A Phase 2, Multicenter, Randomized, Open-Label, Active Control Study of REGN7508, a Factor XI Monoclonal Antibody, for Prevention of Venous Thromboembolism After Elective, Unilateral, Total Knee Arthroplasty (ROXI-VTE II)
Phase: PHASE2
Conditions: Venous Thromboembolism
Sponsor: Regeneron Pharmaceuticals

REGENERON CONFIDENTIAL 
Page 1 of 78 
NCT06454630 
EU CT Number: 2023-508602-14-00 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A PHASE 2, MULTICENTER, RANDOMIZED, OPEN-LABEL, ACTIVE CONTROL 
STUDY OF REGN7508, A FACTOR XI MONOCLONAL ANTIBODY, FOR 
PREVENTION OF VENOUS THROMBOEMBOLISM AFTER ELECTIVE, 
UNILATERAL, TOTAL KNEE ARTHROPLASTY (ROXI-VTE II) 
Compound: 
REGN7508 
Study Name: 
ROXI-VTE II 
Clinical Phase: 
2 
Protocol Number: 
R7508-DVT-2360 Amendment 1 
Original Date of Issue: 
See appended electronic signature page 
Medical Director: 
Clinical Scientist: 
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 given every opportunity under applicable laws to protect its commercial 
interests and/or its trade secrets including the opportunity to object to such disclosure and/or 
provide redaction proposals. 
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AMENDMENT HISTORY 
Amendment 1 
The main purpose of this amendment is to modify the conditions of the interim analyses such 
that they may be performed based on requests from regulatory authorities or for program-level 
decision making rather than based on a pre-specified number of participants. Additionally, minor 
edits were also made to the protocol that were administrative in nature.   
Description of Change 
Brief Rationale 
Section # and Name  
Interim analyses for this study were 
modified such that they may be 
performed 
based 
on 
regulatory 
requests or program-level decision 
making rather than based on a pre-
specified number of participants.  
The data from an interim analysis will 
be reviewed by sponsor team members 
that are not involved in the conduct of 
the study. 
To allow for more flexibility of data 
review and monitoring to inform future 
development plans for REGN7508 
 
 
Section 5.2 Planned 
Interim Analysis 
Section 10.5 Interim 
Analysis 
 
The specific reference for use of either 
a central or local laboratory was 
removed for safety laboratory testing.  
This change was made to provide 
flexibility to study sites to use local or 
central safety laboratory testing due to 
availability of certain analyses in some 
geographic regions where the study is 
being conducted.  
Section 8.2.3.5 Laboratory 
Testing 
Removed reference to specifically use 
only the MDRD equation to calculate 
the GFR. 
Because no single GFR equation offers 
an advantage in estimating kidney 
function, use of only the MDRD 
equation will not be specified per 
protocol.  Sites may use locally 
available GFR calculators. 
Section 6.2.2 Exclusion 
Criteria, Criterion 7 
Section 8.2.1 Procedures 
Performed Only at the 
Screening/Baseline Visit 
Section 8.2.3.5 Laboratory 
Testing 
Table 2 Schedule of 
Events 
The background information on the 
REGN7508 mechanism of action was 
modified for clarity. 
To provide a more accurate description 
of the scientific mechanism of action of 
REGN7508 
Section 1 Introduction 
Minor edits to text and tables were 
made for further clarity and to align 
with the company style guide 
For consistency throughout the 
document 
Section 3.2.2 Rationale 
for Dose Selection 
Section 3.3.1 Risk-Benefit 
for REGN7508 
Section 12.5 Clinical 
Study Data Transparency 
Table 3 Schedule of 
Events: Visit 2 Blood 
Collection 
 
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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 
AUC 
Area under the curve 
AUClast 
Area under the curve computed from time zero to the time of the last positive 
concentration 
Cmax 
Peak concentration 
COVID-19 
Coronavirus Disease 2019 
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 anticoagulant 
DVT 
Deep venous thrombosis 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOS 
End of study 
ER 
Emergency room 
EU 
European Union 
FBR 
Future biomedical research 
FIH 
First in human 
FSH 
Follicle stimulating hormone 
FIX 
Factor IX 
FXI 
Factor XI  
FXIIa 
Factor XIIa 
 
 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
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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 
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 
NHP 
Nonhuman primate 
NOAEL 
No observed adverse effect level 
NSAID 
Non-steroidal anti-inflammatory drug 
OR 
Odds ratio 
ORRE 
the odds ratio of confirmed VTE in participants administered REGN7508 as 
compared to that of enoxaparin 
PD 
Pharmacodynamics  
PE 
Pulmonary embolism 
PK 
Pharmacokinetic 
PRO 
Participant reported outcomes 
PT 
Prothrombin time 
RBQM 
Risk-Based Quality Management 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SmPC 
Summary of product characteristics 
SOC 
System organ class 
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SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
 
