompt a review by the sponsor who will decide to implement, modify, 
or reject the recommendation. Applicable regulatory procedures will be adhered to as required by 
local laws in relation to any decisions related to a change in study conduct, temporary halt, study 
termination, or study restart. 
6.1.2. 
End of Study Definition 
End of study (trial) is the global last participant last visit, withdraws from the study, or is lost to 
follow-up (ie, the study participant can no longer be contacted by the investigator).  
6.2. 
Planned Interim Analysis  
An interim analysis (IA) will be conducted by the Sponsor when there are at least 50 participants 
per arm who have finished the study. The IA will only be used for administrative purpose and will 
not be used to make any decisions regarding the conduct of this study, eg, stop the study. Refer to 
Section 11.5 for further details. 
A description of the statistical methods to be employed is in Section 11.4, and blinding 
implications are discussed in Section 8.6. 
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6.3. 
Study Committees  
6.3.1. 
Independent Data Monitoring Committee 
The IDMC (also known as a Data Monitoring Safety Board) is an independent, multidisciplinary 
group consisting of clinicians and statistician(s) that, collectively, have experience in areas 
relevant to this clinical study and in the conduct and monitoring of randomized clinical studies.  
The IDMC is independent from Regeneron and the study investigators and is responsible for 
reviewing the efficacy and safety data of study participants on an on-going basis in order to 
provide, in a timely fashion, appropriate recommendations to Regeneron regarding the safety and 
the welfare of the participants exposed to REGN9933. Based on these reviews in the context of 
the totality of evidence, the IDMC may make a recommendation to the sponsor to temporarily 
pause, alter, or terminate the study. Once recommendations from the IDMC have been received, 
further discussions may be conducted, if appropriate, and the sponsor will determine if these or 
other actions should be taken. 
Details will be provided in the IDMC charter. 
6.3.2. 
Steering Committee 
The Steering Committee will be comprised of independent experts, selected by Regeneron. The 
Steering Committee will provide advice on all scientific matters (including protocol development 
and publication of results) related to the study.  
Details will be provided in the Steering Committee charter. 
6.3.3. 
Adjudication Committee 
The AC will be comprised of independent experts selected by Regeneron. The AC will review and 
determine interpretation and/or classification of the following events and tests in a blinded manner: 
all imaging procedures used for determination of VTE, including mandatory venography and 
testing for suspected DVT or PE; all deaths; all suspected bleeding events. 
Details will be provided in the Adjudication Committee charter. 
 
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PARTICIPANTS 
7.1. 
Number of Participants Planned 
Up to approximately 360 participants will be enrolled in the study. 
7.2. 
Study Population  
The study population will consist of adults who are at least 50 years of age and undergoing an 
elective, unilateral TKA. 
7.2.1. 
Inclusion Criteria  
A participant must meet the following criteria to be eligible for inclusion in the study: 
1. Is a male or female ≥50 years of age at the screening visit, undergoing elective unilateral 
TKA.  
2. Has a body weight ≤130 kg at screening visit. 
3. Is judged by the investigator to be in good health based on medical history, physical 
examination, vital sign measurements, and ECG's performed at screening and/or prior to 
administration of initial dose of study drug. 
4. Is in good health based on laboratory safety testing obtained during the screening period: 
a. Platelet count >150K 
b. Normal PT, international normalized ration (INR), and aPTT during screening 
c. Hemoglobin >10 g/dL 
d. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 3X upper 
level of normal (ULN), or total bilirubin < 2X ULN 
 
Note: Participants with suspected or confirmed Gilbert’s disease can be enrolled in the 
study 
5. Willing and able to comply with clinic visits and study-related procedures including 
venography. 
6. Provide informed consent signed by study participant.  
7.2.2. 
Exclusion Criteria  
A participant who meets any of the following criteria will be excluded from the study: 
1. Any condition that, as assessed by the investigator, may confound the results of the study 
or poses an additional risk to the subject by study participation.   
2. History of bleeding in the 6 months prior to dosing requiring hospitalization or 
transfusion; history of intracranial or intraocular bleeding, excessive operative or post-
operative bleeding, and traumatic spinal or epidural anesthesia; history of bleeding 
diathesis (eg, Hemophilia A or B, von Willebrand’s Factor deficiency). 
3. History of thromboembolic disease or thrombophilia.  
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4. History of major surgery, including brain, spinal, or ocular, within approximately the past 
6 months. 
5. History of major trauma within approximately the past 6 months prior to dosing. 
6. Hospitalized (>24 hours) for any reason within 30 days of the screening visit. 
7. Using the Modification of Diet in Renal Disease (MDRD) equation, has an estimated 
glomerular filtration rate (GFR) of <45 mL/min/1.73m2 at the screening visit. 
Note: If subject has a GFR below 45 mL/min/1.73m2, one repeat test is allowed. 
Participant may be enrolled if repeat demonstrates GFR of >45 mL/min/1.73m2. 
8. History of hypersensitivity or contraindication (per local label) to any of the study 
treatments or their excipients. 
9. Contraindication to anticoagulation in the opinion of the investigator. 
10. Has received or plans to receive preoperative enoxaparin on the day prior to TKA 
surgery.  
11. Allergy to contrast agents, poor venous access, or other factors that might preclude 
venography. 
12. Expected post-operative use of epidural/spinal catheter. 
13. Patients who have traumatic epidural/spinal anesthesia or excessive intra-operative blood 
loss during TKA surgery should not be randomized to receive study treatment. 
14. Has a history of alcohol or drug abuse. 
15. Known history of human immunodeficiency virus (HIV) infection, or ongoing chronic 
hepatitis B or hepatitis C infection. Prior resolved hepatitis B infection is not an 
exclusion. 
16. Any malignancy, except for nonmelanoma skin cancer or cervical/anus in situ, that have 
been resected with no evidence of metastatic disease for 3 years prior to the screening 
visit. 
17. History of significant multiple and/or severe allergies (eg, latex gloves) or has had an 
anaphylactic reaction to prescription or nonprescription drugs or food. 
18. Participated in any clinical research study evaluating another investigational drug 
including biologics or therapy, including specific immunotherapy, within 90 days or at 
least 5 half-lives (whichever is longer) of an investigational biologic drug or at least 4 
weeks for other investigational drug prior to the screening visit 
19. Unwilling or unable to comply with the prohibited medication specifications for this 
study: 
a. Participants who require therapeutic (full-dose) anticoagulation should be excluded 
b. Participants who require antiplatelet therapy (except for acetylsalicylic acid [ASA] 
≤100 mg/day) should be excluded  
20. Presents any concern to the study investigator that might confound the results of the study 
or poses an additional risk to the subject by their participation in the study 
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21. Members of the clinical site study team and/or his/her immediate family, unless prior 
approval granted by the sponsor. 
22. Has received a COVID-19 vaccination within 1 week of planned start of study 
medication or for which the planned COVID-19 vaccinations would not be completed 1 
week prior to start of study drug. 
23. Sexually active men with WOCBP partners who are unwilling to use medically 
acceptable birth control through day 75 (end of study [EOS]):  vasectomy with medical 
assessment of surgical success OR consistent use of a condom. 
24. Women of childbearing potential*  
*WOCBP are defined as women who are fertile following menarche until becoming 
postmenopausal, unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However, in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a 
postmenopausal state. The above definitions are according to the Clinical Trial 
Facilitation Group (CTFG) guidance. Pregnancy testing and contraception are not 
required for women who are post-menopausal or permanently sterile.  
7.3. 
Premature Withdrawal from the Study 
A participant has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a participant from the study if it is no 
longer in the interest of the participant to continue in the study, or if the participant’s continuation 
in the study places the scientific outcome of the study at risk (eg, if a participant does not or cannot 
follow study procedures). An excessive rate of withdrawals would render the study 
uninterpretable; therefore, unnecessary withdrawal of participants should be avoided. 
Participants who are withdrawn prematurely from the study will be asked to complete the early 
termination visit, as described in Section 9.1.2. 
Rules for discontinuation of study intervention (permanent or temporary) are discussed in 
Section 8.3.2. 
7.4. 
Replacement of Participants 
Participants prematurely withdrawn from the study can be replaced, if needed, to ensure an 
adequate number of evaluable participants. The Medical/Study Director, in cooperation with the 
Study Biostatistician, will decide whether or not to replace a withdrawn participant. 
Participants enrolled and withdrawn from study any time prior to first dose of study drug will not 
be considered evaluable for assessment and will be replaced with another participant. All 
participants who have received a dose of study drug will be included in an as treated analysis. 
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8. 
STUDY TREATMENTS  
8.1. 
Investigational and Reference Treatments 
Study interventions are presented in Table 1.  
Treatment arms are: 
• REGN9933 300 mg IV, single dose administered as 0.5-hour infusion  
• Enoxaparin 40 mg SC, daily through the time of venography (or day 12, whichever is 
earlier) 
• Apixaban 2.5 mg PO, BID through the time of venography (or day 12, whichever is 
earlier) 
For REGN9933, a single IV dose will be administered 12 to 24 hours after surgery (>12 hours 
after removal of the spinal/epidural anesthesia needle/catheter). 
For enoxaparin, dosing will begin 12 to 24 hours after surgery (>12 hours after removal of the 
spinal/epidural anesthesia needle/catheter). Dosing will continue through the time of venography 
(or day 12, whichever is earlier). If a participant is discharged from the hospital prior to the 
venogram, the participant may choose to self-administer enoxaparin or have a designated person 
administer enoxaparin at home. Injection training of enoxaparin will be provided. After training, 
observation of self-administration/designated person will be conducted by clinical site personnel. 
Once this observation is considered satisfactory, then the study drug can be subsequently 
administered independently by the participant/designated person for the remainder of the dosing 
period. 
For apixaban, dosing will begin 12 to 24 hours after surgery (>12 hours after removal of the 
spinal/epidural anesthesia needle/catheter). Dosing will continue through the time of venography 
(or day 12, whichever is earlier). Apixaban dosing will continue at home if a participant is 
discharged from the hospital prior to the venogram.  
A patient diary will be provided to record compliance of at-home dosing of enoxaparin/apixaban. 
The diary should be completed upon each study drug administration. 
Instructions on dose preparation are provided in the pharmacy manual.  
Table 1: 
Study Interventions Administered 
Intervention Name 
REGN9933 
Enoxaparin 
Apixaban 
Intervention Description 
300 mg IV, single dose 
administered as 0.5-hour 
infusion 
40 mg SC, daily through 
the time of venography 
2.5 mg PO, BID through 
the time of venography 
Type  
Biologic 
Drug 
Drug 
Dose Formulation 
Lyophilized Powder 
Pre-filled Syringe-Liquid 
Solution 
Film Coated Tablet 
Unit Dose Strength(s) 
265 mg in 20 mL vial 
40 mg, 0.4 mL, pre-filled 
syringe  
2.5 mg tablets, in a 
blister pack/wallet carton 
Dosage Level(s) 
300 mg, once 
40 mg, daily, through the 
time of venography 
2.5 mg, BID, through the 
time of venography 
Route of Administration 
IV infusion 
SC injection 
Oral 
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Use 
Experimental 
Active Comparator 
Active Calibrator 
IMP and NIMP/AxMP 
IMP 
IMP 
IMP 
Sourcing 
Regeneron Drug Supply 
Provided centrally by the 
sponsor. May be locally 
sourced by sites in 
Canada  
Provided centrally by the 
sponsor. May be locally 
sourced by sites in 
Canada  
8.2. 
Rescue Treatments 
8.2.1. 
Treatment of VTE 
Treatment of symptomatic VTE events that occur during the trial will be managed by the 
investigator per local practice.  
For participants receiving either enoxaparin or apixaban, increasing the dose of either agent to 
therapeutic levels (according to local standards) may be considered. For participants who 
develop a symptomatic VTE after receiving REGN9933, consideration may be given to DOACs, 
which have more predictable anticoagulant activity and lower bleeding liability than other 
anticoagulants. Therapeutic doses of LMWH may also be considered. 
Asymptomatic VTE may be monitored with additional imaging assessments at the discretion of 
the site investigator. In addition, treatment with therapeutic anticoagulation may be considered, 
depending on the clinical situation, and at the discretion of the site investigator. 
8.2.2. 
Treatment of Bleeding Events 
Participants requiring emergent evaluation for bleeding should be first treated with conventional 
bleeding management per standard protocols, including local compression by either manual 
compression or pressure bandages applied to the wounds. If bleeding persists, treatment should be 
provided at the discretion of the treating physician and aligned with local practice and bleeding 
management guidelines. Participants should be treated with respect to their clinical signs and 
symptoms of bleeding and not treated per a normalized aPTT/PT laboratory value nor per a specific 
FXI activity level. 
Of note, activated Factor VII (Factor VIIa) products have been reported as successful bypass 
agents to control bleeding in FXI-deficient patients. Factor VIIa, through multiple portions of the 
coagulation cascade, contributes to activation of thrombin (Factor IIa) without need for FXI. Factor 
VIIa is clinically available as recombinant Factor VIIa (rFVIIa) under the brand name NovoSeven 
(NovoSeven (Summary of Product Characteristics), 2021). 
If NovoSeven or another Factor VIIa formulation is available and selected for use at the discretion 
of the treating physician, the literature has commonly reported NovoSeven doses of 15 μg/kg to 
30 μg/kg administered as an IV bolus in FXI-deficient patients. NovoSeven has a half-life of 
approximately 3 hours and repeat doses of NovoSeven have been reported as administered 2 hours 
to 6 hours following the first dose depending on surgical and bleeding circumstances. Continuous 
infusions of rFVIIa at 1.8 μg/kg to 3.6 μg/kg have also been utilized in clinical practice. These 
lower doses of NovoSeven have been administered with or without anti-fibrinolytics such as 
tranexamic acid. 
Treatment with rescue medications in these events may impact the aPTT and other PD-related 
endpoints. 
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8.3. 
Dose Modification and Study Treatment Discontinuation Rules 
8.3.1. 
Dose Modification 
Dose modification of REGN9933 for an individual participant is not allowed. 
Sites should follow the enoxaparin and apixaban dosing schedule outlined in Section 8.1. 
However, enoxaparin and apixaban may be temporarily interrupted or the dose reduced due to 
medical need, as determined by the investigator.  
The criteria for permanent discontinuation of enoxaparin and apixaban are described in 
Section 8.3.2.2 and Section 8.3.2.3, respectively.  
8.3.2. 
Study Intervention Discontinuation 
Participants who permanently discontinue from study intervention (REGN9933, enoxaparin, or 
apixaban) should be encouraged to remain in the study.  Those who agree and do not withdraw 
from the study will be asked to return to the clinic for all remaining study visits per the visit 
schedule.  
Participants who permanently discontinue from study intervention and who opt to withdraw from 
the study will be asked to complete study assessments, per Section 9.1.2.   
8.3.2.1. 
REGN9933 Discontinuation 
As this is a single dose study of REGN9933, discontinuation of REGN9933 is not applicable. Refer 
to Section 8.4 for the Management of Acute Reactions including interruption and termination of 
REGN9933 IV infusion. 
8.3.2.2. 
Enoxaparin Discontinuation 
Enoxaparin should be discontinued: 
• if there is clinical suspicion of HIT 
• if there is active clinically significant bleeding 
Further management of HIT, the bleeding event, and VTE prophylaxis and is left to the 
discretion of the investigator. 
8.3.2.3. 
Apixaban Discontinuation 
Apixaban should be discontinued: 
• if there is active clinically significant bleeding 
Further management of the bleeding event and VTE prophylaxis is left to the discretion of the 
investigator. 
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8.4. 
Management of Acute Reactions  
8.4.1. 
Acute Intravenous Infusion Reactions 
Emergency equipment and medication for the treatment of infusion reactions must be available for 
immediate use.  All infusion reactions must be reported as AEs (as defined in Section 10.2.4) and 
graded using the grading scales as instructed in Section 10.2.5. 
8.4.1.1. 
Interruption of the Intravenous Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
• Sustained/severe cough 
• rigors/chills 
• rash, pruritus (itching) 
• urticaria (hives, welts, wheals) 
• diaphoresis (sweating) 
• hypotension 
• dyspnea (shortness of breath) 
• vomiting 
• flushing 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of the 
original rate. 
If investigators feel there is a medical need for treatment or discontinuation of the infusion other 
than described above, they should use clinical judgment to provide the appropriate response 
according to typical clinical practice. 
8.4.1.2. 
Termination of the Intravenous Infusion 
The infusion should be terminated and NOT restarted if any of the following AEs occur: 
• Anaphylaxis* 
• laryngeal/pharyngeal edema 
• severe bronchospasm 
• chest pain 
• seizure 
• severe hypotension 
• other neurological symptoms (confusion, loss of consciousness, paresthesia, paralysis, 
etc) 
• any other symptom or sign that, in the opinion of the investigator, warrants 
termination of the IV infusion 
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*Consider anaphylaxis if the following is observed (Sampson, 2006):  acute onset of an illness 
(minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized 
hives, pruritus or ﬂushing, swollen lips-tongue-uvula) AND AT LEAST ONE OF THE 
FOLLOWING  
• Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia) 
• Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence) 
8.4.2. 
Acute Injection Reactions 
8.4.2.1. 
Systemic Injection Reactions 
Emergency equipment and medication for the treatment of systemic reactions must be available 
for immediate use.  All injection reactions must be reported as AEs (as defined in Section 10.2.1) 
and graded using the grading scales as instructed in Section 10.2.5. 
Acute systemic reactions following injection of study intervention (SC) should be treated using 
clinical judgment to determine the appropriate response according to typical clinical practice.  
8.4.2.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to Section 10.2.5. 
8.5. 
Method of Treatment Assignment  
Participants will be randomized after surgery to one of 3 treatment arms—REGN9933, enoxaparin, 
apixaban—in a ratio of 1:1:1, according to a central randomization scheme provided by an 
interactive voice response system (IVRS)/interactive web response system (IWRS) to the 
designated study pharmacist (or qualified designee). Approximately 120 participants will be 
enrolled in each arm, for a total of up to approximately 360 participants in the study. 
Participants will be stratified based on study site and age (<70 vs ≥70 years of age).  
8.6. 
Blinding/Masking  
This is a phase 2 multicenter, multinational, randomized, open label, active-control study of a 
single dose of IV REGN9933 for prevention of VTE in participants undergoing an elective 
unilateral TKA. 
Treatment is administered in an open-label manner because enoxaparin is packaged in pre-filled 
syringes, making blinding operationally challenging. To mitigate bias in outcome assessment, 
adjudication of outcomes related to VTE, and bleeding will be performed by a centralized AC that 
is blinded to treatment assignment (Section 6.3.3). 
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8.7. 
Treatment Logistics and Accountability 
8.7.1. 
Packaging, Labeling, and Storage  
A medication numbering system will be used to label investigational study drug. Lists linking 
medication numbers with product lot numbers will be maintained by the groups (or companies) 
responsible for study drug packaging. 
Open-label study drug will display the product lot number on the label. 
REGN9933 study drug should be stored at the site at a temperature of 2ºC to 8ºC; storage 
instructions will be provided in the pharmacy manual. 
Enoxaparin and Apixaban should be stored at the site as follows:  Do not store above 25°C (77° F); 
storage instructions will be provided in the pharmacy manual.  
8.7.2. 
Supply and Disposition of Treatment 
All study drug will be shipped at a temperature provided in the pharmacy manual to the investigator 
or designee at regular intervals or as needed during the study.   
At specified time points during the study (eg, interim site monitoring visits), at the site close-out 
visit, and following drug reconciliation and documentation by the site monitor, all opened and 
unopened REGN9933 will be destroyed with Sponsor’s approval or returned to the Sponsor or 
designee.  
At specified time points during the study (eg, interim site monitoring visits), at the site close-out 
visit, and following drug reconciliation and documentation by the site monitor, all centrally 
sourced opened and unopened enoxaparin and apixaban will be destroyed with Sponsor’s approval 
or returned to the Sponsor or designee 
8.7.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug. These records 
should contain the dates, quantity, and study medication 
• dispensed to each participant 
• returned from each participant (if applicable), and 
• disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
8.7.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
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8.8. 
Concomitant Medications and Procedures 
Any treatment administered from the time of informed consent to the final study visit will be 
considered concomitant medication. This includes medications that were started before the study 
and are ongoing during the study. 
8.8.1. 
Prohibited Medications and Procedures 
Administration of enoxaparin prior to TKA surgery is prohibited (Section 7.2.2 Exclusion criterion 
10). 
Anti-platelet therapy (except low doses of ASA ≤100 mg/day) is prohibited, unless indicated for 
treatment of an AE. 
The following procedures/devices are prohibited after study drug has started: 
• Use of spinal or epidural analgesia post-operatively 
• Pneumatic compression devices  
Subjects are prohibited from donating blood products through the EOS visit. Subjects are 
prohibited from donating sperm through the EOS visit. Subjects are prohibited from having 
planned, elective surgeries (except for TKA performed on day 1) through the EOS visit. 
For patients assigned to the REGN9933 treatment arm, anticoagulant medications (including, but 
not limited to, vitamin K antagonists, heparins, DOACs) are prohibited after study drug has been 
started, unless they are indicated for treatment of an AE.  
8.8.2. 
Permitted Medications 
Use of standard-of-care medications not listed as prohibited will be allowed.  
For subjects assigned to either the enoxaparin or apixaban treatment arm, continued VTE 
prophylaxis (after completion of protocol-defined treatment, ie through the day of venography [or 
day 12, whichever is earlier]) is permitted, if deemed necessary by the site investigator based on 
local guidelines and/or clinical judgment. For the choice of agent to be used for subsequent VTE 
prophylaxis, it is preferred that the originally assigned treatment (ie enoxaparin or apixaban) is 
used. However, it is permissible to use other agents, as long as they are consistent with local 
regulations and standard of care for VTE prophylaxis after TKA surgery.  
COVID-19 vaccination and any other vaccination can be administered as deemed necessary per 
the investigator based on his/her practice, standard of care, or as required based on mandatory 
vaccination programs. Vaccination is suggested to be administered preferably at least 1 week 
before the first dose of study drug (Section 7.2.2 Exclusion criterion 22), or at the earliest, 21 days 
following the last dose of study drug. Live-attenuated vaccines are generally not recommended 
during the study; however, use is allowed per the investigator’s discretion. 
 