 
TKA 
Total knee arthroplasty 
ULN 
Upper level of normal 
VTE 
Venous thromboembolism 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................3 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................12 
1. 
INTRODUCTION ......................................................................................................17 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................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 ................................................................................................................25 
3.3.1. 
Risk-Benefit for REGN7508 ......................................................................................25 
3.3.2. 
Risk-Benefit for Active Comparator ..........................................................................27 
3.3.2.1. 
Enoxaparin ..................................................................................................................27 
4. 
STUDY VARIABLES................................................................................................28 
4.1. 
Demographic and Baseline Characteristics ................................................................28 
4.2. 
Efficacy Variables ......................................................................................................28 
4.2.1. 
Confirmed VTE ..........................................................................................................28 
4.2.2. 
Major VTE ..................................................................................................................28 
4.3. 
Safety Variables ..........................................................................................................28 
4.3.1. 
Bleeding Events ..........................................................................................................28 
4.4. 
Pharmacokinetic Variables .........................................................................................29 
4.4.1. 
Drug Target Variables ................................................................................................29 
4.5. 
Immunogenicity Variables ..........................................................................................29 
4.6. 
Pharmacodynamic and Other Biomarker Variables ...................................................29 
5. 
STUDY DESIGN .......................................................................................................30 
5.1. 
Study Description and Duration .................................................................................30 
5.1.1. 
Study Stopping Criteria ..............................................................................................31 
5.1.2. 
End of Study Definition ..............................................................................................31 
5.2. 
Planned Interim Analysis ............................................................................................31 
5.3. 
Study Committees .......................................................................................................32 
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5.3.1. 
Independent Data Monitoring Committee ..................................................................32 
5.3.2. 
Steering Committee ....................................................................................................32 
5.3.3. 
Adjudication Committee .............................................................................................32 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PARTICIPANTS ........................................................................................................33 
6.1. 
Number of Participants Planned .................................................................................33 
6.2. 
Study Population .........................................................................................................33 
6.2.1. 
Inclusion Criteria ........................................................................................................33 
6.2.2. 
Exclusion Criteria .......................................................................................................33 
6.3. 
Premature Withdrawal from the Study .......................................................................35 
6.4. 
Replacement of Participants .......................................................................................35 
7. 
STUDY TREATMENTS............................................................................................37 
7.1. 
Investigational and Reference Treatments ..................................................................37 
7.2. 
Rescue Treatments ......................................................................................................37 
7.2.1. 
Treatment of VTE .......................................................................................................37 
7.2.2. 
Treatment of Bleeding Events ....................................................................................38 
7.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................38 
7.3.1. 
Dose Modification ......................................................................................................38 
7.3.2. 
Study Intervention Discontinuation ............................................................................39 
7.3.2.1. 
REGN7508 Discontinuation .......................................................................................39 
7.3.2.2. 
Enoxaparin Discontinuation .......................................................................................39 
7.4. 
Management of Acute Reactions ................................................................................39 
7.4.1. 
Acute Intravenous Infusion Reactions ........................................................................39 
7.4.1.1. 
Interruption of the Intravenous Infusion .....................................................................39 
7.4.1.2. 
Termination of the Intravenous Infusion ....................................................................40 
7.4.2. 
Acute Injection Reactions ...........................................................................................40 
7.4.2.1. 
Systemic Injection Reactions ......................................................................................40 
7.4.2.2. 
Local Injection Site Reactions ....................................................................................40 
7.5. 
Method of Treatment Assignment ..............................................................................41 
7.6. 
Blinding/Masking .......................................................................................................41 
7.7. 
Treatment Logistics and Accountability .....................................................................41 
7.7.1. 
Packaging, Labeling, and Storage ..............................................................................41 
7.7.2. 
Supply and Disposition of Treatment .........................................................................41 
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7.7.3. 
Treatment Accountability ...........................................................................................42 
7.7.4. 
Treatment Compliance ................................................................................................42 
7.8. 
Concomitant Medications and Procedures .................................................................42 
7.8.1. 
Prohibited Medications and Procedures .....................................................................42 
7.8.2. 
Permitted Medications ................................................................................................43 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................44 
8.1. 
Schedule of Events .....................................................................................................44 
8.1.1. 
Footnotes for Table 2 Schedule of Events ..................................................................47 
8.1.2. 
 .........................48 
8.1.3. 
Early Termination Visit ..............................................................................................49 
8.1.4. 
Unscheduled Visits .....................................................................................................49 
8.2. 
Study Procedures ........................................................................................................49 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................49 
8.2.2. 
Efficacy Procedures ....................................................................................................49 
8.2.2.1. 
Venography of the Operated Leg ...............................................................................49 
8.2.2.2. 
Assessment of Symptomatic VTE ..............................................................................50 
8.2.3. 
Safety Procedures .......................................................................................................50 
8.2.3.1. 
Vital Signs ..................................................................................................................50 
8.2.3.2. 
Physical Examination .................................................................................................50 
8.2.3.3. 
Electrocardiogram .......................................................................................................50 
8.2.3.4. 
Assessment for Bleeding ............................................................................................50 
8.2.3.5. 
Laboratory Testing ......................................................................................................51 
8.2.4. 
Drug Concentration and Factor XI Measurements .....................................................52 
8.2.5. 
Immunogenicity Measurements and Samples ............................................................52 
8.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................52 
8.2.6.1. 
Activated Partial Thromboplastin Time and Prothrombin Time ................................52 
8.2.6.2. 
 .........................................................................53 
8.2.6.3. 
 .......................................................................................53 
8.2.6.4. 
 ......................................................................................................53 
8.2.6.5. 
Exploratory Biomarkers ..............................................................................................53 
8.2.7. 
Future Biomedical Research (Optional) .....................................................................53 
8.2.8. 
Pharmacogenomic Analysis (Optional) ......................................................................54 
9. 
SAFETY EVALUATION AND REPORTING .........................................................55 
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9.1. 
Recording and Reporting Adverse Events ..................................................................55 
9.1.1. 
General Guidelines .....................................................................................................55 
9.1.2. 
Reporting Procedure ...................................................................................................56 
9.1.2.1. 
Individual Case Safety Reporting (ICSR) ..................................................................56 
9.1.2.2. 
Aggregate Safety Reporting (Development Safety Update Report) ...........................56 
9.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................56 
9.2. 
Definitions ..................................................................................................................57 
9.2.1. 
Adverse Event .............................................................................................................57 
9.2.2. 
Serious Adverse Event ................................................................................................57 
9.2.3. 
Adverse Events of Special Interest .............................................................................57 
9.2.4. 
Infusion Reactions ......................................................................................................58 
9.2.5. 
Severity .......................................................................................................................58 
9.2.6. 
Causality .....................................................................................................................59 
9.3. 
Safety Monitoring .......................................................................................................60 
9.4. 
Notifying Health Authorities, Institutional Review Board /Ethics Committee, 
and Investigators .........................................................................................................60 
10. 
STATISTICAL PLAN................................................................................................61 
10.1. 
Statistical Hypothesis ..................................................................................................61 
10.2. 
Justification of Sample Size........................................................................................61 
10.3. 
Analysis Sets ...............................................................................................................62 
10.3.1. 
Efficacy Analysis Sets ................................................................................................62 
10.3.2. 
Safety Analysis Set .....................................................................................................62 
10.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................62 
10.3.4. 
Immunogenicity Analysis Sets ...................................................................................62 
10.3.5. 
Pharmacodynamic Analysis Set .................................................................................62 
10.4. 
Statistical Methods ......................................................................................................62 
10.4.1. 
Participant Disposition ................................................................................................62 
10.4.2. 
Demography and Baseline Characteristics .................................................................62 
10.4.3. 
Efficacy Analyses .......................................................................................................63 
10.4.3.1. 
Primary Efficacy Analysis ..........................................................................................63 
10.4.4. 
Control of Multiplicity ................................................................................................63 
10.4.5. 
Safety Analysis ...........................................................................................................63 
10.4.5.1. 
Adverse Events ...........................................................................................................63 
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10.4.5.2. 
Other Safety ................................................................................................................63 
10.4.5.3. 
Treatment Exposure ....................................................................................................64 
10.4.5.4. 
Treatment Compliance ................................................................................................64 
10.4.6. 
Pharmacokinetics ........................................................................................................64 
10.4.6.1. 
Analysis of Drug Concentration Data .........................................................................64 
10.4.7. 
Analysis of Immunogenicity Data ..............................................................................64 
10.4.8. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ..............................65 
10.5. 
Interim Analysis ..........................................................................................................65 
10.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........65 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................66 
11.1. 
Data Management and Electronic Systems ................................................................66 
11.1.1. 
Data Management .......................................................................................................66 
11.1.2. 
Electronic Systems ......................................................................................................66 
11.2. 
Study Monitoring ........................................................................................................66 
11.2.1. 
Monitoring of Study Sites ...........................................................................................66 
11.2.2. 
Source Document Requirements ................................................................................67 
11.2.3. 
Case Report Form Requirements ................................................................................67 
11.3. 
Audits and Inspections ................................................................................................67 
11.4. 
Study Documentation .................................................................................................68 
11.4.1. 
Certification of Accuracy of Data ...............................................................................68 
11.4.2. 
Retention of Records ..................................................................................................68 
11.4.3. 
Recruitment Strategy ..................................................................................................68 
11.4.4. 
Data Protection ...........................................................................................................68 
12. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................70 
12.1. 
Good Clinical Practice Statement ...............................................................................70 
12.2. 
Informed Consent .......................................................................................................70 
12.3. 
Participants Confidentiality and Data Protection .......................................................70 
12.4. 
Institutional Review Board/Ethics Committee ...........................................................71 
12.5. 
Clinical Study Data Transparency ..............................................................................71 
13. 
PROTOCOL AMENDMENTS ..................................................................................72 
14. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................73 
14.1. 
Premature Termination of the Study ...........................................................................73 
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14.2. 
Close-out of a Site ......................................................................................................73 
15. 
CONFIDENTIALITY ................................................................................................73 
16. 
FINANCING AND INSURANCE .............................................................................73 
17. 
PUBLICATION POLICY ..........................................................................................73 
18. 
REFERENCES ...........................................................................................................74 
19. 
INVESTIGATOR’S AGREEMENT ..........................................................................77 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................78 
 
LIST OF TABLES 
Table 1: 
Study Interventions Administered ..............................................................................37 
Table 2: 
Schedule of Events .....................................................................................................45 
Table 3: 
Schedule of Events: Visit 2 Blood Collection ............................................................48 
 
LIST OF FIGURES 
Figure 1: 
 
 .........24 
Figure 2: 
Study Flow Diagram ...................................................................................................31 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 2, Multicenter, Randomized, Open-Label, Active Control Study of 
REGN7508, a Factor XI Monoclonal Antibody, for Prevention of Venous 
Thromboembolism after Elective, Unilateral, Total Knee Arthroplasty 
(ROXI-VTE II) 
Short Title 
A trial to learn how well REGN7508 works for preventing blood clots after 
a knee replacement in adult participants. 
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 REGN7508 
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 REGN7508 after unilateral 
TKA through time of venography, compared to enoxaparin 
• 
To assess overall safety and tolerability of REGN7508 in 
participants undergoing TKA 
• 
To evaluate the efficacy of REGN7508 in prevention of 
clinically relevant VTE, compared to enoxaparin 
• 
To evaluate the efficacy of REGN7508 in prevention of DVT 
detected by venography, compared to enoxaparin 
• 
To evaluate the pharmacokinetics (PK) of REGN7508 after 
single intravenous (IV) administration 
• 
To assess pharmacodynamic (PD) effects of REGN7508 on 
intrinsic and extrinsic coagulation pathways (ie, activated 
partial thromboplastin time [aPTT], prothrombin time [PT]) 
• 
To assess immunogenicity following a single dose of 
REGN7508 over time 
Study Design 
This is a phase 2 multicenter, multinational, randomized, open-label, active 
control study of a single dose of IV REGN7508 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 1 of 2 treatment arms – 
REGN7508 or enoxaparin – in a ratio of 2:1, 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 the REGN7508 
arm, and 60 participants will be enrolled in the comparator arm, for a total 
of up to approximately 180 participants in the study. 
Participants will be randomized after completion of surgery to receive a 
single dose of REGN7508 
, or enoxaparin 40 mg subcutaneous 
(SC) 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 
 