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9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct, and oversight may require implementation of temporary or alternative mechanisms.  
Examples of such mechanisms may include, but are not limited to, any of the following:  phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff. Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted. All 
temporary mechanisms utilized, and deviations from planned study procedures are to be 
documented as being related to COVID-19 and will remain in effect only for the duration of the 
public health emergency. 
Study assessments and procedures are presented by study period and visit in Table 2. 
Definitions 
For safety variables, 3 observation periods are defined: 
• Screening period - the time from signing the ICF to before the first dose of study 
drug. 
• On-treatment period - the day from first dose of study drug to the date of day 12.  
• Follow-up period - the end of the on-treatment period to EOS visit. 
 
 
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Table 2: 
Schedule of Events 
 
Screening  
On-treatment  
Follow-up 
Study Procedure 
Visit 1 
Baseline 
Visit 2 
Visit1,2 3 
Visit1 4 
Visit 5 
End of Study/ Visit 6 
Day 
-30 to -1 
1 
5 
10 
30 
75 
Window (day) 
 
 
±1 
±2 
±3 
±5 
Screening/Baseline: 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Informed consent for 
pharmacogenomics research 
(optional) 
X 
 
 
 
 
 
Informed consent for future 
biomedical research (optional) 
X 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
FSH3 
X 
 
 
 
 
 
GFR (MDRD) 
X 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
Randomization 
 
X4 
 
 
 
 
Treatment: 
 
 
 
 
 
 
TKA 
 
X 
 
 
 
 
Administer REGN9933 
 
X5 
 
 
 
 
Administer enoxaparin 
 
X6 
 
 
Administer apixaban 
 
X6 
 
 
Patient diary (for self-
administration of 
apixaban/enoxaparin) 
 
X 
 
 
Efficacy: 
 
 
 
 
 
 
Venography of the operated leg 
 
 
 
X 
 
 
Assessment for symptomatic 
VTE7 
 
X 
X 
X 
X 
X 
Safety: 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
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Screening  
On-treatment  
Follow-up 
Study Procedure 
Visit 1 
Baseline 
Visit 2 
Visit1,2 3 
Visit1 4 
Visit 5 
End of Study/ Visit 6 
Vital Signs 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
 
X 
Electrocardiogram 
X 
 
 
 
 
 
Assessment for surgical site 
bleeding 
 
X 
X 
X 
 
 
Assessment for bleeding events 
 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
Concomitant medications and 
treatment 
X 
X 
X 
X 
X 
X 
Laboratory Testing  
 
 
 
 
 
 
Hematology 
X 
X8 
 
X 
 
X 
Blood chemistry 
X 
X8 
 
X 
 
X 
Coagulation panel  
X 
X8 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
X 
Pharmacokinetics and 
Immunogenicity Sampling 
 
 
 
 
 
 
Drug concentration sample 
(REGN9933) 
 
X8 
X 
X 
X 
X 
ADA (REGN9933) 
 
X9 
 
 
 
X 
Plasma for total FXI 
concentration 
 
X8 
X 
X 
X 
X 
Biomarkers 
Plasma for aPTT, PT (central lab) 
 
X8 
X 
X 
X 
X 
Plasma for FXI activity (FXI:C) 
and TGA 
 
X8 
X 
X 
X 
X 
Serum for exploratory research  
 
X8 
X 
 
X 
X 
Plasma for exploratory research  
 
X8 
X 
 
X 
X 
Optional Pharmacogenomics samples 
Whole blood sample for RNA 
isolation (optional)10 
 
X 
 
 
 
X 
Whole blood sample for DNA 
isolation (optional)10 
 
X11 
 
 
 
 
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ADA: anti-drug antibody; aPTT: activated partial thrombin time; GFR: glomerular filtration rate; FSH: follicle-stimulating hormone; FXI: Factor XI; FXI:C: 
Factor XI functional activity; MDRD: Modification of Diet in Renal Disease; PT: prothrombin time; TGA: thrombin generation assay; TKA: total knee 
arthroplasty; VTE: venous thromboembolism 
 
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Table 3: 
Schedule of Events: Visit 2 Blood Collection  
Baseline  
Visit 2  
(Day 1) 
Study Procedure 
Pre-operatively 
Post-operatively 
Pre-dosing 
Up to 1 hour prior to 
dosing 
Post-dosing 
REGN9933 only:  as 
close as possible to 
1 hour post-dose 
Laboratory Testing 
Hematology 
X1 
 
 
Blood chemistry 
X1 
 
 
Coagulation panel  
X1 
 
 
Urinalysis 
 
 
 
Pharmacokinetics and Immunogenicity Sampling 
Drug concentration 
sample (REGN9933) 
 
X2 
X2 
ADA (REGN9933) 
 
X2 
 
Plasma for total FXI 
concentration 
X1 
X3 
X2 
Biomarkers 
Plasma for aPTT, PT 
(central lab) 
X1 
X3 
X2 
Plasma for FXI activity 
(FXI:C) and TGA 
X1 
X3 
X2 
Serum for exploratory 
research  
X1 
X3 
 
Plasma for exploratory 
research  
X1 
X3 
 
ADA: anti-drug antibody; aPTT: activated partial thrombin time; FXI: Factor XI; FXI:C: Factor XI functional 
activity; PT: prothrombin time; TGA: thrombin generation assay 
9.1.1. 
Footnotes for the Schedule of Events Table 
9.1.1.1. 
Table 2 Schedule of Events 
1. Assessments for this visit may be performed in the hospital if the participant has not yet 
been discharged.  
2. If the participant is discharged prior to this visit, then information may be collected by 
telephone call, and assessments requiring blood draw may be omitted. 
3. To be performed in women 55 years of age or younger 
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4. Randomization will occur after completion of surgery on day 1. 
5. Dosing will occur 12 to 24 hours after the end of surgery, and at least 12 hours after 
removal of the needle/catheter used for spinal/epidural anesthesia.  
6. First dose will be given 12 to 24 hours after the end of surgery 
7. May include confirmatory studies for DVT of the leg or PE, as described in 
Section 9.2.2.2. Confirmatory studies for suspected DVT of the leg or PE may be 
required more than once, per the discretion of the investigator. 
8. Refer to Table 3 for detailed information on Visit 2 samples. 
9. Samples for ADA must be collected prior to dose administration on the same day that 
study drug is administrated. Refer to Table 3.   
10. The genomics sub-study informed consent form (ICF; for RNA and DNA analysis) must 
be signed prior to performing this sample collection. 
11. Samples for DNA extraction should be collected at the baseline visit (predose) but may 
also be collected at any later study visit. 
9.1.1.2. 
Table 3 Schedule of Events: Visit 2 Blood Collection 
1. Samples may be collected up to 24 hours prior to surgery. Samples to be collected in all 3 
treatment groups. 
2. Samples to be collected in REGN9933 group only. 
3. Samples to be collected in all 3 treatment groups. 
9.1.2. 
Early Termination Visit 
Participants who are withdrawn from the study will be asked to return to the clinic once for an 
early termination visit consisting of the End of Study assessments described in Table 2. 
9.1.3. 
Unscheduled Visits 
All attempts should be made to keep participants on the study schedule. Unscheduled visits may 
be necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for 
any other reason, as warranted. 
9.2. 
Study Procedures 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population:   
• Informed consent 
• Review of inclusion/exclusion criteria (Section 7.2.1 and Section 7.2.2) 
• Medical History 
• Demographics 
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• FSH (women 55 years of age or younger) 
• MDRD calculation of eGFR 
• Urine drug screen 
9.2.2. 
Efficacy Procedures  
9.2.2.1. 
Venography of the Operated Leg 
Unilateral venography of the operated leg will be performed on day 10 (±2 days). Detailed 
instructions for performing the venography are provided in the Study Imaging Manual for 
Venography and Event Reporting. 
If DVT or PE is suspected at any point during the study, objective confirmatory testing should be 
carried out as described in Section 9.2.2.2.  If the confirmatory tests do not demonstrate DVT/PE, 
or if a distal DVT is demonstrated by ultrasound, then venography on day 10 (±2 days) should be 
performed as specified in the protocol. On the other hand, if the presence of DVT (if diagnosed by 
ultrasound, then DVT must be proximal) or PE is confirmed prior to the protocol-defined 
venogram on day 10 (±2 days), then the venogram is not performed. 
Venograms of low quality and/or venograms with imaging artifacts that cannot be used to confirm 
presence or absence of DVT will be labeled “non-evaluable”. Examples of reasons that contribute 
to low image quality or artifact include insufficient contrast filling and poor exposure. Detailed 
instructions for labeling non-evaluable images are provided in the Site Manual for Venography 
and Event Reporting. 
9.2.2.2. 
Assessment of Symptomatic VTE 
While in the hospital after surgery and at subsequent study visits, participants will be assessed by 
the investigator for signs and symptoms of symptomatic DVT of the leg -- including lower 
extremity swelling, warmth, redness, and pain—and PE—including shortness of breath, chest pain 
exacerbated by inspiration, and hemoptysis. If DVT is suspected, objective confirmatory testing 
should be obtained using either lower extremity ultrasound, conventional venography, CT 
venography, or MR venography; the test performed will be selected by the investigator. If PE is 
suspected, objective confirmatory testing should be obtained using spiral CT, ventilation/perfusion 
scan, or pulmonary angiography; the test performed will be selected by the investigator. The 
diagnostic tests for symptomatic DVT or PE can be performed per standard of care in the hospital. 
Images of the venography and all diagnostic tests performed for suspected symptomatic DVT, or 
PE should be sent in for central reading. This process is also described in the Study Imaging 
Manual for Venography and Event Reporting. 
9.2.3. 
Safety Procedures  
9.2.3.1. 
Body Weight 
Body weight will be assessed using calibrated scales. Participants should void (empty bladder) 
prior to weight assessment. Participants should be wearing undergarments only and no shoes 
during weight assessments. Body weight will be recorded to the nearest 0.1 kg. 
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9.2.3.2. 
Height 
Participants should not be wearing shoes during height assessment. Height will be recorded to 
the nearest 1 cm. 
9.2.3.3. 
Vital Signs 
Vital signs, including temperature, semi-recumbent blood pressure, pulse, and respiration will be 
collected time points according to Table 2. 
9.2.3.4. 
Physical Examination 
A thorough and complete physical examination will be performed at time points according to 
Table 2.  Care should be taken to examine and assess any abnormalities that may be present, as 
indicated by the participant’s medical history. 
9.2.3.5. 
Electrocardiogram 
A standard 12-lead ECG will be performed at time points according to Table 2. Heart rate will be 
recorded from the ventricular rate and the PR, QRS, and QT (identify QTcB or QTcF) intervals 
will be recorded. The ECG strips or reports will be retained with the source. 
9.2.3.6. 
Assessment for Bleeding 
Participants will be assessed for surgical site bleeding events at time points according to Table 2. 
Description of surgical site bleeding events will include the following: onset and duration; 
associated clinical symptoms (if any) and sequelae, including prolonged hospitalization or deep 
wound infection; requirement for additional surgical or interventional procedure 
Participants will also be assessed for overall bleeding events at time points according to Table 2. 
Description of bleeding events will include the following: location; onset and duration; associated 
symptoms (if any); precipitating factors (if any). 
For all bleeding events (surgical and extrasurgical), the following will be recorded: associated 
changes in hemoglobin, hematocrit; requirement for, timing of, and quantity of transfusion.  
In addition, for all participants, peri- and post-operative blood loss will be recorded, as per local 
practice.  
All bleeding events will need to be recorded as an AE with documentation sent to the central AC 
as instructed in the Study Manual for Venography and Event Reporting. Events will be classified 
by the AC using the ISTH criteria for both major (Schulman, 2010) and CRNM (Kaatz, 2015) 
bleeds as described in Section 5.3.1.  
9.2.3.7. 
Laboratory Testing 
Hematology, chemistry, urinalysis, and the coagulation panel will be analyzed by local laboratory. 
Plasma for PT and aPTT biomarkers will be analyzed by a central laboratory. Detailed instructions 
for blood sample collection are in the laboratory manual provided to study sites. 
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Samples for laboratory testing will be collected at visits according to Table 2.  Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin (check direct and 
indirect if total is elevated) 
Potassium 
Creatinine 
 
Chloride 
Blood urea nitrogen  
 
Carbon dioxide 
AST 
 
Calcium 
ALT 
 
Glucose 
Alkaline phosphatase 
 
Albumin 
 
 
Hematology 
Hemoglobin 
Differential:  
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Urinalysis* 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
* dipstick urinalysis should be performed initially, with subsequent 
analysis by microscopy if dipstick is abnormal 
 