. 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 using either lower extremity 
ultrasound, conventional venography, computed tomography venography, 
or magnetic resonance venography. 
Participants will be followed until the end-of-study (EOS) visit on 
. 
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 
, 
excluding the screening period. 
End of Study Definition 
The definition for EOS (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 180 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 a primary elective unilateral TKA. 
Treatment(s) 
 
 
Study Drug 
 
Dose/Route/Schedule: 
REGN7508 
  
 
Reference Drug 
Enoxaparin 
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Dose/Route/Schedule: 
40 mg SC, 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 
 (REGN7508 vs enoxaparin).  
 
Secondary: 
The secondary endpoints are: 
• 
Incidence of major bleeding and CRNM bleeding through time 
of venography (or 
, whichever is earlier) 
• 
Incidence of treatment-emergent adverse events (TEAE) 
 
• 
Incidence of major VTE 
 (REGN7508 vs 
enoxaparin) 
• 
Incidence of DVT as measured by venography of the operated 
leg on 
 (REGN7508 vs enoxaparin) 
• 
Concentrations of REGN7508 
 
• 
Change in aPTT from baseline 
 
• 
Change in PT from baseline 
 
• 
Incidence and titer of anti-drug antibodies (ADA) to 
REGN7508 
 
Procedures and Assessments 
Efficacy Procedures: Venography of the operated leg will be performed on 
. 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 monitoring of vital 
signs, physical examination, ECG, assessment for bleeding, laboratory 
testing, and the monitoring and reporting of AEs. 
Blood samples will be collected for drug concentration, Factor XI 
concentration, ADA, and exploratory biomarker and research measurements 
and assessments. 
Statistical Plan 
Statistical Hypothesis: The clinical hypothesis comparing the efficacy of 
REGN7508 to enoxaparin will be assessed through a 
 
 
 
 
 
 
 
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Justification of Sample Size: Up to a total of approximately 
180 participants will be randomized in a 2:1 allocation ratio to REGN7508 
and enoxaparin.  
The sample size was determined through Bayesian approach. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Methods: The treatment effect will be estimated using the 
posterior distribution of ORRE. For comparison of REGN7508 vs 
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) will be 
computed, along with the cumulative posterior distribution, which quantifies 
evidence for all possible treatment effects. 
 
. Bayesian summary statistics including 
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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. 
Safety will be assessed by 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) 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 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 agents that 
reduce the synthesis of FXI or directly inhibit FXI activation or FXIa activity have demonstrated 
increased efficacy in preventing VTE after TKA compared with enoxaparin, without evidence of 
increased bleeding risk (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 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). Selective inhibition of FXI represents a strategy to block 
thrombosis initiated by the intrinsic pathway triggers, while maintaining hemostatic mechanisms 
of the extrinsic pathway. 
REGN7508 is a monoclonal antibody 
 
. Thus, REGN7508 may prevent 
 
 
. 
Single doses of REGN7508 in NHP PK/PD preclinical studies prolonged aPTT 
 
 
. Furthermore, repeat doses of REGN7508 in 
an NHP toxicology study 
 
. These data suggest that REGN7508 may inhibit thrombosis without 
 
risk. 
REGN7508 is being evaluated in an ongoing randomized, double-blind, placebo-controlled 
phase 1 clinical study in healthy volunteers (study R7508-HV-21102). 
 
 
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. No 
significant bleeding events or AESIs have been reported to date in this ongoing study. There has 
been 1 SAE of “injuries following road traffic accident” in the study which occurred in a 
participant that received 
 REGN7508/placebo and was not related to study drug.  
As of 06 Oct 2023, a dose-dependent prolongation of the aPTT was observed with a mean peak of 
about 
 elevation in aPTT observed at the 
 dose level, which was maintained for 
>21 days for all participants. No dose-dependent trends have been observed in the PT, bleeding 
time test or fecal occult blood tests to date. 
Refer to the IB for additional background information on REGN7508 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 DVT of the lower extremities and 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 REGN7508 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 AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
• To evaluate the efficacy of REGN7508 for 
the prevention of VTE after unilateral 
TKA, compared to enoxaparin 
• 
Incidence of confirmed, adjudicated VTE 
 
 
(REGN7508 
vs 
enoxaparin) 
Secondary 
 
• To evaluate the bleeding risk (ie, major and 
CRNM bleeding) of REGN7508 after 
unilateral 
TKA 
through 
time 
of 
venography, compared to enoxaparin 
• 
Incidence of major bleeding and CRNM 
bleeding through time of venography (or 
 whichever is earlier) 
• To assess overall safety and tolerability of 
REGN7508 in participants undergoing 
TKA 
• 
Incidence of TEAEs 
 
• To evaluate the efficacy of REGN7508 in 
prevention of clinically relevant VTE, 
compared to enoxaparin 
• 
Incidence of major VTE 
 