Other Laboratory Tests 
• FSH (women 55 years of age or younger) 
• MDRD calculation of GFR 
• Urine drug screen 
• Coagulation panel: PT/INR, aPTT. Note these are performed at the local lab; separate 
samples are collected for PT/INR and aPTT for analysis at a central laboratory 
(Section 9.2.6). 
Refer to the laboratory manual for collection procedures. 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality.  When necessary, appropriate ancillary investigations 
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should be initiated.  If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the Medical/Study Director must 
be consulted.   
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 10.1.1. 
9.2.4. 
Drug Concentration and Total Factor XI Measurements 
Samples for REGN9933 concentration measurement and samples total FXI concentration 
measurements will be collected at visits listed in Table 2 and Table 3 . Detailed instructions for 
blood sample collection are provided in the laboratory manual.  
Any unused samples may be used for exploratory research, biomarker research and/or future 
biomedical research as described in Section 9.2.6.4 and Section 9.2.7.  
9.2.5. 
Immunogenicity Measurements and Samples 
Samples for ADA assessment will be collected at time points listed in Table 2 and Table 3. 
Detailed instructions for blood sample collection are provided in the laboratory manual.  
Any unused samples may be used for exploratory research and/or future biomedical research as 
described in Section 9.2.6.4 and Section 9.2.7. 
9.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures 
This study includes measurements of aPTT, PT, as well as the exploratory coagulation endpoints 
FXI:C and intrinsic- and extrinsic-pathway triggered thrombin generation assessed by TGA. 
The main PD variable aPTT will be used to measure the anticipated anticoagulant effect of 
REGN9933. Prothrombin time is a measure of extrinsic and/or common pathway function. Both 
FXI:C and TGA are used to measure the inhibition of FXI.  
9.2.6.1. 
Activated Partial Thromboplastin Time and Prothrombin Time 
Activated partial thrombin time is a standard clinically validated measure of intrinsic/common 
pathway activation. Elevations of aPTT in the context of disruption to the intrinsic coagulation 
pathway are anticipated and are not considered a safety signal since elevations are not necessarily 
associated with bleeding risk. Activated partial thromboplastin prolongation has been used to 
monitor REGN9933 effect in the healthy volunteer study R9933-HV-2107. Samples for aPTT 
measurements will be collected at time points listed in Table 2 and Table 3. Change from baseline 
in aPTT is a secondary endpoint and considered the main PD variable. Prothrombin time is a 
standard clinically validated measure of extrinsic/common pathway function. Factor XI deficiency 
does not affect PT time, and interim data from the healthy volunteer study R9933-HV-2107 
suggest that REGN9933 does not alter PT. Samples for PT measurements will be collected at time 
points listed in Table 2 and Table 3. Change from baseline in PT is a secondary endpoint. 
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9.2.6.2. 
Factor XI Functional Activity Levels  
Factor XI functional activity is a clinically validated assessment of intrinsic pathway coagulation 
utilizing a one-stage clotting assay, but unlike aPTT, it is a more specific measure of FXI activity 
and its contribution to coagulation. FXI:C will be measured from samples collected at time points 
indicated in Table 2 and Table 3. Modulation of FXI:C is an exploratory measure. 
9.2.6.3. 
Thrombin Generation Assay 
Thrombin generation assay is an in vitro and ex vivo assessment of coagulation through both the 
intrinsic and extrinsic pathways and provides an estimation of the ability to generate thrombin. 
Thrombin generation assay is not routinely used to monitor anticoagulation clinically but 
complements other clinically validated coagulation assessments and is useful to determine the risk 
of bleeding or thrombosis. Thrombin generation is an essential process of coagulation because 
thrombin is responsible for the activation of other coagulation factors and propagation of additional 
thrombin (via FXI activation) for the conversion of fibrinogen to fibrin. Using tissue factor or 
ellagic acid as the trigger in the TGA can provide an estimation of the thrombin being generated 
by the extrinsic/common pathway and the intrinsic/common pathway, respectively. Thrombin 
generation will be measured from samples collected at time points indicated in Table 2 and 
Table 3. Change from baseline in thrombin generation is an exploratory endpoint. 
9.2.6.4. 
Exploratory Biomarkers 
Serum and plasma will be collected at time points according to Table 2 and Table 3. These samples 
may be used to measure biomarkers related to the pathophysiology of VTE, mechanism of action 
for REGN9933, biology of FXI and related pathways, and possible toxicities. 
Any unused samples, collected for any purpose in this study, may be used for exploratory research, 
as allowed per local regulation. 
Biomarker results will be reported separately from the clinical study report (CSR) unless 
biomarker measurements are included in primary or secondary objectives. 
9.2.7. 
Future Biomedical Research (Optional) 
Participants who agree to participate in the future biomedical research (FBR) sub-study will be 
required to consent to this optional sub-study before samples are banked for FBR. Residual 
biomarker samples for study-related research, as well as unused PK and ADA samples, will be 
stored for up to 15 years after the final date of the database lock (or for a shorter time period if 
required per regional laws and regulations).  The samples may be utilized for FBR that may or 
may not be directly related to the study, including being used as reference samples and assay 
development or validation.  The results of these future biomedical research analyses will not be 
presented in the CSR. 
9.2.8. 
Pharmacogenomic Analysis (Optional) 
Participants who agree to participate in the genomics sub-study will be required to consent to this 
optional sub-study before collection of the samples.  Whole blood samples for DNA extraction 
should be collected on day 1/baseline (predose) but can be collected at a later study visit.  Whole 
blood samples for RNA extraction will be collected at time points according to Table 2 and 
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Table 3.  DNA and RNA samples will be collected for pharmacogenomics analyses to understand 
the genetic determinants of efficacy and safety associated with the treatments in this study and the 
molecular basis of coagulation FXI, thromboembolic diseases, and related diseases. These samples 
will be single-coded as defined by the ICH guideline E15.  Samples will be stored for up to 15 
years after the final date of the database lock (or for a shorter time period if required per regional 
laws and regulations).  If there are specific site or country requirements involving the 
pharmacogenomic analyses which the sponsor is unable to comply with, samples will not be 
collected at those sites.   
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or 
biomarker response to REGN9933, other thromboembolic clinical outcome measures and possible 
AEs.  In addition, associations between genomic variants and prognosis or progression of 
thromboembolic diseases as well as related bleeding disorder-related diseases may also be 
studied. These data may be used or combined with data collected from other studies to identify 
and validate genomic markers related to the study drug, target pathway, or thromboembolic 
diseases and related diseases.  
Analyses may include sequence determination or single nucleotide polymorphism studies of 
candidate genes and surrounding genomic regions.  Other methods, including whole-exome 
sequencing, whole-genome sequencing, DNA copy number variation, and transcriptome 
sequencing (or other methods for quantitating RNA expression) may also be performed.  The list 
of methods may be expanded to include novel methodology that may be developed during the 
course of this study or sample storage period.  Results from the genomic analyses will not be 
reported in the CSR. 
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10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events  
10.1.1. 
General Guidelines 
The investigator must promptly record all clinical events occurring during the study data 
collection, from the time of signing the ICF to the end of study (see Section 11.4.5.1).  Medical 
conditions that existed or were diagnosed prior to the signing of the Informed Consent will be 
recorded as part of medical history.  Abnormal laboratory values and vital signs observed at the 
time of Informed Consent should also be recorded as medical history.  Any subsequent worsening 
(ie, any clinically significant change in frequency and/or intensity) of a pre-existing condition that 
is temporally associated with the use of the study drug should also be recorded as an AE. 
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
participant.  Adverse events may be directly observed, reported spontaneously by the participant, 
or by questioning the participant at each study visit.  Participants should be questioned in a general 
way, without asking about the occurrence of any specific symptoms.  The Investigator must assess 
all AEs to determine seriousness, severity, and causality, in accordance with the definitions in 
Section 10.2.  The Investigator’s assessment must be clearly documented in the site’s source 
documentation with the Investigator’s signature.  The Investigator should follow up on SAEs (and 
AESIs) until they have resolved or are considered clinically stable; AEs should be followed until 
they are resolved or last study visit, whichever comes first. 
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available.  If the signs and symptoms are distinct and do not suggest 
a common diagnosis, report them as individual entries of AE or SAE.   
Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
Investigator to determine their clinical significance.  Isolated abnormal laboratory results, vital 
sign findings, or other diagnostic findings (ie, not part of a reported diagnosis) should be reported 
as AEs if they are symptomatic, lead to study drug discontinuation, dose reduction, require 
corrective treatment, or constitute an AE in the investigator’s clinical judgment. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the serious adverse event (diagnosis or symptom requiring hospitalization).  A procedure is not 
an AE or SAE, but the reason for the procedure may be an AE or SAE.  Pre-planned (prior to 
signing the ICF) procedures, treatments requiring hospitalization for pre-existing conditions that 
do not worsen in severity, and admission for palliative or social care should not be reported as 
SAEs (see Section 10.2 for Definitions).   
For deaths, the underlying or immediate cause of death should always be reported as an SAE.   
Any SAE that may occur subsequent to the reporting period (end of the on-treatment period) that 
the Investigator assesses as related to study drug should also be reported. 
All AEs, SAEs, AESIs, and pregnancy reports are to be reported according to the procedures in 
Section 10.1.3.   
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10.1.2. 
Reporting Procedure  
10.1.2.1. Individual Case Safety Reporting (ICSR) 
All events (serious and non-serious) must be reported with investigator’s assessment of the event’s 
seriousness, severity, and causality to the (when applicable: blinded) study drug.  For SAEs and 
AESIs, a detailed narrative summarizing the course of the event, including its evaluation, 
treatment, and outcome should be provided on the AE CRF.  Specific or estimated dates of event 
onset, treatment, and resolution should be included, when available.  Medical history, concomitant 
medications, and laboratory data that are relevant to the event should also be summarized in the 
narrative.  For fatal events, the narrative should state whether an autopsy was or will be performed 
and include the results if available.  Information not available at the time of the initial report must 
be documented in a follow-up report.  Source documents (including hospital or medical records, 
diagnostic reports, etc) will be summarized in the narrative on the AE CRF and retained at the 
study center and available upon request.   
Urgent safety queries must be followed up and addressed promptly.  Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.  
10.1.2.2. Aggregate Safety Reporting (Development Safety Update Report) 
Relevant safety information on the comparators will be addressed in the REGN9933 Development 
Safety Update Report. 
10.1.3. 
Events that Require Expedited Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
• SAEs. 
• Selected Adverse Events of Special Interest (serious and nonserious):  Adverse 
events of special interest for this study include the following:   
− Moderate or severe infusion reactions 
− Moderate or severe hypersensitivity reactions potentially related to study 
treatment 
− Moderate to severe bleeding (both spontaneous and non-spontaneous) 
• Pregnancy: Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female or female partner of a male , during the study or 
within 75 days of the dose of REGN9933, and within 3 days of the last dose of 
comparators enoxaparin and apixaban.  Any complication of pregnancy affecting a 
female study patient or female partner of a male study patient, and/or fetus and/or 
newborn that meets the SAE criteria must be reported as an SAE. Outcome for all 
pregnancies should be reported to the sponsor. 
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• Symptomatic overdose: Accidental or intentional overdose of at least 2 times the 
intended dose of study treatment within the intended therapeutic window, if 
associated with an AE.  
10.2. 
Definitions 
10.2.1. 
Adverse Event 
An AE is any untoward medical occurrence in a participant administered a study drug which may 
or may not have a causal relationship with the study drug.  Therefore, an AE is any unfavorable 
and unintended sign (including abnormal laboratory finding), symptom, or disease which is 
temporally associated with the use of a study drug, whether or not considered related to the study 
drug (ICH, 1994). 
For studies with patient reported outcomes (PRO), the PRO data are generally not reportable as 
individual AEs and thus will not be reported or reconciled as such. 
10.2.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (eg, a car accident in which a participant is a passenger). 
• Is life-threatening – in the view of the investigator, the participant is at immediate 
risk of death at the time of the event.  This does not include an AE that had it 
occurred in a more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization.  
Inpatient hospitalization is defined as a hospital admission (any duration) or an 
emergency room visit for longer than 24 hours.  Prolongation of existing 
hospitalization is defined as a hospital stay that is longer than was originally 
anticipated for the event or is prolonged due to the development of a new AE as 
determined by the investigator or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions).   
• Is a congenital anomaly/birth defect 
• Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant 
or may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events.  
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10.2.3. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical interest specific to the sponsor’s 
product or program, for which ongoing monitoring and rapid communication by the investigator 
to the sponsor can be appropriate.  Such an event might warrant further investigation in order to 
characterize and understand it.   
10.2.4. 
Infusion Reactions 
Infusion reactions are defined as any relevant AE that occurs during the infusion or within 2 hours 
after the infusion is completed.  
10.2.5. 
Severity 
The severity of AEs will be graded according to the following scale: 
Mild:  Does not interfere in a significant manner with the participant normal functioning level.  It 
may be an annoyance.  Prescription drugs are not ordinarily needed for relief of symptoms but may 
be given because of personality of the participant. 
Moderate:  Produces some impairment of functioning but is not hazardous to health.  It is 
uncomfortable or an embarrassment.  Treatment for symptom may be needed. 
Severe:  Produces significant impairment of functioning or incapacitation and is a definite hazard 
to the subject’s health.  Treatment for symptom may be given and/or participant hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Infusion Reactions 
The severity of infusion reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of the grade): 
Mild:  Mild transient reaction; infusion interruption not indicated; intervention not indicated. 
Moderate:  Therapy or infusion interruption indicated but responds promptly to symptomatic 
treatment (eg, antihistamines, NSAIDs, narcotics, IV fluids); prophylactic medications indicated 
for ≤24 hours. 
Severe:  Prolonged (eg, not rapidly responsive to symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for 
clinical sequelae; life-threatening consequences; urgent intervention indicated; death. 
Injection Site Reactions 
The severity of injection site reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of grade: 
Mild:  Pain that does not interfere with activity; mild discomfort to touch; <5 cm of erythema or 
induration that does not interfere with activity 
Moderate:  Pain that requires repeated use of non-narcotic pain reliever >24 hours or interferes 
with activity; discomfort with movement; 5.1 cm to 10 cm erythema or induration or induration 
that interferes with activity 
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Severe:  Pain that requires any use of narcotic pain reliever or that prevents daily activity; 
significant discomfort at rest; >10 cm erythema or induration; prevents daily activity; requires ER 
visit or hospitalization; necrosis or exfoliative dermatitis 
10.2.6. 
Causality 
The investigator must provide causality assessment as whether or not there is a reasonable 
possibility that the drug caused the adverse event, based on evidence or facts, his/her clinical 
judgment, and the following definitions.  The causality assessment must be made based on the 
available information and can be updated as new information becomes available. 
The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset vs time drug was administered 
• Nature of the reactions: immediate vs. long term 
• Clinical and pathological features of the events  
• Existing information about the drug & same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
• Response to dechallenge (drug discontinuation) or dose reduction  
• Response to rechallenge (re-introduction of the drug) or dose increase, when 
applicable  
• Patient’s medical and social history  
Causality to the study drug (including study drug administration): 
• Related: 
− The AE follows a reasonable temporal sequence from study drug administration 
and cannot be reasonably explained by the nature of the reaction, patient’s clinical 
(eg, disease under study, concurrent diseases, concomitant medications), or other 
external factors. 
or 
− The AE follows a reasonable temporal sequence from study drug administration 
and is a known reaction to the drug under study or its class of drugs or is 
predicted by known pharmacology. 
• Not Related: 
− The AE does not follow a reasonable sequence from study drug administration or 
can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
Causality to the study conduct (protocol specified procedure): 
• Related: 
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− The AE follows a reasonable temporal sequence from a protocol specified 
procedure and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
• Not Related: 
− The AE does not follow a reasonable sequence from a protocol specified 
procedure or can be reasonably explained by the nature of the reaction, patient’s 
clinical state (eg, disease under study, concurrent diseases, and concomitant 
medications) or other external factors. 
10.3. 
Safety Monitoring 
The investigator will monitor the safety of study participant at his/her site(s) as per the 
requirements of this protocol and consistent with current Good Clinical Practice (GCP).  Any 
questions or concerns should be discussed with the sponsor in a timely fashion.  The sponsor will 
monitor the safety data from across all study sites.  The Medical/Study Director will have primary 
responsibility for the emerging safety profile of the compound, but will be supported by other 
departments (eg, Global Patient Safety; Biostatistics and Data Management).  Safety monitoring 
will be performed on an ongoing basis (eg, individual review of SAEs) and on a periodic 
cumulative aggregate basis. 
10.4. 
Notifying Health Authorities, Institutional Review Board /Ethics 
Committee, and Investigators 
During the study, the sponsor and/or the contract research organization (CRO) will inform health 
authorities, IECs/IRBs, and the participating investigators of any SUSARs (Suspected Unexpected 
Serious Adverse Reactions) occurring in other study centers or other studies of the active study 
drug (REGN9933; an FXI binder), as appropriate per applicable reporting requirements, including 
Regulation EU No 536/2014. In addition, the sponsor and/or CRO will comply with any additional 
local safety reporting requirements. All notifications to investigators will contain only blinded 
information.  
Upon receipt of the sponsor’s notification of a SUSAR that occurred with the study drug, the 
investigator will inform the Institutional Review Board (IRB)/Ethics Committee (EC) unless 
delegated to the sponsor. 
Event expectedness for REGN9933 is assessed against the Reference Safety Information section 
of the Investigator’s Brochure that is effective for expedited safety reporting.  
Event expectedness for enoxaparin and apixaban is assessed against the SmPC.  
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the CSR to health authorities and IECs/IRB as appropriate. 
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11. 
STATISTICAL PLAN 
11.1. 
Statistical Hypothesis  
The clinical hypothesis comparing the efficacy of REGN9933 to enoxaparin or apixaban will be 
assessed through a Bayesian estimation framework. Bayesian posterior probabilities will be 
reported to estimate the incidence of confirmed VTE for participants treated with REGN9933 and 
enoxaparin, as well as the odds ratio (OR) of confirmed VTE in participants administered 
REGN9933 as compared to that of enoxaparin (ORRE). The statistical hypothesis is ORRE <1. 
Specifically, the following will be reported: 
• Probability that REGN9933 has a lower incidence of confirmed VTE through day 12 
as compared to enoxaparin, ie the probability that the OR of VTE in REGN9933 
versus enoxaparin, Pr(ORRE<1).  Other quantities will be used to estimate the 
magnitude of effect, eg P(ORRE < 0.5, 0.8, 0.9, etc. | data) 
11.2. 
Justification of Sample Size 
Up to total of approximately 360 participants will be randomized in a 1:1:1 allocation ratio to 
REGN9933, apixaban or enoxaparin. Each arm will have an approximate number of 120 
participants.  
The sample size was determined using the following assumptions: 
• The event rate of VTE for REGN9933 was assumed to be 13% and was set to be 
22.4% for enoxaparin (Verhamme, 2021) (Weitz, 2020).  
• The prior distribution of the treatment difference, was assumed to be 
log(OR)~N(0,0.843), which was expressed as the log(OR). The prior distribution 
follows a normal distribution centered around no treatment difference and with a 
variance such that extreme treatment differences are expected to be unlikely, ie, the 
probability that OR is between 0.25 and 4 is 90%. 
Using these assumptions, and for the purpose of choosing a sample size, the following quantities 
were simulated: 
• The probability of any beneficial effect of REGN9933 over enoxaparin, ie, the 
posterior distribution of the odds ratio comparing REGN9933 to enoxaparin of 
confirmed VTE. A beneficial effect is where ORRE < 1, and thus the study will 
estimate P(ORRE < 1 | data). 
• In 75% of the simulated trials, in studies where the P(ORRE < 1 | data) > 0.95, the 
sample size was 120 participants or less. Therefore, a sample size of 120 subjects per 
group was chosen. 
11.3. 
Analysis Sets 
11.3.1. 
Efficacy Analysis Sets 
The primary analysis will be conducted in the modified intention to treat population (mITT) 
population, consisting of randomized participants that have either an evaluable venogram, a 
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confirmed episode of venous thromboembolism, or both. A sensitivity analysis will be conducted 
on the full analysis set (FAS) that includes all randomized participants who received any study 
drug; it is based on the treatment allocated (as randomized).   
11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized participants who received any study drug; 
it is based on the treatment received (as treated).  Treatment compliance/administration and all 
clinical safety variables will be analyzed using the SAF. 
11.3.3. 
Pharmacokinetic Analysis Sets 
The PK analysis population includes all participants in the REGN9933 treatment group who 
received study drug and who had at least 1 non-missing result following the first dose of study 
drug. 
11.3.4. 
Immunogenicity Analysis Sets 
The ADA analysis set includes all participants who received study drug and had at least 1 non-
missing ADA result following the first study dose.  
11.3.5. 
Pharmacodynamic Analysis Set  
The pharmacodynamic analysis set includes all randomized participants who received any study 
drug and who had a at least 1 non-missing PD result following the first dose of study drug; it is 
based on the treatment received (as treated). 
11.4. 
Statistical Methods  
For continuous variables, descriptive statistics will include the following information: the number 
of participants reflected in the calculation (n), mean, standard deviation, Q1, median, Q3, 
minimum, and maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
11.4.1. 
Participant Disposition 
The number and percentage of participants screened, randomized, and the primary reasons for 
screening failure and discontinuation will be summarized. 
11.4.2. 
Demography and Baseline Characteristics 
Demographic variables (eg, age, race, and gender), baseline characteristics, medical history, and 
prior and concomitant mediations and therapies will be summarized by treatment group.  See 
Section 5.1 for a full list of demographic and baseline variables.  No statistical hypothesis tests 
will be performed on these characteristics.  
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11.4.3. 
Efficacy Analyses 
11.4.3.1. Primary Efficacy Analysis 
The treatment effect will be estimated using the posterior distribution of ORRE. For comparison of 
REGN9933 versus enoxaparin, different posterior probabilities will be provided, such as 
P(OR<0.5, 0.9, 1.0, 1.1, 1.2 etc|data). 
The entire posterior density function for the treatment effect (ORRE and the OR of confirmed VTE 
in participants administered REGN9933 as compared to that of apixaban) will be computed, along 
with the cumulative posterior distribution, which quantifies evidence for all possible treatment 
effects. A prior for treatment difference log(OR)~N(0,0.843) will be used. Bayesian summary 
statistics including two-sided 95% Highest Density Interval, posterior mean, and median will be 
reported. Summary statistics based on the raw data including the number of participants reflected 
in the calculation (n), mean, standard deviation, Q1, median, Q3, minimum, and maximum will be 
reported. 
The Kaplan-Meier plot for cumulative incidence of confirmed VTE over time will be provided by 
treatment groups. Participants dropped out before the venogram or with missing venograms are 
considered as censored. 
11.4.4. 
Control of Multiplicity 
Not applicable. 
11.4.5. 
Safety Analysis 
Safety will be assessed by clinical and statistical review of all relevant parameters, including 
vital signs, physical examinations, ECGs, laboratory evaluations, and AEs. 
11.4.5.1. Adverse Events 
Definitions 
For safety variables, the 3 observation periods are defined in Section 9.1. Treatment-emergent 
adverse events are defined as those that are not present at baseline or represent the exacerbation of 
a pre-existing condition after the dose administrations. 
Analysis 
Summaries of all TEAEs by treatment group will include: 
• The number (n) and percentage (%) of participants with at least 1 TEAE by SOC and 
PT 
• TEAEs by severity (according to the grading scale outlined in Section 10.2.5), 
presented by SOC and PT 
• Treatment-emergent AESIs  
• Treatment-emergent adverse events leading to permanent treatment discontinuation 
will be summarized by treatment group. 
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11.4.5.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized. 
Laboratory Tests 
Laboratory test results will be summarized. 
Number and percentage of participants with a potentially clinically significant value will be 
tabulated.  
11.4.5.3. Treatment Exposure 
The duration of exposure during the treatment period will be presented by treatment group and 
calculated as:  
• For participants assigned to the enoxaparin or apixaban arm, exposure will be 
summarized by the number of days that the subject received enoxaparin or apixaban 
administrations. 
11.4.5.4. Treatment Compliance 
The compliance with study treatment will be calculated as follows: 
𝑐𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 % = 100% × 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑎𝑐𝑡𝑢𝑎𝑙 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑖𝑜𝑛𝑠
𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑙𝑎𝑛𝑛𝑒𝑑 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑖𝑜𝑛𝑠 
The number of planned administrations will be calculated as: 
• For participants assigned to the enoxaparin arm, the number of planned 
administrations is the number of days in the on-treatment period  
• For participants assigned to the apixaban arm, the number of planned administrations 
is two times of the number of days in the on-treatment period  
• For participants assigned to the REGN9933 arm, the number of planned 
administrations is one 
11.4.6. 
Pharmacokinetics 
11.4.6.1. Analysis of Drug Concentration Data 
The PK parameters may include, but are not limited to: 
• Cmax – peak concentration 
• 
AUClast -area under the curve computed from time zero to the time of the last positive 
concentration  
The concentrations of total REGN9933 over time and selected PK parameters will be summarized 
by descriptive statistics for each of the treatment groups for the purpose of estimating exposures 
in these groups. This descriptive statistical assessment will include the geometric means and ratios 
of the geometric means for selected PK parameters, as deemed appropriate. 
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No formal statistical hypothesis testing will be performed.  
11.4.7. 
Analysis of Immunogenicity Data 
Immunogenicity will be characterized by the ADA response observed:  
• Pre-existing immunoreactivity, defined as a positive ADA assay response at baseline, 
with all post-dose ADA results negative, or a positive assay response at baseline, with 
all post-dose ADA assay responses less than 9-fold over baseline titer levels 
• Treatment-emergent ADA response, defined as any post-dose positive ADA assay 
response when the baseline results are negative 
• Treatment boosted ADA response, defined as any post-dose positive ADA assay 
response that is 9-fold over baseline titer levels when baseline is positive in the ADA 
assay  
• Maximum ADA Titer values 
− Low (titer <1,000) 
− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000)  
Listings of pre-existing, treatment-boosted, and treatment-emergent ADA responses, ADA titers 
positivity presented by participant, time point, and dose cohort will be provided. Incidence of 
treatment-emergent ADA will be assessed as absolute occurrence (N) and percent of participants 
(%), grouped by study cohorts and ADA titer level. 
Plots of drug concentrations will be examined and the influence of ADAs on individual PK profiles 
evaluated.  Assessment of impact of ADA on safety and efficacy may be provided. 
11.4.8. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
The PD biomarker population will consist of all subjects in the PD analysis set. 
For biomarkers including FXI:C and thrombin generation (following intrinsic and extrinsic 
pathway activation), the following descriptive data will be generated: raw data at baseline, by 
treatment group, and overall. Biomarkers measured post-treatment will be summarized over time; 
change and/or percent change from baseline to each scheduled assessment time will be 
summarized by treatment with descriptive statistics. 
Additional details on the biomarker analyses will be provided in the statistical analysis plan. 
11.5. 
Interim Analysis  
An IA will be conducted by the sponsor when there are at least 50 participants per arm who have 
finished the study. The timing of IA was determined for the minimal number of subjects required 
to observe a high probability that REGN9933 reduced confirmed VTE relative to enoxaparin, ie 
the smallest sample size where the posterior probability could be at least 90%, ie, Pr(ORRE ≤ 1 | 
data) ≥90%.   
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The IA will only be used for administrative purpose and will not be used to make any decisions 
regarding the conduct of this study, eg, to stop the study. 
11.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized.  Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 15.1. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE  
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted, and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s) including Regulation EU No 536/2014 in the 
EU.  The planned quality assurance and quality control procedures for the study are described in 
this section.   
12.1. 
Data Management and Electronic Systems 
12.1.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at Regeneron (Sponsor). 
Adverse events and medical history will be coded using MedDRA. A medical coding plan will 
specify the processes and the dictionary used for coding.  All data coding (eg, AEs, baseline 
findings, medication, medical history/surgical history) will be done using internationally 
recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC), Medidata 
Rave 
12.1.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IVRS/IWRS system – randomization, study drug supply 
• EDC system – data capture – Medidata Rave 
• Statistical Analysis System – statistical review and analysis 
• Pharmacovigilance safety database 
12.2. 
Study Monitoring  
12.2.1. 
Monitoring of Study Sites 
Regeneron uses a study-specific risk-based approach to study monitoring and oversight, aligned 
with risk-based quality principles, outlined in ICH E6 (R2) Guideline for Good Clinical Practice. 
Risk-Based Quality Monitoring (RBQM) methodology focuses on employing a fit-for-purpose 
monitoring strategy, supported either directly by Regeneron as sponsor, or via our CRO partners.  
RBQM strategies include: reduced source data verification, targeted source data review, the use of 
off-site/remote and triggered on-site monitoring visits, and Centralized Monitoring to identify site 
level risks and study level trends. The investigator must allow study-related monitoring activities 
to occur. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
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that the safety and rights of participants are being protected, and that the study is being conducted 
in accordance with the current approved protocol version and any other study agreements, ICH 
GCP, and all applicable regulatory requirements. 
12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate participant records 
(source documents).  The site is responsible to ensure quality within their records and systems and 
are accountable for ensuring that all source data and CRF data are timely, accurate and complete. 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF).  Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
12.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic Case Report 
Forms (CRFs) within the EDC system by trained site personnel.  All required CRFs must be 
completed for each, and every participant enrolled in the study.  The investigator must ensure the 
accuracy, completeness, and timeliness of the data reported to the sponsor in the CRFs.  After 
review of the clinical data for each participant, the investigator must provide an electronic 
signature.  A copy of each participant CRF casebook is to be retained by the investigator as part 
of the study record and must be available at all times for inspection by authorized representatives 
of the sponsor and regulatory authorities. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee.  
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system.  For corrections made via data queries, a reason for any alteration 
must be provided. 
12.3. 
Audits and Inspections  
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
• Informing the sponsor of a planned inspection by the authorities as soon as 
notification is received, and authorizing the sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the 
inspection or audit 
• Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
• Taking all appropriate measures requested by the sponsor to resolve the problems 
found during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities.  Conditions of study material storage are also subject to inspection.  In 
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addition, representatives of the sponsor may observe the conduct of any aspect of the clinical study 
or its supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
12.4. 
Study Documentation 
12.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF must be signed 
electronically by the investigator.  This signed declaration accompanies each set of participant 
final CRF that will be provided to the sponsor. 
12.4.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities.  The investigator must obtain written approval from the sponsor before 
discarding or destroying any essential study documents during the retention period following study 
completion or discontinuation. Records must be destroyed in a manner that ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination.  
12.4.3. 
Recruitment Strategy 
Potential study participants may be identified by the investigator through a variety of means, such 
as publicizing the trial or using existing patient lists. Recruitment resources may include, but are 
not limited to, recruitment flyers, brochures, social media ads, newspaper ads, radio ads, etc. A 
third-party vendor may assist in recruitment efforts, such as the development of recruitment 
materials. All patient-facing recruitment material, including media advertising and receptionist 
scripts, will be reviewed and approved by the appropriate IRB/EC/authority prior to use. Resources 
may be in paper or electronic form. Regeneron will not access any patient identifiable information 
as part of recruitment efforts.  
12.4.4. 
Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 
• The participant must be informed that their personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for 
their data to be used as described in the informed consent  
• The participant must be informed that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
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sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
• The contract between sponsor and study sites specifies responsibilities of the parties 
related data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. 
• Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect 
such data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access. 
 
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13. 
ETHICAL AND REGULATORY CONSIDERATIONS  
13.1. 
Good Clinical Practice Statement  
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
13.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC.  A copy of the IRB/EC -approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each participant prior to his/her participation in the study and after 
the aims, methods, objectives, and potential hazards of the study have been explained to the 
participant in language that he/she can understand.  The ICF should be signed and dated by the 
participant and by the investigator or authorized designee who reviewed the ICF with the 
participant.   
• Participants who can write but cannot read will have the ICF read to them before 
signing and dating the ICF. 
• Participants who can understand but who can neither write nor read will have the ICF 
read to them in presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the participant’s study record, and 
a copy of the signed ICF must be given to the participant. 
If new safety information results in significant changes in the risk/benefit assessment, or if there 
are significant changes to the study procedures, the ICF must be reviewed and updated 
appropriately. All study participants must be informed of the new information and provide their 
written consent if they wish to continue in the study. The original signed revised ICF must be 
maintained in the participant’s study record and a copy must be given to the participant. 
13.3. 
Participants Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
participant will be maintained. Participants should be identified by a participant identification 
number only, on CRFs or other documents submitted to the sponsor. Documents that will not be 
submitted to the sponsor (eg, signed ICF) must be kept in strict confidence. 
The participant's and investigator's personal data, which may be included in the sponsor database, 
will be treated in compliance with all applicable laws and regulations.  The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
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13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the participants 
(eg, advertising) before any participant may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the participant, in 
which case the IRB/EC should be informed as soon as possible  
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of participants 
or the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their functions 
must be received by the sponsor prior to shipment of drug supplies to the investigator.  The 
approval letter should include the study number and title, the documents reviewed, and the date of 
the review. 
Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial registries according to applicable 
local guidelines and regulations. For data integrity, scientific, and statistical reasons, published 
results from all participants will be disclosed following End of Study (Section 6.1.2). Treatment 
codes will be disseminated to each investigation site thereafter. 
For purposes of data disclosure, interim analyses included in a CSR will be available for disclosure 
when required by local regulations.  If the integrity of the ongoing study cannot be ensured or 
study blinding cannot be maintained, then only final results will be disclosed. 
 
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14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB/EC-
approved amendment.  Where required per local legislation, regulatory authority approval will also 
be sought.  
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15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSEOUT 
OF A SITE 
15.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
15.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice.  The final decision should be made through mutual agreement with the sponsor.  
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others:  
• The investigator has received all items and information necessary to perform the 
study, but has not enrolled any participant within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
• The total number of participants required for the study are enrolled earlier than 
expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the participants’ interests. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
17. 
FINANCING AND INSURANCE  
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY  
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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19. 
REFERENCES  
 
Agnelli G. Prevention of venous thromboembolism in surgical patients. Circulation 2004; 110(24 
Suppl 1):Iv4-12. 
 
Al-Horani RA,Afosah DK. Recent advances in the discovery and development of factor XI/XIa 
inhibitors. Med Res Rev 2018; 38(6):1974-2023. 
 
Büller HR, Gailani D,Weitz JI. Factor XI antisense oligonucleotide for venous thrombosis. N Engl 
J Med 2015; 372(17):1672. 
 
Comp PC, Spiro TE, Friedman RJ, Whitsett TL, Johnson GJ, Gardiner GA, Jr., et al. Prolonged 
enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement. 
Enoxaparin Clinical Trial Group. J Bone Joint Surg Am 2001; 83(3):336-345. 
 
Eikelboom JW, Quinlan DJ,Douketis JD. Extended-duration prophylaxis against venous 
thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. 
Lancet 2001; 358(9275):9-15. 
 
Eliquis [Product Monograph].   2019; Bristol-Myers Squibb Canada Co., Montreal, Canada. 
 
Eliquis [Summary of Product Characteristics].   2021; Bristol-Myers Squibb/Pfizer EEIG, Dublin, 
Ireland. 
 
Gallus AS, Hirsh J, O'Brien SE, McBride JA, Tuttle RJ,Gent M. Prevention of venous thrombosis 
with small, subcutaneous doses of heparin. Jama 1976; 235(18):1980-1982. 
 
Harter K, Levine M,Henderson SO. Anticoagulation drug therapy: a review. West J Emerg Med 
2015; 16(1):11-17. 
 
Hsu C, Hutt E, Bloomfield DM, Gailani D,Weitz JI. Factor XI Inhibition to Uncouple Thrombosis 
From Hemostasis: JACC Review Topic of the Week. J Am Coll Cardiol 2021; 78(6):625-631. 
 
ICH. E2A. Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.  
In:ICH Harmoised Tripartite Guideline. 1994. 
 