(REGN7508 vs enoxaparin) 
• To evaluate the efficacy of REGN7508 in 
prevention 
of 
DVT 
detected 
by 
venography, compared to enoxaparin 
• 
Incidence of DVT as measured by 
venography of the operated leg on 
 
 (REGN7508 vs enoxaparin) 
• To evaluate the PK of REGN7508 after 
single IV administration 
• 
Concentrations of REGN7508 
 
 
• To assess PD effects of REGN7508 on 
intrinsic 
and 
extrinsic 
coagulation 
pathways (ie, aPTT, PT) 
• 
Change in aPTT from baseline 
 
 
• 
Change in PT from baseline 
 
• To assess immunogenicity following a 
single dose of REGN7508 over time 
• 
Incidence and titer of ADA to REGN7508 
 
Exploratory 
 
• Explore the efficacy of REGN7508 in 
prevention of VTE after unilateral TKA 
through the EOS, compared to enoxaparin 
• 
Incidence of major VTE 
 
• Explore the efficacy of REGN7508 in 
prevention 
of 
symptomatic, 
clinical 
thrombosis, compared to enoxaparin 
• 
Incidence of confirmed symptomatic 
DVT in either leg 
 
 
• 
Incidence of confirmed PE 
 
 
• 
Incidence of fatal PE, which includes 
sudden death for which PE cannot be ruled 
out, 
 
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• Explore the extent of DVT burden on 
venography 
in 
participants 
receiving 
REGN7508 compared to enoxaparin 
• 
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 
• Explore the bleeding risk (ie, major bleeds 
and CRNM) of REGN7508 after unilateral 
TKA through EOS compared to enoxaparin 
• 
Incidence of major bleeding and CRNM 
bleeding 
 
• Explore the occurrence of minor bleeding 
compared to enoxaparin 
• 
Incidence of minimal bleeding 
 
 
• Expand molecular understanding of venous 
thromboembolism, and related diseases 
 
• Explore 
relationships 
between 
PK, 
biomarkers of anticoagulant activity, and 
efficacy 
 
• To study REGN7508 mechanism of action 
in 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 collected from consented 
participants 
 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypotheses 
REGN7508 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 
HIT will not be enrolled. Several risk factors for abnormal bleeding or clotting are also 
exclusionary. Finally, 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 many WOCBP. 
Participants will be stratified by 2 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 LMWH, is approved for the prevention of VTE after orthopedic surgery. In EU 
countries, the approved dose is 40 mg SC once daily (Inhixa [Summary of Product Characteristics], 
2021) (CLEXANE [SmPC], 2022). Dosing will start 
 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) (CLEXANE [SmPC], 
2022) 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.  
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. Enoxaparin will be started 
at 
 post-operatively, consistent with labeled dosing regimens and REGN7508 will 
also be dosed at 
 post-surgery, to allow a direct comparison. Dosing of FXI inhibitors 
in this time range, as well as pre-operatively, has been shown to be well-tolerated in published 
trials of FXI inhibitors (Büller, 2015) (Verhamme, 2021) (Weitz, 2020). 
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Regarding duration of treatment, for participants assigned to study drug treatment with enoxaparin, 
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 7.8.2). 
However, for participants assigned to REGN7508, use of anticoagulants for VTE prophylaxis is 
prohibited, because REGN7508 is expected to elevate aPTT 
, returning to baseline 
by 
 (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 some (one third) 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 independent AC that is 
blinded to treatment assignment (Section 5.3.3). 
The primary efficacy endpoint, which is a composite of confirmed asymptomatic DVT, confirmed 
symptomatic VTE (symptomatic DVT of the leg or nonfatal 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 
 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 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.  
Minor 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 minor bleeding occurs more frequently 
and might therefore be of interest, incidence of minor bleeding will be tabulated separately as an 
exploratory endpoint. Minor bleeding comprises any bleeding AE that does not qualify as either 
major bleeding or CRNM. 
The length of study follow-up is 
. Data from the ongoing FIH study, R7508-HV-21102, 
showed that aPTT had returned to 
 
following a single 
, which is the dose used in this trial (Section 3.2.2). Enoxaparin 
will be dosed through the time of venography (or day 12, whichever is earlier); based on the 
half-life (4.5 to 7 hours), pharmacologically relevant levels are not present a few days after the last 
dose. 
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3.2.2. 
Rationale for Dose Selection  
A single 
 dose of REGN7508 has been selected based on data from the ongoing FIH 
study, a single ascending dose study with REGN7508 in healthy volunteers (study 
R7508-HV-21107), which explores the safety, PK, and PD effects, of single IV doses of 
REGN7508 up to 
. Study participants each 
 of 
REGN7508 or matching placebo and blood samples for measurement of concentrations of 
REGN7508 in serum and PD assays (including 
, PT and aPTT) were collected 
at intervals. REGN7508 exposure (AUC and Cmax) increased proportionally to dose between 
 
. Based on limited data (concentration on day 8 only), exposure appears to increase 
proportionally with the 
 dose. REGN7508 treatment had no apparent effect on PT, but 
produced a rapid, 
 and a rapid, dose-dependent 
increase in aPTT without significant safety, tolerability, or bleeding findings. Refer to the current 
IB edition for preliminary analyses of available data.  
Single doses of REGN7508 
 produced a dose-dependent sustained inhibition of FXI 
activity and increases in aPTT, with a mean 
, which was achieved at 
the 
 dose (Figure 1). Further increase in dose did not result in an increase in the magnitude 
of aPTT prolongation, but in longer duration of the effect. Based on these observed data it is 
expected that a REGN7508 dose of 
 will 
 and 
maximal effects on aPTT 
 