Inhixa [Summary of Product Characteristics].   2021; Techdow Pharma Netherlands B.V, 
Amsterdam, Netherlands. 
 
Kaatz S, Ahmad D, Spyropoulos AC,Schulman S. Definition of clinically relevant non-major 
bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in 
non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015; 
13(11):2119-2126. 
 
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Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D,Hornick P. Apixaban versus enoxaparin for 
thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. 
Lancet 2010; 375(9717):807-815. 
 
Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D,Portman RJ. Apixaban or enoxaparin for 
thromboprophylaxis after knee replacement. N Engl J Med 2009; 361(6):594-604. 
 
Lee SY, Ro du H, Chung CY, Lee KM, Kwon SS, Sung KH, et al. Incidence of deep vein 
thrombosis after major lower limb orthopedic surgery: analysis of a nationwide claim registry. 
Yonsei Med J 2015; 56(1):139-145. 
 
Lovenox [Package Insert].   2022; Sanofi-Aventis U.S. LLC. 
 
Lovenox [Product Monograph].   2021; sanofi-aventis Canada Inc, Laval Quebec, Canada. 
 
NovoSeven (Summary of Product Characteristics).   2021; Novo Nordisk A/S, Bagsværd, 
Denmark. 
 
Preis M, Hirsch J, Kotler A, Zoabi A, Stein N, Rennert G, et al. Factor XI deficiency is associated 
with lower risk for cardiovascular and venous thromboembolism events. Blood 2017; 
129(9):1210-1215. 
 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report--second 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. Ann Emerg Med 2006; 47(4):373-380. 
 
Schellong SM, Beyer J, Kakkar AK, Halbritter K, Eriksson BI, Turpie AG, et al. Ultrasound 
screening for asymptomatic deep vein thrombosis after major orthopaedic surgery: the VENUS 
study. J Thromb Haemost 2007; 5(7):1431-1437. 
 
Schulman S, Angerås U, Bergqvist D, Eriksson B, Lassen MR,Fisher W. Definition of major 
bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J 
Thromb Haemost 2010; 8(1):202-204. 
 
Thrombosis Canada. Thromboprophylaxis After Orthopedic Suegery. 2013. 
 
Verhamme P, Yi BA, Segers A, Salter J, Bloomfield D, Büller HR, et al. Abelacimab for 
Prevention of Venous Thromboembolism. N Engl J Med 2021; 385(7):609-617. 
 
Wang X, Cheng Q, Xu L, Feuerstien GZ, Hsu M-Y, Smith PL, et al. Effects of factor IX or factor 
XI deficiency on ferric chloride-induced carotid artery occlusion in mice. Journal of Thrombosis 
and Haemostasis 2005; 3(4):695-702. 
 
Warwick D,Rosencher N. The ''critical thrombosis period'' in major orthopedic surgery: when to 
start and when to stop prophylaxis. Clin Appl Thromb Hemost 2010; 16(4):394-405. 
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Weitz JI, Bauersachs R, Becker B, Berkowitz SD, Freitas MCS, Lassen MR, et al. Effect of 
Osocimab in Preventing Venous Thromboembolism Among Patients Undergoing Knee 
Arthroplasty: The FOXTROT Randomized Clinical Trial. Jama 2020; 323(2):130-139. 
 
Weitz JI, Strony J, Ageno W, Gailani D, Hylek EM, Lassen MR, et al. Milvexian for the Prevention 
of Venous Thromboembolism. N Engl J Med 2021; 385(23):2161-2172. 
 
Yau JW, Liao P, Fredenburgh JC, Stafford AR, Revenko AS, Monia BP, et al. Selective depletion 
of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits. 
Blood 2014; 123(13):2102-2107. 
 
 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Phase 2, Multicenter, Randomized, Open-Label, Active-
Control Study of REGN9933, a Factor XI Monoclonal Antibody, for Prevention of Venous 
Thromboembolism after Elective, Unilateral, Total Knee Arthroplasty and agree to abide by all 
provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved.  I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC.  I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory 
Representative, Clinical Study Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the planned conduct of the study. 
Study Title: 
 A Phase 2, Multicenter, Randomized, Open-Label, Active-Control Study of 
REGN9933, a Factor XI Monoclonal Antibody, for Prevention of Venous Thromboembolism after 
Elective, Unilateral, Total Knee Arthroplasty 
Protocol Number: 
R9933-DVT-2230  
Protocol Version:  
R9933-DVT-2230 Amendment 1 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
 
 
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Signature Page for VV-RIM-00207608 v2.0
Signature Page for VV-RIM-00207608 v2.0 Approved
Approval/eSignature
-2023 16:57:40 GMT+0000
Approval/eSignature
-2023 17:20:13 GMT+0000
Approval/eSignature
23 18:03:34 GMT+0000
Approval/eSignature
000
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SAP_001.pdf: 
 
 
 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 43 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-3.0 
July 1, 2022 
 
  
 
STATISTICAL ANALYSIS PLAN                                
VERSION: 1.0  
CLINICAL STUDY PROTOCOL TITLE:  
A Phase 2, Multicenter, Randomized, Open-Label, Active-Control Study of 
REGN9933, A Factor XI Monoclonal Antibody, for Prevention of Venous 
Thromboembolism After Elective, Unilateral, Total Knee Arthroplasty                            
 
Compound:                        REGN9933 
Protocol Number:             R9933-DVT-2230 Amendment 1 
Clinical Phase:                  Phase 2 
Sponsor:                            Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:       
 
Clinical Trial Manager:   
 
Study Medical Director:   
 
Version/Date:                     Original Statistical Analysis Plan / 02AUG2023 
                                            
 
 
 
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Clinical Development and Regulatory Affairs 
 
 
Biostatistics and Data Management 
REGENERON CONFIDENTIAL 
Page 2 of 43 
 
 
STATISTICAL ANALYSIS PLAN 
VERSION: 1.0 
 
Clinical Study Protocol Title: 
 A PHASE 2, MULTICENTER, 
RANDOMIZED, OPEN-LABEL, ACTIVE-
CONTROL STUDY OF REGN9933, A 
FACTOR XI MONOCLONAL ANTIBODY, 
FOR PREVENTION OF VENOUS 
THROMBOEMBOLISM AFTER ELECTIVE, 
UNILATERAL, TOTAL KNEE 
ARTHROPLASTY 
Compound: 
REGN9933 
Protocol Number: 
R9933-DVT-2230 
Clinical Phase: 
Phase 2 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Versions/Dates: 
Original Statistical Analysis Plan / 02AUG2023 
 
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Protocol: R9933-DVT-2230 
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The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
See appended electronic signature page 
Study Biostatistician 
 
 
See appended electronic signature page 
Study Clinical Pharmacologist 
 
 
See appended electronic signature page 
Study Bioanalytical Scientist 
 
 
See appended electronic signature page 
Study Precision Medicine Scientist 
 
 
See appended electronic signature page 
Study Clinical Scientist 
 
 
See appended electronic signature page 
Study Medical Director 
 
 
See appended electronic signature page 
Project Biostatistician 
 
 
See appended electronic signature page 
Head of BDM or designee 
 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................7 
1. 
OVERVIEW .................................................................................................................9 
1.1. 
Study Description and Objectives ................................................................................9 
1.1.1. 
Primary Objective .........................................................................................................9 
1.1.2. 
Secondary Objectives .................................................................................................10 
1.2. 
Exploratory Objectives ...............................................................................................10 
1.3. 
Statistical Hypothesis ..................................................................................................11 
1.4. 
Modifications from the Statistical Section in the Final Protocol ................................11 
1.5. 
Revision History for SAP Amendments .....................................................................11 
2. 
INVESTIGATION PLAN ..........................................................................................12 
2.1. 
Study Design ...............................................................................................................12 
2.2. 
Sample Size and Power Considerations .....................................................................13 
3. 
ANALYSIS SETS ......................................................................................................14 
3.1. 
Efficacy Analysis Set ..................................................................................................14 
3.2. 
Safety Analysis Set .....................................................................................................14 
3.3. 
Pharmacokinetic Analysis Set ....................................................................................14 
3.4. 
Immunogenicity Analysis Sets ...................................................................................14 
3.5. 
Pharmacodynamic Analysis Sets ................................................................................14 
4. 
ANALYSIS VARIABLES .........................................................................................15 
4.1. 
Demographic and Baseline Characteristics ................................................................15 
4.2. 
Medical History ..........................................................................................................15 
4.3. 
Prior / Concomitant Medication .................................................................................15 
4.4. 
Efficacy Variables ......................................................................................................16 
4.4.1. 
Primary Efficacy Variable ..........................................................................................16 
4.4.2. 
Secondary Efficacy Variables .....................................................................................16 
4.4.3. 
Exploratory Efficacy Variables ..................................................................................16 
4.5. 
Safety Variables ..........................................................................................................17 
4.5.1. 
Adverse Events and Serious Adverse Events .............................................................17 
4.5.2. 
Bleeding Events ..........................................................................................................18 
4.5.3. 
Laboratory Safety Variables .......................................................................................19 
4.5.4. 
Vital Signs ..................................................................................................................19 
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4.5.5. 
ECG ............................................................................................................................20 
4.6. 
Pharmacokinetic Variables .........................................................................................20 
4.6.1. 
Drug Target Variables ................................................................................................20 
4.7. 
Immunogenicity Variables ..........................................................................................20 
4.8. 
Pharmacodynamic and Other Biomarker Variables ...................................................20 
5. 
STATISTICAL METHODS .......................................................................................21 
5.1. 
Demographics and Baseline Characteristics ...............................................................21 
5.2. 
Medical History ..........................................................................................................21 
5.3. 
Prior / Concomitant Medications ................................................................................21 
5.4. 
Subject Disposition .....................................................................................................21 
5.5. 
Measurement of Treatment Compliance ....................................................................22 
5.6. 
Treatment Exposure ....................................................................................................22 
5.7. 
Analysis of Efficacy Variables ...................................................................................22 
5.7.1. 
Analysis of Primary Efficacy Variable .......................................................................23 
5.7.2. 
Analysis of Secondary and Exploratory Efficacy Variables ......................................23 
5.7.3. 
Sensitivity Analysis ....................................................................................................24 
5.7.4. 
Subgroup Efficacy Analysis .......................................................................................24 
5.7.5. 
Multiplicity Control ....................................................................................................24 
5.8. 
Analysis of Safety Data ..............................................................................................24 
5.8.1. 
Analysis of Adverse Events ........................................................................................24 
5.8.2. 
Assessment for Bleeding ............................................................................................25 
5.8.3. 
Analysis of Clinical Laboratory Measurements .........................................................26 
5.8.4. 
Analysis of Vital Signs ...............................................................................................26 
5.8.5. 
Analysis of ECG .........................................................................................................26 
5.8.6. 
Analysis of Pharmacokinetics Drug Concentration Data ...........................................27 
5.8.7. 
Analysis of Immunogenicity Data ..............................................................................27 
5.8.8. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................28 
5.8.9. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ..............................28 
6. 
DATA CONVENTIONS ............................................................................................29 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................29 
6.2. 
General Data Handling Conventions ..........................................................................29 
6.3. 
Data Handling Convention for Missing Data .............................................................29 
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6.4. 
Visit Windows ............................................................................................................30 
7. 
INTERIM ANALYSIS ...............................................................................................32 
8. 
STUDY COMMITTEES ............................................................................................33 
8.1. 
Independent Data Monitoring Committee ..................................................................33 
8.2. 
Steering Committee ....................................................................................................33 
8.3. 
Adjudication Committee .............................................................................................33 
9. 
SOFTWARE ...............................................................................................................34 
10. 
REFERENCES ...........................................................................................................35 
11. 
APPENDIX.................................................................................................................35 
11.1. 
Summary of Statistical Analyses ................................................................................35 
11.2. 
Schedule of Time and Events .....................................................................................37 
11.2.1. 
Footnotes for the Schedule of Events .........................................................................38 
11.2.2. 
Footnotes for Schedule of Events: Visit 2 Blood Collection ......................................40 
11.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................40 
11.4. 
SAS Code for Efficacy Analysis ................................................................................43 
11.4.1. 
SAS Code for Primary Efficacy Analysis Using Bayesian Logistic 
Regression ...................................................................................................................43 
11.4.2. 
SAS Code for Stratified CMH ....................................................................................43 
 
LIST OF TABLES 
Table 1: 
Efficacy/PD Analyses .................................................................................................35 
Table 2: 
Safety Analyses ..........................................................................................................36 
Table 3: 
Schedule of Events .....................................................................................................37 
Table 4: 
Schedule of Events: Visit 2 Blood Collection ............................................................39 
 
LIST OF FIGURES 
Figure 1:     Study Flow Diagram ..................................................................................................13 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ASA 
Acetylsalicylic acid 
ATC 
Anatomical therapeutic chemical  
AUClast 
Area under the curve computed from time zero to the time of the last positive 
concentration 
BID 
Twice daily 
BMI 
Body mass index  
BUN 
Blood urea nitrogen 
Cmax 
Peak concentration 
CMH 
Cochran-Mantel-Haenszel 
CRNM 
Clinically relevant non-major 
DOAC 
Direct oral anticoagulants 
DNA 
Deoxyribonucleic acid 
DVT 
Deep venous thrombosis 
ECG 
Electrocardiogram 
EOT 
End of test 
EOS 
End of study 
ET 
Early termination  
FAS 
Full analysis set 
FSH 
Follicle stimulating hormone 
FXI 
Factor XI 
FXIIa 
Factor XIIa 
FXI:C 
Factor XI functional activity 
GFR 
Glomerular filtration rate 
IA 
Interim analysis 
ICF 
Informed consent form 
ICH 
International Conference for Harmonisation 
ID 
Identification 
ISTH 
International Society on Thrombosis and Hemostasis 
INR 
International normalized ration 
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IV 
Intravenous 
LOQ 
Limit of quantification 
MCMC 
Markov Chain Monte Carlo  
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities  
mITT 
Modified intent to treat 
OR 
Odds ratio 
ORRE 
the odds ratio of confirmed VTE in participants administered REGN9933 as 
compared to that of enoxaparin 
PCSV 
Potentially Clinically Significant Value 
PD 
Pharmacodynamic(s)  
PE 
Pulmonary embolism 
PK 
Pharmacokinetic(s) 
PRO 
Patient reported outcomes 
PT 
Prothrombin time 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RNA 
Ribonucleic acid  
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SD 
Standard deviation 
SOC 
System organ class 
TD 
Target day 
TE 
Treatment-emergent 
TEAE 
Treatment-emergent adverse event 
TGA 
Thrombin generation assay 
TKA 
Total knee arthroplasty 
ULN 
Upper level of normal 
VTE 
Venous thromboembolism 
WBC 
White blood cell 
WHO 
World Health Organization 
WHODD 
World Health Organization Drug Dictionary 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for analyses prior to database lock. The SAP is 
intended to be a comprehensive and detailed description of the statistical methods, timing of 
analyses and analysis presentation to be used in the analysis of data for study R9933-DVT-2230. 
This plan may be revised during the study to accommodate protocol amendments and/or to make 
changes to adapt to unexpected issues in study execution and/or data that affect planned 
analyses. The final plan, if revised, will document all changes and be issued prior to database 
lock. 
1.1. 
Study Description and Objectives 
Anticoagulants are medications used to treat and prevent venous and arterial thrombotic and 
embolic events by interfering with components of the coagulation cascade. The major 
complication of anticoagulants in clinical usage (such as warfarin, heparins, direct oral 
anticoagulants [DOAC]) is bleeding, since these drugs not only reduce thrombus formation, but 
also impair hemostasis. 
REGN9933 is a monoclonal antibody which binds to FXI and prevents its activation by FXIIa. 
Thus, REGN9933 may prevent pathologic thrombosis due to activation of the intrinsic pathway 
of coagulation, while potentially maintaining hemostatic mechanisms distal to FXIIa activation 
of FXI.  
REGN9933 has been evaluated in a randomized, double-blind, placebo-controlled phase 1 
clinical study in healthy volunteers (R9933-HV-2107). A dose-dependent prolongation of the 
activated partial thromboplastin time (aPTT) was observed across these 5 cohorts with an aPTT 
mean change from baseline of approximately 2.7-fold at 300 mg IV dose levels. No dose-
dependent trends have been observed in the prothrombin time (PT), and no safety concerns have 
been identified to date. Refer to the Investigator’s Brochure (IB) for additional background 
information on REGN9933 and the development program to date. 
This Phase 2, multicenter, randomized, open-label, active-control study is designed to evaluate 
the efficacy and safety of REGN9933 for prevention of venous thromboembolism (VTE) in 
participants undergoing an elective, unilateral, total knee arthroplasty (TKA), which is a 
commonly used clinical setting to demonstrate proof-of-concept of the antithrombotic effects of 
novel anticoagulants.  
Additional information on the background is described in the study protocol. 
1.1.1. 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of REGN9933 for the prevention of 
venous thromboembolism (VTE) after unilateral total knee arthroplasty (TKA), compared to 
enoxaparin.  
 
 
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1.1.2. 
Secondary Objectives 
The secondary objectives of the study are:To evaluate the bleeding risk (i.e., major and clinically 
relevant non-major [CRNM] bleeding) of REGN9933 after unilateral TKA through time of 
venography, compared to enoxaparin 
• To assess overall safety and tolerability of REGN9933 in participants undergoing TKA 
• To evaluate the efficacy of REGN9933 in prevention of clinically relevant VTE, compared 
to enoxaparin 
• To evaluate the efficacy of REGN9933 in prevention of DVT detected by venography, 
compared to enoxaparin 
• To evaluate the pharmacokinetics (PK) of REGN9933 after single intravenous (IV) 
administration 
• To assess pharmacodynamic (PD) effects of REGN9933 on intrinsic and extrinsic 
coagulation pathways (i.e., aPTT, PT) 
• To assess immunogenicity following a single dose of REGN9933 over time 
• To compare the efficacy of enoxaparin and apixaban in prevention of VTE after unilateral 
TKA 
1.2. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• Explore the efficacy of REGN9933 in prevention of VTE after unilateral TKA through the 
end of study, compared to enoxaparin and apixaban  
• Explore the efficacy of REGN9933 in prevention of symptomatic, clinical thrombosis, 
compared to enoxaparin and apixaban 
• Explore the efficacy of REGN9933 in prevention of DVT detected by venography, 
compared to apixaban 
• Explore the extent of DVT burden on venography in participants receiving REGN9933 
compared to enoxaparin and apixaban 
• Explore the bleeding risk (i.e., major bleeds and CRNM) of REGN9933 after unilateral 
TKA through end of study compared to enoxaparin and apixaban 
• Explore the occurrence of minor bleeding compared to enoxaparin and apixaban 
• Explore biomarkers related to FXI inhibition by REGN9933 
• Develop a molecular understanding of venous thromboembolism, and related diseases  
• Explore relationships between PK, biomarkers of anticoagulant activity, and efficacy 
• To study REGN9933 mechanism of action the coagulation cascade, VTE, and related 
diseases  
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• Explore whether potential differences in participant efficacy and safety are associated with 
genotype and gene expression and further study FXI and coagulation-related diseases, 
using optional whole blood DNA and RNA collected from consented participants  
1.3. 
Statistical Hypothesis 
The clinical hypothesis comparing the efficacy of REGN9933 to enoxaparin or apixaban will be 
assessed through a Bayesian estimation framework. Bayesian posterior probabilities will be 
reported to estimate the incidence of confirmed VTE for participants treated with REGN9933 
and enoxaparin, as well as the odds ratio (OR) of confirmed VTE in participants administered 
REGN9933 as compared to that of enoxaparin (ORRE). The statistical hypothesis ORRE <1, i.e. 
that incidence of confirmed VTE is lower in the REGN9933 arm compared to the enoxaparin 
arm. 
1.4. 
Modifications from the Statistical Section in the Final Protocol 
There is no modification from the statistical section in the final protocol.  
1.5. 
Revision History for SAP Amendments 
This is the original version of the SAP. 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design  
The study consists of the following periods: a screening period (day -30 to day -1) and a 75-day 
open-label treatment and follow-up period with REGN9933 or enoxaparin or apixaban. 
Participants who are at least 50 years of age and undergoing elective, unilateral TKA will be 
randomized after surgery to one of 3 treatment arms—REGN9933, enoxaparin, apixaban—in a 
ratio of 1:1:1, in a parallel manner. Randomization will be stratified based on study site and age 
(<70 vs ≥ 70 years of age). Approximately 120 participants will be enrolled in each arm, for a 
total of up to approximately 360 participants in the study. 
After providing informed consent, participants will undergo screening, which can occur from 
approximately day -30 to -1 (day 1 is defined as the day of TKA surgery). Participants will be 
randomized after completion of surgery to treatment in one of the following groups: 
• REGN9933 300 mg IV, once 
• Enoxaparin 40 mg subcutaneous (SC), daily through the time of venography or day 12, 
whichever is earlier 
• Apixaban 2.5 mg orally (PO), BID, daily through the time of venography or day 12, 
whichever is earlier 
Dosing with REGN9933 will occur 12 to 24 hours after the end of surgery. 
Dosing with enoxaparin or apixaban will begin 12 to 24 hours after the end of surgery and will 
continue through the day of venography (or day 12, whichever is earlier). Administration of 
enoxaparin prior to TKA surgery is not permitted in this study (see protocol Section 7.2.2 
Exclusion criterion 10 and Section 8.8.1). All investigators must comply and satisfy all 
requirements for the local risk management plan or equivalent for apixaban and enoxaparin 
where applicable and before dosing participants. 
Below is the study flow diagram depicting the different periods of the study with the scheduled 
visits and treatment administrations.  
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Figure 1:     Study Flow Diagram 
 
2.2. 
Sample Size and Power Considerations 
Approximately 360 participants will be randomized in a 1:1:1 allocation ratio to REGN9933, 
apixaban or enoxaparin. Each arm will have approximately 120 participants. 
The sample size was determined through Bayesian approach. The treatment difference was 
expressed as the log(OR), and the prior distribution of the treatment difference was assumed to 
be N(0,0.843), which follows a normal distribution centered around no treatment difference and 
with a variance such that extreme treatment differences are expected to be unlikely, i.e., 90% 
probability that OR is between 0.25 and 4.0. 
The probability of any beneficial effect of REGN9933 over enoxaparin can be assessed by the 
posterior distribution of the odds ratio comparing REGN9933 to enoxaparin of confirmed VTE.  
A beneficial effect is where ORRE  < 1, and thus the study will estimate Prob(ORRE <1 | data). 
The sample size of 120 patients per arm was determined through 10000 trial simulation, 
assuming confirmed VTE event rates of 13% for REGN9933 and 22.4% for enoxaparin.  
(Enoxaparin rates taken from (Verhamme, 2021) (Weitz, 2020). Out of the 10000 simulated 
trials, 75% of the simulated trials with Prob(ORRE <1 | data) >0.95 have  the sample size of 120 
or less.  
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3. 
ANALYSIS SETS 
The following defines the set(s) of participants whose data will be used for statistical analysis. 
3.1. 
Efficacy Analysis Set  
The primary analysis will be conducted in the modified intention to treat population (mITT) 
population, consisting of randomized and treated participants that have either an evaluable 
venogram, a confirmed episode of venous thromboembolism, or both through day 12.  It is based 
on the treatment allocated (as randomized). 
3.2. 
Safety Analysis Set  
The safety analysis set (SAF) includes all randomized participants who received any study drug; 
it is based on the treatment received (as treated). Treatment compliance/administration and all 
clinical safety variables will be analyzed using the SAF. 
3.3. 
Pharmacokinetic Analysis Set  
The pharmacokinetic analysis set (PK) includes all participants in the REGN9933 treatment 
group who received study drug and who had at least 1 non-missing result following the first dose 
of study drug. 
3.4. 
Immunogenicity Analysis Sets 
The ADA analysis set (AAS) includes all participants who received study drug (REGN9933) and 
had at least 1 non-missing ADA result following the first study dose. 
3.5. 
Pharmacodynamic Analysis Sets 
The pharmacodynamic analysis set (PDAS) includes all randomized participants who received 
any study drug and who had a at least 1 non-missing PD result following the first dose of study 
drug; it is based on the treatment received (as treated). 
 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic variables will be summarized by treatment group:  
• Age at screening (year) 
• Age categories (<70, ≥ 70) 
• Sex (Male, Female) 
• Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White and Other) 
• Ethnicity (Hispanic/Latino, Not Hispanic or Latino) 
• Weight (kg) 
• Height (cm) 
• Body mass index (BMI) (kg/m2) 
Other baseline characteristics may include: 
• Medication history (antiplatelets; NSAIDs; hormone replacement therapy) 
• aPTT (sec) 
• PT (sec) 
• FXI functional activity level 
• TKA information (including but not limited to operative leg, blood loss during 
surgery, and type of anesthesia)  
4.2. 
Medical History 
Medical histories will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to the latest available version of the Medical Dictionary for Regulatory 
Activities (MedDRA). 
4.3. 
Prior / Concomitant Medication 
Any treatment administered from the time of informed consent to the final study visit will be 
considered concomitant medication. This includes medications that were started before the study 
and are ongoing during the study. 
Medications will be recorded from the day of informed consent until the end of study (EOS) 
visit. Medications will be coded to the anatomical therapeutic chemical (ATC) classification 
level 2 (therapeutic main group) and ATC level 4 (chemical/therapeutic subgroup), according to 
the latest available version of WHO Drug Dictionary (WHODD). Participants will be counted 
once in all ATC categories linked to the medication. 
 
 
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Prohibited concomitant medications/procedures 
Administration of enoxaparin prior to TKA surgery is prohibited (see protocol Section 7.2.2 
Exclusion criterion 10, and Section 8.8.1). 
Anti-platelet therapy (except low doses of Acetylsalicylic acid (ASA) ≤100 mg/day) is 
prohibited, unless indicated for treatment of an adverse event (AE). 
The following procedures/devices are prohibited after study drug has started: 
• Use of spinal or epidural analgesia post-operatively 
• Pneumatic compression devices 
Participants are prohibited from donating blood products through the EOS visit. Participants are 
prohibited from donating sperm through the EOS visit. Participants are prohibited from having 
planned, elective surgeries (except for TKA performed on day 1) through the EOS visit. 
For participants assigned to the REGN9933 treatment arm, anticoagulant medications (including, 
but not limited to, vitamin K antagonists, heparins, DOACs) are prohibited after study drug has 
been started, unless they are indicated for treatment of an AE. 
4.4. 
Efficacy Variables 
4.4.1. 
Primary Efficacy Variable 
The primary endpoint is adjudicated, confirmed VTE through day 12. This composite endpoint 
consists of: asymptomatic deep DVT detected by unilateral venography of the operated leg; 
confirmed symptomatic DVT of either leg; confirmed fatal or nonfatal pulmonary embolism (PE) 
including unexplained death for which PE cannot be ruled out. 
Adjudicated VTE outcomes are generated by the Adjudication Committee that will review and 
determine interpretation and/or classification in a blinded manner. 
4.4.2. 
Secondary Efficacy Variables 
• Incidence of major VTE through day 12 (REGN9933 versus enoxaparin). Major VTE 
includes: proximal DVT; confirmed symptomatic DVT of either leg; confirmed fatal 
or nonfatal PE including unexplained death for which PE cannot be ruled out 
• Incidence of DVT as measured by venography of the operated leg on day 10 ±2 days 
(REGN9933 vs enoxaparin)  
• Incidence of confirmed, adjudicated VTE through day 12 (enoxaparin vs apixaban) 
4.4.3. 
Exploratory Efficacy Variables 
• Incidence of confirmed VTE through day 12 (REGN9933 vs apixaban) and through the 
end of study 
• Incidence of major VTE through the end of study 
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• Incidence of confirmed symptomatic DVT in either leg through day 12 or through the 
end of the study 
• Incidence of confirmed PE through day 12 and through the end of study 
• Incidence of fatal PE, which includes sudden death for which PE cannot be ruled out, 
through day 12 and through the end of study 
• Incidence of DVT as measured by venography of the operated leg on day 10 ±2 days 
(REGN9933 vs apixaban) 
• In participants with DVT detected on venogram: 
− distribution of DVT (proximal versus distal) 
− for proximal DVT, size of VTE 
− for distal DVT, the number of veins affected 
4.5. 
Safety Variables 
The safety variables include physical examination, vital signs, electrocardiograms (ECGs), 
laboratory evaluations (hematology, chemistry, urinalysis, other laboratory tests), concomitant 
medications, bleeding events (major bleeding and CRNM bleeding), and AEs. 
4.5.1. 
Adverse Events and Serious Adverse Events 
AEs and serious adverse events (SAEs) will be collected from the time of informed consent 
signature and then at each visit until the end of the study. All adverse events are to be coded to a 
PT and associated primary SOC according to the latest available version of MedDRA. 
An AE is any untoward medical occurrence in a participant administered a study drug which 
may or may not have a causal relationship with the study drug. Therefore, an AE is any 
unfavorable and unintended sign (including abnormal laboratory finding), symptom, or disease 
which is temporally associated with the use of a study drug, whether or not considered related to 
the study drug(ICH, 1994) 
For studies with participant reported outcomes (PRO), the PRO data are generally not reportable 
as individual AEs and thus will not be reported or reconciled as such.  
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (e.g., a car accident in which a participant is a passenger). 
• Is life-threatening – in the view of the investigator, the participant is at immediate 
risk of death at the time of the event. This does not include an AE that had it occurred 
in a more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
Inpatient hospitalization is defined as a hospital admission (any duration), or an 
emergency room visit for longer than 24 hours. Prolongation of existing hospitalization 
is defined as a hospital stay that is longer than was originally anticipated for the event 
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or is prolonged due to the development of a new AE as determined by the investigator 
or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
• Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant 
or may require intervention to prevent one of the other serious outcomes listed above 
(e.g., intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development of 
drug dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events as per study protocol. 
An adverse event of special interest (AESI) (serious or non-serious) is one of scientific and 
medical interest specific to the sponsor’s product or program, for which ongoing monitoring and 
rapid communication by the investigator to the sponsor can be appropriate. Such an event might 
warrant further investigation in order to characterize and understand it. 
Adverse Events of Special Interest for this study are: 
• Moderate or severe infusion reactions 
• Moderate or severe hypersensitivity reactions potentially related to study treatment 
• Moderate to severe bleeding (both spontaneous and non-spontaneous) 
4.5.2. 
Bleeding Events 
The ISTH criteria will be used for both major bleeding events and CRNM events as described 
below. Minimal bleeding will be captured separately as an exploratory endpoint. 
Major bleeding, CRNM bleeding and  minimal bleeding through time of venography (or day 12, 
whichever is earlier) and through the end of study will be summarized by each treatment group. 
Major Bleeding (ISTH): 
• Fatal bleeding and/or 
• Bleeding that is symptomatic and occurs in a critical area or organ, such as intracranial, 
intraspinal, intraocular, retroperitoneal, pericardial, in a non-operated joint, or 
intramuscular with compartment syndrome, assessed in consultation with the surgeon, 
and/or 
• Overt extra surgical site bleeding causing a fall in hemoglobin level of 20 g/L (1.24 
mmol/L) or more, or leading to transfusion of two or more units of whole blood or packed 
red cells, with temporal association within 24 to 48 hours to the bleeding, and/or 
• Surgical site bleeding that requires a second intervention (open, arthroscopic, 
endovascular) or a hemarthrosis of sufficient size as to interfere with rehabilitation by delay 
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in mobilization or delayed wound healing, resulting in prolonged hospitalization or a deep 
wound infection, and/or 
• Surgical site bleeding that is unexpected and prolonged and/or is sufficiently large to cause 
hemodynamic instability, as assessed by the surgeon. There should be an associated fall in 
hemoglobin level of at least 20 g/L (1.24 mmol/L), or transfusion indicated by the bleeding, 
of at least two units of whole blood or red cells, with temporal association within 24 hours 
to the bleeding. 
Clinically Relevant Non-Major Bleeding (ISTH): 
• Any sign or symptom of hemorrhage (e.g., more bleeding than would be expected for a 
clinical circumstance, including bleeding found by imaging alone) that does not fit the 
criteria for the ISTH definition of major bleeding but does meet at least one of the following 
criteria: 
− requiring medical intervention by a healthcare professional 
− leading to hospitalization or increased level of care 
− prompting a face to face (i.e., not just a telephone or electronic communication) 
evaluation 
Minimal Bleeding: 
Any overt bleeding event that does not meet the criteria for either major or CRNM bleeding will 
be categorized as a minor bleeding event. Minimal bleeding will be captured separately as an 
exploratory endpoint. 
4.5.3. 
Laboratory Safety Variables 
Hematology, chemistry, urinalysis, and the coagulation panel will be analyzed by local laboratory. 
Plasma for PT and aPTT biomarkers will be analyzed by a central laboratory. Detailed instructions 
for blood sample collection are in the laboratory manual provided to study sites. 
Samples for laboratory testing will be collected at visits according to Table 4. Tests (Blood 
Chemistry, Hematology, Urinalysis, and Other Laboratory Tests) are described in protocol Section 
9.2.3.7. 
4.5.4. 
Vital Signs 
The following vital signs parameters will be collected at each clinic visit from screening to end of 
study (EOS) or at the time of early termination (ET): 
• Temperature (°C) 
• Semi-recumbent blood pressure (mmHg) 
• Pulse rate (beats/min) 
• Respiratory rate (breaths/min) 
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4.5.5. 
ECG 
A standard 12-Lead ECG will be performed at time points according to Table 3. Heart rate will be 
recorded from the ventricular rate and the PR, QRS, and QT (QTcB and QTcF) intervals will be 
recorded. The ECG strips or reports will be retained with the source. 
4.6. 
Pharmacokinetic Variables 
The Pharmacokinetic (PK) variable is the concentration of total REGN9933 in serum at 
scheduled time points on Table 3 and Table 4. 
4.6.1. 
Drug Target Variables 
The drug target variable is the concentration of total FXI in plasma at each time point. These 
sampling timepoints are specified in Table 3 and Table 4. 
4.7. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, and time-point/visit. Samples in this study 
will be collected at the clinical visits as specified in Table 3 and Table 4. 
4.8. 
Pharmacodynamic and Other Biomarker Variables 
Plasma for aPTT and PT biomarkers will be analyzed by a central laboratory, and they will be 
used for the secondary PD endpoints. 
Additional PD and biomarker variables include FXI:C (a measure of FXI activity), intrinsic-
pathway-triggered thrombin generation, and extrinsic-pathway-triggered thrombin generation. 
Samples in this study will be collected at the clinic visits specified in Table 3 and Table 4. 
 