) in all individuals for 
. PD data from study 
R7508-HV-21107 show that aPTT values returned to within 
 
. 
REGN7508 exposures from a 
 dose are projected to be 
 
than corresponding exposures at the non-clinical toxicology NOAEL. Detailed information can be 
found in the current IB edition. 
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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 
 increase from 
baseline) throughout the assessment period eg (Verhamme, 2021). It is therefore anticipated that a 
 dose of REGN7508 will produce maximal efficacy for prevention of VTE in this clinical 
setting. 
3.3. 
Risk-Benefit 
Recognizing 
that 
an 
event 
of 
unforeseen 
circumstances, 
eg, 
COVID-19, 
restrictions/national/international emergencies may 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 
emergency is deemed manageable and no longer interfering with the conduct of trials at individual 
sites, and participants can safely participate in this study.  
The continuity of clinical study conduct dictated by the schedule of events 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. Any study data collected using an alternative 
mechanism will be documented. 
For information regarding the permitted timing of COVID-19 vaccinations, see Section 6.2.2 
Exclusion Criteria, criterion #22, and Section 7.8.1 Prohibited Concomitant Medications and 
Procedures. 
A risk-benefit statement with respect to the overall development program is provided in Section 7 
of the IB. 
3.3.1. 
Risk-Benefit for REGN7508 
REGN7508 is a monoclonal antibody that binds to FXI and 
 
. 
There is no clinical evidence that REGN7508 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 REGN7508 may 
be limited since it has a distinct mode of binding to FXI. Single doses of REGN7508 have been 
studied in healthy volunteers (study R7508-HV-21102) and REGN7508 treatment produced a 
rapid, dose dependent increase in magnitude and duration of aPTT prolongation, 
indicating- inhibition of the intrinsic pathway (refer to the preliminary analyses of available data 
in the current IB edition). The magnitude of aPTT prolongation is comparable to that 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 
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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 REGN7508. 
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.  
 
 
 Details are provided in the IB. 
In toxicology studies with cynomolgus monkeys, 
 
 
 
. No findings of unexplained 
uncontrolled bleeding were found. 
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 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 Criteria (Section 5.1.1), the IDMC will monitor the overall 
rates of both VTE and bleeding and can recommend pausing of REGN7508 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. 
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3.3.2. 
Risk-Benefit for Active Comparator  
As with other anticoagulants, participants taking enoxaparin are to be carefully observed for signs 
of bleeding. In countries where enoxaparin has 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 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 5.3.1). Emergent evaluation and 
management of bleeding should be conducted according to standard local protocols aligned with 
bleeding management guidelines, as described in Section 7.2.  
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) (CLEXANE [SmPC], 
2022). In this study, enoxaparin is being administered at the dose recommended by the EU SmPC. 
Once daily dosing is also expected to improve compliance with dosing. There are no additional 
benefits and risks to participants apart from those described in the approved prescribing 
information for enoxaparin. See Section 3.2.1 for information on the rationale for inclusion of 
enoxaparin. 
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4. 
STUDY VARIABLES  
4.1. 
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. 
4.2. 
Efficacy Variables 
4.2.1. 
Confirmed VTE 
The primary efficacy variable is adjudicated, confirmed VTE as confirmed by a centralized 
independent AC that is blinded to treatment assignment. This is a composite endpoint that includes: 
asymptomatic 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. 
4.2.2. 
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. 
4.3. 
Safety Variables 
The safety variables include physical examination (including temperature, and other vital signs), 
ECGs, laboratory evaluations (hematology, chemistry, urinalysis, other laboratory tests), 
concomitant medications, bleeding events (major bleeding and CRNM bleeding), and AEs 
(Section 8.2.3). 
4.3.1. 
Bleeding Events 
The ISTH criteria will be used for both major bleeding events and CRNM events as described 
below. Minor 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 2 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 2 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 
Minor 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. 
4.4. 
Pharmacokinetic Variables 
The PK variables include the concentration of REGN7508 at each time point. These sampling 
timepoints are specified in Table 2 and Table 3.  
4.4.1. 
Drug Target Variables 
The drug target variable is the concentration of FXI at each time point. These sampling timepoints 
are specified in Table 2 and Table 3. 
4.5. 
Immunogenicity Variables 
The immunogenicity variables include 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. 
4.6. 
Pharmacodynamic and Other Biomarker Variables 
aPTT and PT are the variables for the secondary PD endpoints. 
Additional PD and biomarker variables include 
 
. 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 REGN7508. 
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5. 
STUDY DESIGN  
5.1. 
Study Description and Duration 
This is a phase 2 multicenter, multinational, randomized, open-label, active control study of a 
single dose of IV REGN7508 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 1 of 2 treatment arms – REGN7508 or enoxaparin –in a ratio of 2:1, 
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 the REGN7508 arm, and 
60 participants in the comparator arm, for a total of up to approximately 180 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: 
• REGN7508 
 