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5. 
STATISTICAL METHODS 
Unless otherwise stated, the following conventions will be applied when presenting summary level 
statistics for data. 
Continuous variables will be summarized within each treatment group, presenting the following 
descriptive statistics: the number of participants reflected in the calculation (n), average, sample 
standard deviation (SD), median, minimum, maximum, 1st quartile and 3rd quartile. 
Categorical or ordinal data will be summarized within each treatment group by frequency (i.e. total 
number of observations within each level of the categorical variable in a given treatment group) 
and percentages.  All levels of the categorical variable will be included.  If there are observations 
where the level of the categorical variable is missing, a separate category titled “Missing” will be 
created.  For categorical variables that are ordinal in nature, the order in which the levels of the 
categories are displayed will be consistent with the natural ordering of the category levels.  
Percentages will also be calculated for each level of the categorical variables with respect to the 
total sample size for the respective treatment arm.   
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group 
based on SAF.  
5.2. 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®). 
The frequency and percentage of each medical history will be summarized by associated primary 
SOC and PT for each treatment arm on the SAF. The table will be sorted by decreasing frequency 
of SOC followed by PT based on the overall incidence across treatment groups.  
5.3. 
Prior / Concomitant Medications 
The prior and concomitant medication will be descriptively summarized by treatment group on 
the SAF, sorted by decreasing frequency of ATC Level 2 and ATC level 4 of the total group. The 
use of anti platelets, anticoagulants (outside of assigned treatments), and NSAIDs may be 
included if deemed necessary. 
5.4. 
Subject Disposition 
The following summaries of number and percentage by each treatment group and overall group 
will be provided: 
• The number of participants screened (signed the informed consent form) and the reasons 
for screen failure 
• The number of participants randomized (received a randomization number) 
• The number of participants treated 
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• The total number of participants who discontinued the study treatment and the reasons for 
the discontinuation 
• A cross-tabulation of participants by planned and actual randomization strata for 
quantifying the mis-stratification 
5.5. 
Measurement of Treatment Compliance 
Treatment compliance will be summarized by treatment group. 
 For each study arm, its compliance will be calculated as follows: 
 
where the number of planned administrations by each study drug  is calculated as: 
• For participants assigned to the enoxaparin arm, the number of planned administrations is 
the number of days in the on-treatment period, which is defined as the period from the 
date of the first dose of study drug to the time of venography (or day 12, whichever is 
earlier).   
• For participants assigned to the apixaban arm, the number of planned administrations is 
two times of the number of days in the on-treatment period, which is defined as the period 
from the date of the first dose of study drug to the time of venography (or day 12, whichever 
is earlier). 
• For participants assigned to the REGN9933 arm, the number of planned administrations 
is one. 
5.6. 
Treatment Exposure 
The duration of exposure during the treatment period will be presented by treatment group and 
calculated as: 
• For participants assigned to the enoxaparin or apixaban arm, exposure will be summarized 
by the number of days that the participant received enoxaparin or apixaban administrations. 
5.7. 
Analysis of Efficacy Variables 
The efficacy analyses will be performed using the mITT analysis set.  
Pooling of Sites/Centers 
For this multi-center study, a small number of participants are ancipated at some sites. Since 
these study sites may not provide appropriate information to allow the analysis, the efficacy 
analyses adjusted/stratified by country instead of site will be conducted. 
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5.7.1. 
Analysis of Primary Efficacy Variable 
The primary analysis is to evaluate the efficacy of REGN9933 for the prevention of VTE after 
unilateral TKA, compared to enoxaparin. The primary efficacy variable is a binary indicator 
whether a particiant has an adjudicated, confirmed VTE through day 12. 
For any participant i, let 𝑝𝑖 denote the VTE probability,  𝑡𝑟𝑡𝑖 denote the treatment assignment ( 0:   
enoxaparin, 1: REGN9933, 2: apixaban) , 𝑐𝑜𝑢𝑛𝑡𝑟𝑦𝑖 denote the country indicator (1, 2, .., K), and 
𝑎𝑔𝑒_𝑔𝑟𝑝𝑖 be the age group indicator (0: 𝑎𝑔𝑒< 70 𝑎𝑛𝑑 1: 𝑎𝑔𝑒≥70).  
The following Bayesian logistic regression model adjusted by stratification factors (country and 
age group) is specified to compare the event rates of VTE among enoxaparin, REGN9933, and 
apixaban: 
𝑙𝑜𝑔𝑖𝑡(𝑝𝑖) = 𝛽0 + 𝛽1 ∗𝐼(𝑡𝑟𝑡𝑖= 1) + 𝛽2 ∗𝐼(𝑡𝑟𝑡𝑖= 2) + ∑𝜃𝑘∗𝐼(𝑐𝑜𝑢𝑛𝑡𝑟𝑦𝑖= 𝑘) +
𝐾−1
𝑘=1
𝛾∗𝑎𝑔𝑒_𝑔𝑟𝑝𝑖 
 
where 𝛽0 is the log odds of the VTE rate from enoxaparin, 𝛽1 is the log odds ratio of REGN9933 
relative to enoxaparin, and 𝛽2 is the log odds ratio of apixaban relative to enoxaparin after 
adjustment by country and age group. The benefit of the treatment effect of REGN9933 over 
enoxaparin is  expressed in terms of the odds ratio (=𝑒𝛽1) that is less than 1. 
A weak prior N(0,0.843) is chosen for parameters 𝛽1 and 𝛽2. With this weak prior, the extreme 
treatment difference is unlikely, i.e., the probability of the odd ratio between 0.25 and 4 is around 
90%. A vague prior 𝑁(0,104) is used for the other regression parameters. 
The treatment effect will be estimated using the Markov Chain Monte Carlo (MCMC) method 
via PROC BGLIMM in SAS. The SAS code for implementing the Bayesian logistic regression 
model is provided in Appendix 11.4.1  
Bayesian summary statistics (posterior mean and median, and two-sided 90% credible interval) of 
the treatment effect of REGN9933 vs enoxaparin (odds ratio = 𝑒𝛽1) will be reported.  
Based on the logistic regression model, the treatment effect (odds ratio = 𝑒𝛽1−𝛽2) of REGN9933 
vs apixaban and the treatment effect (odds ratio = 𝑒𝛽2) of apixaban vs enoxaparin will be reported.  
Their crediable interval such as two sided 90% credible interval will also be reported.  
The probability-based quantities for the magnitude of treatment effect at thresholds of clinical 
interest may be provided, e.g., Prob(OR < 0.5, 0.8, 0.9, etc. | data). 
5.7.2. 
Analysis of Secondary and Exploratory Efficacy Variables 
Unless otherwise specified, categorical efficacy endpoints (defined in Section 4.4.2 and 
Section 4.4.3 ) will be analyzed by Bayesian logistic regression models in a similar manner for 
the primary efficacy variable on the mITT set. 
Bayesian summary statistics (posterior mean and median, and two-sided 90% credible interval) of 
the treatment effect (odds ratio) will be reported.  
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For the explaratory analyses, the distribution of DVT (proximal versus distal) will be 
summarized descriptively for participants detected on venogram. Proximal DVT will be 
characterized by the size of the venous thromboembolism (VTE), while distal DVT will be 
summarized by the number of affected veins. 
5.7.3. 
Sensitivity Analysis 
To assess the robustness of the Bayesian model on the choice of prior distributions, sensitivity 
analyses will be performed and reported for these possible prior distributions for parameters 𝛽0, 
𝛽1,  𝑎𝑛𝑑 𝛽2 (including but not limited: N(0,1), N(0,10), N(0,100), and N(0,106)). 
A Bayesian logistic regression model with these two covariates (country and treatment group) will 
be explored to assess the treatment effect conditional on country only. 
To assess the sensitivity of the Bayesian logistic model, the stratified Cochran-Mantel-Haenszel 
(CMH) method by both country and age group will be performed. The SAS code for CMH 
analysis is provided in Appendix 11.4.2. The stratified CMH by country only as the  stratification 
factor will also be explored. 
5.7.4. 
Subgroup Efficacy Analysis 
Subgroup efficacy analyses on the primary efficacy variable and secondary efficacy variables will 
be performed on the following subgroups: 
• Gender (Male, Female) 
• BMI 
• Age group(<70 vs ≥ 70) 
• Site 
• Country 
• Duration of TKA surgery 
However, as such analyses may not have enough power for hypothesis tests, the analysis will be 
exploratory in nature. 
5.7.5. 
Multiplicity Control 
As the statistical inference for this study is to focus on estimation rather than testing a formal 
hypothesis and the Bayesian analysis is performed, the multiplicity adjustments of the different 
comparisons between groups will not be done. 
5.8. 
Analysis of Safety Data 
The safety analysis will be performed on the SAF. 
5.8.1. 
Analysis of Adverse Events 
AE incidence tables will be presented for each treatment group, including the number (n) and 
percentage (%) of participants experiencing an AE, where multiple instances of the same event 
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occur in the same participant the event will be counted only once for that participant. The 
denominator for computation of percentages is the number of participants in each treatment group. 
Treatment Emergent Adverse Events (TEAEs) are defined as AEs with either initial onset after the 
first dose of study treatment or that worsen after the first dose of study treatment. The number and 
proportion of participants reporting TEAEs will be summarized by SOC and PT. 
Overall TEAE summary 
The overall summary of TEAEs will be provided with number and proportions of participants with 
any: 
• TEAEs 
• Treatment-emergent serious adverse events (TE-SAEs) 
• TEAEs of special interest (TE-AESI) 
• Summary of deaths 
TEAE incidence 
Number and proportions of participants reporting TEAEs will be summarized for the following 
TEAEs: 
• TEAEs 
− TEAEs  by primary SOC and PT  
− TEAEs by primary SOC, PT and severity 
− TEAEs related to study drug by primary SOC and PT 
− Treatment-related TEAEs by primary SOC, PT and maximum severity 
− TE-AESI by primary SOC and PT 
− TEAEs leading to permanent treatment withdrawal by primary SOC and PT 
• TE-SAEs  
− TE-SAEs by SOC and PT 
− Treatment-related TE-SAEs by primary SOC and PT 
• TEAEs leading to death by primary SOC and PT 
5.8.2. 
Assessment for Bleeding 
Participants will be assessed for surgical site bleeding events at time points according to Table 3. 
Description of surgical site bleeding events will include the following: onset and duration; 
associated clinical symptoms (if any) and sequelae, including prolonged hospitalization or deep 
wound infection; requirement for additional surgical or interventional procedure. 
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Participants will also be assessed for overall bleeding events at time points according to Table 3. 
Description of bleeding events will include the following: location; onset and duration; 
associated symptoms (if any); precipitating factors (if any). 
For all bleeding events (surgical and extra surgical), the following will be recorded: associated 
changes in hemoglobin, hematocrit; requirement for, timing of, and quantity of transfusion. 
In addition, for all participants, peri- and post-operative blood loss will be recorded, as per local 
practice. 
All bleeding events will need to be recorded as an AE with documentation sent to the central AC 
as instructed in the Study Manual for Venography and Event Reporting. Events will be classified 
by the AC using the ISTH criteria for both major (Schulman, 2010) and CRNM (Kaatz, 2015) 
bleeds as described in Section 4.5.2. 
5.8.3. 
Analysis of Clinical Laboratory Measurements 
Laboratory measurements include clinical chemistry, hematology and urinalysis results, and will 
be converted to standard international units and US conventional units. Summaries of laboratory 
variables will include: 
• Descriptive statistics of laboratory result and change from baseline by visit 
• The number (n) and percentage (%) of participants with treatment-emergent PCSVs during 
study 
• Shift tables based on baseline normal/abnormal may be used to present the results for 
parameters of interest 
5.8.4. 
Analysis of Vital Signs 
Summaries of vital sign variables will include: 
• Descriptive statistics of vital sign variable and change from baseline by visit 
• The number (n) and percentage (%) of participants with treatment-emergent PCSV, 
depending on data 
5.8.5. 
Analysis of ECG 
Summaries of 12-lead ECG parameters by treatment group will include: 
• Each ECG parameter and change from baseline 
• The number (n) and percentage (%) of participants with PCSV, depending on data 
• ECG status (i.e. normal, abnormal) summarized by a shift table 
 
 
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5.8.6. 
Analysis of Pharmacokinetics Drug Concentration Data 
The PK parameters may include, but are not limited to: 
• Cmax – peak concentration 
• AUClast -area under the curve computed from time zero to the time of the last positive 
concentration 
The concentrations of total REGN9933 and total FXI over time will be summarized by 
descriptive statistics for each of the treatment groups for the purpose of estimating exposures in 
these groups. This descriptive statistical assessment will include the geometric means and ratios 
of the geometric means for selected PK parameters, as deemed appropriate. 
5.8.7. 
Analysis of Immunogenicity Data 
Immunogenicity variables described in Section 4.7 will be summarized by ADA status, ADA 
category and maximum titer observed in participants in the ADA analysis set. For samples 
confirmed as drug specific ADA positive, but found negative at the lowest titer dilution, the 
lowest dilution in the titer assay is imputed.  
The ADA status of each participants may be classified as one of the following: 
• Positive  
• Pre-existing immunoreactivity: if the baseline sample is positive and all post baseline   
ADA titers are reported as less than 9-fold the baseline titer value.   
• Negative: if all samples are found to be negative in the ADA assay. 
The ADA category of each positive participants is classified as: 
•  Treatment-emergent ADA response: A negative results or missing result at baseline 
with at lease one positive post baseline result in the ADA assay.  
• Treatment-boosted ADA response: A positive result at baseline in the ADA assay 
with at least one post baseline result ≥9-fold the baseline titer value 
Maximum ADA Titer category of each participants is classified as: 
• Low (titer <1,000) 
• Moderate (1,000≤ titer ≤10,000) 
• High (titer >10,000) 
The following will be summarized by treatment group and ADA titer level:  
• Number (n) and percent (%) of ADA-negative participants  
• Number (n) and percent (%) of pre-existing participants  
• Number (n) and percent (%) of treatment-emergent ADA positive participants 
• Number (n) and percent (%) of treatment-boosted ADA positive participants 
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5.8.8. 
Association of Immunogenicity with Exposure, Safety and Efficacy 
Immunogenicity and Exposure  
Potential association between immunogenicity and systemic exposure to REGN9933 will be 
explored by treatment groups. Plots of individual REGN9933 concentration time profiles may be 
provided to examine the potential impact of ADA category, maximum titer category.  
Immunogenicity and Safety and Efficacy  
Potential association between immunogenicity variables and safety may be explored with a 
primary focus on the following safety events during the TEAE period:  
• Infusion reactions  
• Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
• Anaphylaxis (SMQ: Anaphylactic Reaction [Narrow])  
Potential association between immunogenicity variables and efficacy endpoints may be explored 
(e.g., scatter plot or spaghetti plot).   
 
The safety and efficacy analyses mentioned above will be conducted using the following 
categories:  
• ADA Positive 
• Treatment-emergent 
• Treatment-boosted  
• Maximum post-baseline titer category in ADA positive participants 
The association of immunogenicity with exposure, safety and efficacy analysis will be performed 
and reported separately.  
5.8.9. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
The analysis of Pharmacodynamic and Biomarker will be performed in the PD analysis set using 
all observed data. 
For biomarkers including aPTT, PT, FXI:C and thrombin generation (following intrinsic and 
extrinsic pathway activation), the following descriptive data will be generated: raw data at 
baseline, by treatment group, and overall. Biomarkers measured post-treatment will be 
summarized over time.  Change, percent change, and/or fold change from baseline to each 
scheduled assessment time will be summarized by treatment with descriptive statistics if deemed 
appropriate. 
TGA for extrinsic and intrinsic pathways will be analyzed separately. 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis. 
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the baseline measurement for all measurements will be the latest 
available valid measurement taken prior to the administration of study drug. If any randomized 
participants are not treated, the baseline will be the last value on or prior to the randomization. The 
following rules specify the determination by both date/time information: 
1. For the AE, lab (including biomarker), drug concentration and ADA data, both date and 
time of the measurement will be used to determine baseline by comparing with the first 
infusion date and time. 
2. For other data except AE, lab (including biomarker), drug concentration or ADA, only date 
of measurement will be used to determine baseline by comparing with the first infusion 
date.  
For the rescreened participants, all data from the same participant will be used to derive baseline 
regardless if the data is from the screen- failure subject ID or enrolled subject ID. 
6.2. 
General Data Handling Conventions 
For the laboratory safety variables and biomarker data, if the data below the lower limit of 
quantification (LLOQ) / limit of linearity, half of the lower limit value (i.e., LLOQ/2) will be used 
for quantitative analyses. For data above the upper limit of quantification (ULOQ) / limit of 
linearity, the upper limit value (i.e., ULOQ) will be used for quantitative analyses. 
6.3. 
Data Handling Convention for Missing Data 
Missing data will not be imputed in listing. This section includes the methods for missing data 
imputation for some summary analyses, if necessary.  
Adverse event  
If the intensity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
intensity of TEAEs. If the assessment of relationship of a TEAE to the investigational product is 
missing, it will be classified as related to the investigational product. 
Missing date 
Every effort will be made to collect the start dates of all AEs and concomitant 
medications/procedures.  However, in the case the start date of an AE or concomitant medication 
is incomplete or missing, it will be assumed to have occurred on or after the first dose of study 
medication, except if an incomplete date (e.g., month and year) clearly indicates that the event 
started prior to treatment.  If the partial date indicates the same month or year of the first dose of 
study medication date, then the start date of the first dose will be imputed, otherwise, the missing 
day or month by the first day or the first month will be imputed.  
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Potentially Clinically Significant Value (PCSV) 
If a participant has a missing baseline value, this participant will be grouped in the category 
“normal/missing at baseline”. 
For PCSVs with 2 conditions, one based on a change from baseline value and the other on a 
threshold value or a normal range, with the first condition being missing, the PCSV will be based 
only on the second condition.  
For a PCSV defined on a threshold and/or a normal range, this PCSV will be derived using this 
threshold if the normal range is missing; e.g., for eosinophils the PCSV is >0.5 giga/L or >ULN if 
ULN0.5 giga/L. When ULN is missing, the value 0.5 should be used.  
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSVs. 
For laboratory results below the quantifiable LOQ, half of the LOQ will be imputed for calculating 
the descriptive summary. 
No imputations for missing laboratory data, ECG data, vital sign data, or physical examination 
data will be made. 
6.4. 
Visit Windows 
Data analyzed by-visit-analysis (including efficacy, laboratory data, visit sign, ECG) will be 
summarized by the study scheduled visits described Appendix 11.2, “Schedule of Event”. The 
analysis visit windows will be exhaustive so that all available values obtained from unscheduled 
visits and early termination (ET) visit have the potential to be summarized. No analysis visit 
windows will be applied for the study scheduled visits. The visit windows are constructed using 
ranges applied to the number of days in study (study days) when the measure is collected.    
The following analysis visit windows will be used to map the unscheduled visits and ET visits, 
based on the study day: 
Visit 
Target Day (TD) 
Analysis Time Window 
Based on Study Day 
Visit 1 (Screening) 
-30 to -1 
-29 to -2 
Visit 2 (Baseline) 
1 
1 
Visit 3  
5 
[4, 6] 
Visit 4  
10 
[8, 12] 
Visit 5 
30 
[27, 33] 
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Visit 6 (End of Study) 
75 
[70, 80] 
Notes:  
1. Additional visits will be created as needed depending on the aPTT results per cohort 
2. End of Study visit will be mapped according to its actual day 
In general, the following order will be used to select the record for analysis at give visit: 
1. Scheduled visit 
2. Early termination (ET) or end of study (EOS), whichever comes first if scheduled visit is 
not available 
3. Unscheduled visit if both scheduled visit and ET/EOT/EOS are not available 
For multiple measurements of the same test in the same window, the following rules will be used 
to select the analysis value: 
1. If multiple valid values of a variable within an analysis visit window, the closest from the 
target study day will be selected. 
2. If the difference is a tie, the value after the target study day will be used. 
3. If multiple available values of a variable exist within a same day, then the first value of the 
day will be selected 
 