• Enoxaparin 40 mg SC, daily 
Dosing with REGN7508 will occur 
 after the end of surgery. 
Dosing with enoxaparin will begin 
 after the end of surgery and will continue through 
the day of venography (or 
, whichever is earlier). Administration of enoxaparin prior to 
TKA surgery is not permitted in this study (Section 6.2.2 Exclusion criterion 10 and Section 7.8.1). 
All investigators must comply and satisfy all requirements for the local risk management plan or 
equivalent for 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 
. 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 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. 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 
, then the venogram is not performed.  
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Participants will continue to be followed until the EOS visit on 
. 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 
5.1.1. 
Study Stopping Criteria 
The IDMC will monitor unblinded data on an ongoing basis to assess the risk/benefit profile of 
REGN7508. 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 REGN7508 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. 
5.1.2. 
End of Study Definition 
A typical definition for EOS (trial) is the global last participant’s last visit, withdraws from the 
study, or lost to follow-up (ie, the study participant can no longer be contacted by the investigator).  
5.2. 
Planned Interim Analysis 
Interim analyses may be conducted either to address requests from regulatory authorities or for 
internal decision-making purposes. The schedule and specifics of any intended interim analyses 
will be clearly outlined in the SAP. The interim data will be evaluated by sponsor team members 
who neither have direct contact with the sites nor participate in the execution of the study. Any IA 
performed will not be used to make decisions regarding the conduct of this study, eg, stop the 
study. 
A description of the statistical methods to be employed is in Section 10.4, and blinding 
implications are discussed in Section 7.6. 
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5.3. 
Study Committees  
5.3.1. 
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 ongoing basis in order to provide, 
in a timely fashion, appropriate recommendations to Regeneron regarding the safety and the 
welfare of the participants exposed to REGN7508. 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. 
5.3.2. 
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. 
5.3.3. 
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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6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PARTICIPANTS 
6.1. 
Number of Participants Planned 
Up to approximately 180 participants will be enrolled in the study. 
6.2. 
Study Population  
The study population will consist of adults who are at least 50 years of age and undergoing a 
primary elective, unilateral TKA. 
6.2.1. 
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 a primary 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 INR and aPTT during screening 
c. Hemoglobin >10 g/dL 
d. ALT or AST <3× ULN, or total bilirubin <2× ULN 
 
Note: Participants with suspected or confirmed Gilbert’s disease can be enrolled in the 
study 
Note: Laboratory assessments for eligibility may be repeated once at the principal 
investigator’s discretion. The participant can be enrolled if the repeat test demonstrates a 
laboratory value that meets eligibility criteria.  
5. Willing and able to comply with clinic visits and study-related procedures including 
venography. 
6. Provide informed consent signed by the study participant.  
6.2.2. 
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 participant 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 
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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.  
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. Has an estimated GFR of <45 mL/min/1.73m2 at the screening visit using one of the 
following formulas: the MDRD equation, the Chronic Kidney Disease Epidemiology 
Collaboration equation, or equivalent equation. 
Note: If participant has a GFR below 45 mL/min/1.73m2, 1 repeat test is allowed. 
Participant may be enrolled if repeat test 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. Participants 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.  
Note: Urine drug screen may be collected according to the site’s operating procedures 
and/or at the discretion of the investigator 
15. Known history of 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 
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b. Participants who require antiplatelet therapy (except for 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 participant by their participation in the study. 
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 
: 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 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 CTFG guidance. Pregnancy testing and 
contraception are not required for women who are postmenopausal or permanently sterile.  
6.3. 
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 8.1.3. 
Rules for discontinuation of study intervention (permanent or temporary) are discussed in 
Section 7.3.2. 
6.4. 
Replacement of Participants 
Participants prematurely withdrawn from the study can be replaced, if needed, to ensure an 
adequate number of evaluable participants. The Medical Director, in cooperation with the Study 
Biostatistician, will decide whether or not to replace a withdrawn participant. 
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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. 
Participants prematurely discontinued from the study/study drug will not be replaced directly. 
However, the sponsor will monitor the dropout rate during the study and may consider enrolling 
more participants to be randomized if the observed dropout rate is higher than 15% in any cohort. 
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7. 
STUDY TREATMENTS  
7.1. 
Investigational and Reference Treatments 
Study interventions are presented in Table 1.  
Treatment arms are: 
• REGN7508 
  
• Enoxaparin 40 mg SC, daily through the time of venography (or day 12, whichever is 
earlier) 
For REGN7508, a single IV dose will be administered 
 after surgery 
 