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7. 
INTERIM ANALYSIS  
An informal IA will be conducted by the sponsor when there are approximately 50 participants per 
arm who have evaluable primary endpoints (i.e. adjudicated, evaluable venography or confirmed 
VTE through day 12).  
The IA will only be used for administrative purpose and will not be used to make any decisions 
regarding the conduct of this study. 
The IA may include safety, efficacy and demographic and other baseline charateristics variables. 
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REGENERON CONFIDENTIAL 
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8. 
STUDY COMMITTEES 
8.1. 
Independent Data Monitoring Committee 
The IDMC (also known as a Data Monitoring Safety Board) is an independent, multidisciplinary 
group consisting of clinicians and statistician(s) that, collectively, have experience in areas 
relevant to this clinical study and in the conduct and monitoring of randomized clinical studies. 
The IDMC is independent from Regeneron and the study investigators and will perform regular 
safety data assessment of study participants and provide recommendations to Regeneron 
regarding the safety and the welfare of the participants exposed to REGN9933. 
Detailed information regarding the DMC procedures are  provided in a separate DMC charter. 
8.2. 
Steering Committee 
The Steering Committee is composed of independent experts, selected by Regeneron. The 
Steering Committee will provide advice on all scientific matters (including protocol development 
and publication of results) related to the study. 
Details are provided in a separate Steering Committee charter. 
8.3. 
Adjudication Committee 
The AC is comprised of independent experts selected by Regeneron. The AC will review and 
determine interpretation and/or classification of the following events and tests in a blinded 
manner: all imaging procedures used for determination of VTE, including mandatory 
venography and testing for suspected DVT or PE; all deaths; all suspected bleeding events. 
Details are explained in a separate Adjudication Committee charter. 
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9. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or higher, and R version 3.5.0 or higher.  
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REGENERON CONFIDENTIAL 
Page 35 of 43 
10. 
REFERENCES 
ICH. E2A. Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. 
In: ICH Harmoised Tripartite Guideline. 1994. 
Kaatz S, Ahmad D, Spyropoulos AC,Schulman S. Definition of clinically relevant non-major 
bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in 
non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015; 
13(11):2119-2126. 
Schulman S, Angerås U, Bergqvist D, Eriksson B, Lassen MR,Fisher W. Definition of major 
bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J 
Thromb Haemost 2010; 8(1):202-204. 
Verhamme P, Yi BA, Segers A, Salter J, Bloomfield D, Büller HR, et al. Abelacimab for 
Prevention of Venous Thromboembolism. N Engl J Med 2021; 385(7):609-617. 
Weitz JI, Bauersachs R, Becker B, Berkowitz SD, Freitas MCS, Lassen MR, et al. Effect of 
Osocimab in Preventing Venous Thromboembolism Among Patients Undergoing Knee 
Arthroplasty: The FOXTROT Randomized Clinical Trial. Jama 2020; 323(2):130-139. 
11. 
APPENDIX 
11.1. 
Summary of Statistical Analyses 
Table 1: 
Efficacy/PD Analyses 
Endpoint 
Analysis 
Populations 
Primary Statistical Method/Analysis 
Sensitivity 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoint 
Proportions of 
participants with 
adjudicated, 
confirmed VTE 
through day 12 
mITT 
Bayesian logistic regression 
Stratified 
CMH 
analysis 
Yes 
No 
Secondary/PD Endpoints 
Secondary 
efficacy endpoints 
mITT 
Bayesian logistic regression  
Stratified 
CMH 
analysis 
Yes 
No 
aPTT, PT 
PDAS 
Descriptive Statistics 
No 
No 
No 
FXI:C, TGA 
PDAS 
Descriptive Statistics 
No 
No 
No 
 
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Table 2: 
Safety Analyses 
Endpoint 
Analysis 
Populations 
Statistical Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Adverse Events 
SAF 
Descriptive Statistics 
No 
No 
No 
Laboratory 
Measures 
SAF 
Descriptive Statistics 
No 
No 
No 
Vital Signs 
SAF 
Descriptive Statistics 
No 
No 
No 
ECG 
SAF 
Descriptive Statistics 
No 
No 
No 
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11.2. 
Schedule of Time and Events 
Table 3: 
Schedule of Events 
 
Screening  
On-treatment  
Follow-up 
Study Procedure 
Visit 1 
Baseline 
Visit 2 
Visit1,2 3 
Visit1 4 
Visit 5 
End of Study/ 
Visit 6 
Day 
-30 to -1 
1 
5 
10 
30 
75 
Window (day) 
 
 
±1 
±2 
±3 
±5 
Screening/Baseline: 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Informed consent for 
pharmacogenomics 
research (optional) 
X 
 
 
 
 
 
Informed consent for 
future biomedical 
research (optional) 
X 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
FSH3 
X 
 
 
 
 
 
GFR (MDRD) 
X 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
Randomization 
 
X4 
 
 
 
 
Treatment: 
 
 
 
 
 
 
TKA 
 
X 
 
 
 
 
Administer REGN9933 
 
X5 
 
 
 
 
Administer enoxaparin 
 
X6 
 
 
Administer apixaban 
 
X6 
 
 
Participant diary (for 
self-administration of 
apixaban/enoxaparin) 
 
X 
 
 
Efficacy: 
 
 
 
 
 
 
Venography of the 
operated leg 
 
 
 
X 
 
 
Assessment for 
symptomatic VTE7 
 
X 
X 
X 
X 
X 
Safety: 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
 
X 
Electrocardiogram 
X 
 
 
 
 
 
Assessment for surgical 
site bleeding 
 
X 
X 
X 
 
 
Assessment for bleeding 
events 
 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
Concomitant 
medications and 
treatment 
X 
X 
X 
X 
X 
X 
Laboratory Testing  
 
 
 
 
 
 
Hematology 
X 
X8 
 
X 
 
X 
Blood chemistry 
X 
X8 
 
X 
 
X 
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Screening  
On-treatment  
Follow-up 
Study Procedure 
Visit 1 
Baseline 
Visit 2 
Visit1,2 3 
Visit1 4 
Visit 5 
End of Study/ 
Visit 6 
Coagulation panel  
X 
X8 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
X 
Pharmacokinetics and 
Immunogenicity 
Sampling 
 
 
 
 
 
 
Drug concentration 
sample (REGN9933) 
 
X8 
X 
X 
X 
X 
ADA (REGN9933) 
 
X9 
 
 
 
X 
Plasma for total FXI 
concentration 
 
X8 
X 
X 
X 
X 
Biomarkers 
Plasma for aPTT, PT 
(central lab) 
 
X8 
X 
X 
X 
X 
Plasma for FXI activity 
(FXI:C) and TGA 
 
X8 
X 
X 
X 
X 
Serum for exploratory 
research  
 
X8 
X 
 
X 
X 
Plasma for exploratory 
research  
 
X8 
X 
 
X 
X 
Optional Pharmacogenomics samples 
Whole blood sample for 
RNA isolation 
(optional)10 
 
X 
 
 
 
X 
Whole blood sample for 
DNA isolation 
(optional)10 
 
X11 
 
 
 
 
ADA: anti-drug antibody; aPTT: activated partial thrombin time; GFR: glomerular filtration rate; FSH: follicle-stimulating 
hormone; FXI: Factor XI; FXI:C: Factor XI functional activity; MDRD: Modification of Diet in Renal Disease; PT: 
prothrombin time; TGA: thrombin generation assay; TKA: total knee arthroplasty; VTE: venous thromboembolism 
11.2.1. 
Footnotes for the Schedule of Events 
1. Assessments for this visit may be performed in the hospital if the participant has not yet been 
discharged.  
2. If the participant is discharged prior to this visit, then information may be collected by telephone 
call, and assessments requiring blood draw may be omitted. 
3. To be performed in women 55 years of age or younger. 
4. Randomization will occur after completion of surgery on day 1. 
5. Dosing will occur 12 to 24 hours after the end of surgery, and at least 12 hours after removal of 
the needle/catheter used for spinal/epidural anesthesia.  
6. First dose will be given 12 to 24 hours after the end of surgery. 
7. May include confirmatory studies for DVT of the leg or PE, as described in protocol Section 
9.2.2.2. Confirmatory studies for suspected DVT of the leg or PE may be required more than once, 
per the discretion of the investigator. 
8. Refer to Table 4 for detailed information on Visit 2 samples.  
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9. Samples for ADA must be collected prior to dose administration on the same day that study drug 
is administrated. Refer to Table 4.  
10. The genomics sub-study informed consent form (ICF; for RNA and DNA analysis) must be signed 
prior to performing this sample collection. 
11. Samples for DNA extraction should be collected at the baseline visit (predose) but may also be 
collected at any later study visit. 
 
Table 4: 
Schedule of Events: Visit 2 Blood Collection 
Baseline  
Visit 2  
(Day 1) 
Study Procedure 
Pre-operatively 
Post-operatively 
Pre-dosing 
Up to 1 hour prior to 
dosing 
Post-dosing 
REGN9933 only:  as 
close as possible to 1-
hour post-dose 
Laboratory Testing 
Hematology 
X1 
 
 
Blood chemistry 
X1 
 
 
Coagulation panel  
X1 
 
 
Urinalysis 
 
 
 
Pharmacokinetics and Immunogenicity Sampling 
Drug concentration 
sample (REGN9933) 
 
X2 
X2 
ADA (REGN9933) 
 
X2 
 
Plasma for total FXI 
concentration 
X1 
X3 
X2 
Biomarkers 
Plasma for aPTT, PT 
(central lab) 
X1 
X3 
X2 
Plasma for FXI activity 
(FXI:C) and TGA 
X1 
X3 
X2 
Serum for exploratory 
research  
X1 
X3 
 
Plasma for exploratory 
research  
X1 
X3 
 
ADA: anti-drug antibody; aPTT: activated partial thrombin time; FXI: Factor XI; FXI:C: Factor XI functional activity; PT: 
prothrombin time; TGA: thrombin generation assay 
 
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11.2.2. 
Footnotes for Schedule of Events: Visit 2 Blood Collection 
1. Samples may be collected up to 24 hours prior to surgery. Samples to be collected in all 3 
treatment groups. 
2. Samples to be collected in REGN9933 group only. 
3. Samples to be collected in all 3 treatment groups. 
 
11.3. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Parameter 
PCSV Criteria 
Comments and References 
Clinical Chemistry 
ALT* 
>3 ULN and baseline 
≤1 ULN* 
>6 ULN and baseline 
≤3 ULN 
Enzyme activity must be expressed in ULN, not in 
IU/L. 
U. S. Food and Drug Administration. Center for Drug 
Evaluation and Research. (2009). Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation 
Each category is calculated independently. 
AST* 
>3 ULN and baseline 
≤1 ULN* 
>6 ULN and baseline 
≤3 ULN 
Enzyme activity must be expressed in ULN, not in 
IU/L. 
U. S. Food and Drug Administration. Center for Drug 
Evaluation and Research. (2009). Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation 
Each category is calculated independently. 
* At least one level is required, multiple levels are 
optional for phase 2/3 studies. If it is desirable to get 
the distribution across the different PCSV levels, 
additional shift table on ≤3, >3 to ≤5, > 5 to ≤10, >10 
to ≤20, and > 20 category for baseline vs. post 
baseline may be provided 
Alkaline Phosphatase 
>2.5 ULN and baseline 
≤1.5 ULN 
Enzyme activity must be expressed in ULN, not in 
IU/L. 
U. S. Food and Drug Administration. Center for Drug 
Evaluation and Research. (2009). Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation 
Total Bilirubin* 
>2 ULN and baseline 
≤1.5 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
U. S. Food and Drug Administration. Center for Drug 
Evaluation and Research. (2009). Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation 
* At least one level is required, multiple levels are 
optional for phase 2/3 studies. If it is desirable to get 
the distribution of significant level, additional shift 
table on ≤1.5, >1.5 to ≤2.0 and > 2.0 category for 
baseline vs. post baseline may be provided 
ALT and Total Bilirubin 
ALT>3 ULN and 
TBILI>2 ULN, and 
baseline ALT ≤1 ULN 
or TBILI ≤1.5ULN 
U. S. Food and Drug Administration. Center for Drug 
Evaluation and Research. (2009). Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation 
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Parameter 
PCSV Criteria 
Comments and References 
Creatinine 
≥150 μmol/L (Adults) 
and baseline < 100 
μmol/L 
≥30% change from 
baseline 
≥100% change from 
baseline 
Benichou C., 1994. 
3 independent criteria 
Blood Urea Nitrogen 
≥30 mmol/L and 
baseline <17 mmol/L 
One independent criteria 
Sodium 
Hyponatremia 
Hypernatremia 
≤125 mmol/L and 
baseline >129 mmol/L 
≥160 mmol/L and 
baseline <155 mmol/L 
Two independent criteria 
Potassium 
Hypokalemia 
Hyperkalemia 
<3 mmol/L and baseline 
≥3 mmol/L 
≥5.5 mmol/L and 
baseline <4.9 mmol/L 
FDA Feb 2005. 
Two independent criteria 
Glucose  
Hypoglycaemia  
 
Hyperglycaemia 
≤3.9 mmol/L and <LLN 
and baseline >5.9 
mmol/L 
 
11.1 mmol/L  
ADA Jan 2008. 
Albumin 
≤32 g/L and baseline 
>35 g/L 
Hematology 
WBC 
<2.0 Giga/L and 
baseline ≥4.0 Giga/L 
≥16.0 Giga/L and 
baseline <10 Giga/L 
Increase in WBC: not relevant. 
*The default criteria. Summary by race (black and 
Non-black) are optional. 
To be interpreted only if no differential count 
available. 
Neutrophils 
<1.0 Giga/L and 
baseline ≥2 Giga/L 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
Eosinophils 
>1 Giga/L and baseline 
≤0.4 Giga/L 
Harrison- Principles of internal Medicine 17th Ed., 
2008. 
Hemoglobin 
≤10 g/L and baseline 
>12 g/L 
*Decrease from Baseline 
≥30 % 
Two criteria are independent. 
Criteria based upon decrease from baseline are more 
relevant than based on absolute value. Other 
categories for decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
*based on expected post-operative changes 
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Parameter 
PCSV Criteria 
Comments and References 
Hematocrit 
≤0.32 v/v and baseline 
>0.38 v/v 
*Decrease from Baseline 
≥30 % 
The first criteria is the follow up value. 
 
*based on expected post-operative changes 
Platelets 
<50 Giga/L and 
baseline ≥100 Giga/L 
≥700 Giga/L and 
baseline <400 Giga/L 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
Two independent criteria 
Vital signs 
HR 
≤50 bpm 
≥130 bpm 
To be applied for all positions except STANDING. 
SBP 
≤95 mmHg and 
decrease from baseline 
≥20 mmHg 
≥165 mmHg and 
increase from baseline 
≥20 mmHg 
To be applied for all positions except STANDING. 
DBP 
≤45 mmHg and 
decrease from baseline 
≥10 mmHg 
≥105 mmHg and 
increase from baseline 
≥10 mmHg 
To be applied for all positions except STANDING. 
ECG 
HR 
≤45 bpm 
≥130 bpm 
Two independent criteria and evaluate follow up 
values. 
PR 
≥220 ms 
QRS 
≥120 ms 
QTc 
Prolonged** 
 
Prolonged: 
>450 ms for male or 
>470 ms for female 
 
QT correction formula to be applied is the Fridericia. 
*The default criteria. By gender (male and female) are 
optional. 
**QTc prolonged and ΔQTc>60 ms are the PCSV to 
be identified in individual subjects/patients listings. 
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11.4. 
SAS Code for Efficacy Analysis 
11.4.1. 
SAS Code for Primary Efficacy Analysis Using Bayesian Logistic Regression 
The Bayesian logistic regression model is implemented below by SAS PROC BGLIMM. The 
variable and dataset names are for illustration purpose and may be subject to change: 
 
proc bglimm data=adeff nmc=20000        seed=205169; 
     class country age_grp vte trt; 
      model vte(event=’yes’) = trt country age_grp / dist=binary cprior=normal(input=priordata);         
run; 
11.4.2. 
SAS Code for Stratified CMH 
The stratified CMH method is implemented by Proc Freq. The variable event is a binary 
indicator, which is used for illustration purpose only. 
   
Proc freq data= adeff ;  
      tables country*age_grp*trt*event/cmh commonriskdiff;  
      ods output cmh=cmh;  
run; 
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