after removal of the spinal/epidural anesthesia needle/catheter). 
For enoxaparin, dosing will begin 
 after surgery 
 after removal of the 
spinal/epidural anesthesia needle/catheter). Dosing will continue through the time of venography 
(or 
 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. 
A participant diary will be provided to record compliance of at home dosing of enoxaparin. 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 
Enoxaparin 
Intervention Description 
40 mg SC, daily through the time of 
venography 
Dose Formulation 
Pre-filled Syringe-Liquid Solution 
Unit Dose Strength(s) 
40 mg, 0.4 mL, pre-filled syringe  
Dosage Level(s) 
40 mg, daily, through the time of venography 
Route of Administration 
SC injection 
Use 
Active Comparator 
IMP and NIMP/AxMP 
IMP 
Sourcing 
Provided centrally by the sponsor  
7.2. 
Rescue Treatments 
7.2.1. 
Treatment of VTE 
Treatment of symptomatic VTE events that occur during the trial will be managed by the 
investigator per local practice.  
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For participants receiving enoxaparin, increasing the dose of the agent to therapeutic levels 
(according to local standards) may be considered. For participants who develop a symptomatic 
VTE after receiving REGN7508, 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. 
7.2.2. 
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. 
7.3. 
Dose Modification and Study Treatment Discontinuation Rules 
7.3.1. 
Dose Modification 
Dose modification of REGN7508 for an individual participant is not allowed. 
Sites should follow the enoxaparin dosing schedule outlined in Section 7.1. However, enoxaparin 
may be temporarily interrupted or the dose reduced due to medical need, as determined by the 
investigator.  
The criteria for permanent discontinuation of enoxaparin are described in Section 7.3.2.2.  
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7.3.2. 
Study Intervention Discontinuation 
Participants who permanently discontinue from study intervention (REGN7508 or enoxaparin) 
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 8.1.3.  
7.3.2.1. 
REGN7508 Discontinuation 
As this is a single dose study of REGN7508, discontinuation of REGN7508 is not applicable. Refer 
to Section 7.4 for the Management of Acute Reactions including interruption and termination of 
REGN7508 IV infusion. 
7.3.2.2. 
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. 
7.4. 
Management of Acute Reactions  
7.4.1. 
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 9.2.4) and 
graded using the grading scales as instructed in Section 9.2.5. 
7.4.1.1. 
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 
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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. 
7.4.1.2. 
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 
*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). 
7.4.2. 
Acute Injection Reactions 
7.4.2.1. 
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 9.2.1) 
and graded using the grading scales as instructed in Section 9.2.5. 
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.  
7.4.2.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to Section 9.2.5. 
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7.5. 
Method of Treatment Assignment  
Participants will be randomized after surgery to 1 of 2 treatment arms – REGN7508 or enoxaparin 
– in a ratio of 2:1, according to a central randomization scheme provided by an IVRS/IWRS to the 
designated study pharmacist (or qualified designee). Approximately 120 participants will be 
enrolled in the R7508 arm, and 60 participants in the comparator arm for a total of up to 
approximately 180 participants in the study. 
Participants will be stratified based on study site and age (<70 vs ≥70 years of age).  
7.6. 
Blinding/Masking  
This is a phase 2 multicenter, multinational, randomized, open-label, active control study of a 
single dose of IV REGN7508 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 5.3.3). 
7.7. 
Treatment Logistics and Accountability 
7.7.1. 
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. 
REGN7508 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 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.  
7.7.2. 
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 REGN7508 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 will be destroyed with sponsor’s approval or returned 
to the sponsor or designee 
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7.7.3. 
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. 
7.7.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
7.8. 
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. 
• If a participant intends to receive a COVID-19 vaccine (initial series or booster) before 
the start of study drug administration, day 1 of the study and the events associated with 
day 1 should not occur until at least 1 week after any COVID-19 vaccination dosing.  
• Participants currently enrolled in a study involving the administration of investigational 
product who wish to receive a COVID-19 vaccine should postpone the administration 
of the vaccine until 21 days following the last dose of the study drug. 
• If a participant receives a COVID-19 vaccination during the study period despite the 
aforementioned recommendations, either as an initial series or as a booster dose, the 
COVID-19 vaccination will be treated as a concomitant medication. 
7.8.1. 
Prohibited Medications and Procedures 
Administration of enoxaparin prior to TKA surgery is prohibited (Section 6.2.2 Exclusion 
criterion 10). 
Antiplatelet 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 postoperatively 
• Pneumatic compression devices  
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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 REGN7508 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.  
7.8.2. 
Permitted Medications 
Use of standard-of-care medications not listed as prohibited will be allowed.  
For participants assigned to the enoxaparin treatment arm, continued VTE prophylaxis (after 
completion of protocol-defined treatment, ie through the day of venography [
, 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 assigned treatment (such as enoxaparin) 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 6.2.2 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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8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
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 
.  
• 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 
Visit 31,2 
Visit 41 
Visit 5 
End of Study/ Visit 6 
Screening/Baseline: 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
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  
X 
 
 
 
 
 
TKA 
 
X 
 
 
 
 
Randomization 
 
X4 
 
 
 
 
Treatment: 
 
 
 
 
 
 
Administer REGN7508 
 
X5 
 
 
 
 
Administer enoxaparin 
 
X6 
 
 
Participant diary (for self-
administration of 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 
 
 
 
 
 
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Screening 
On-treatment 
Follow-up 
Study Procedure 
Visit 1 
Baseline 
Visit 2 
Visit 31,2 
Visit 41 
Visit 5 
End of Study/ Visit 6 
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 
(REGN7508) 
 
X8 
X 
X 
X 
X 
ADA (REGN7508) 
 
X9 
 
 
 
X 
FXI concentration 
 
X8 
X 
X 
X 
X 
Biomarkers 
Plasma for aPTT, PT (central 
lab) 
 
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 
DNA isolation (optional)10 
 
X11 
 
 
 
 
ADA: anti-drug antibody; aPTT: activated partial thrombin time; GFR: glomerular filtration rate; FSH: follicle stimulating hormone; 
 
; PT: prothrombin time; 
; TKA: total knee arthroplasty; VTE: venous thromboembolism 
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8.1.1. 
Footnotes for 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; vital signs 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
 after the end of surgery, and at least
 after removal 
of the needle/catheter used for spinal/epidural anesthesia. 
6. First dose will be given 
 after the end of surgery. 
7. May include confirmatory studies for DVT of the leg or PE, as described in Section 8.2.2.2. 
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 substudy ICF (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. 
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8.1.2. 
 
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8.1.3. 
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 EOS assessments described in Table 2. 
8.1.4. 
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. 
8.2. 
Study Procedures 
8.2.1. 
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 6.2.1 and Section 6.2.2) 
• Medical History 
• Demographics 
• FSH (women 55 years of age or younger) 
• Calculation of GFR 
8.2.2. 
Efficacy Procedures  
8.2.2.1. 
Venography of the Operated Leg 
Unilateral venography of the operated leg will be performed on 
. 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 8.2.2.2. If the confirmatory tests do not demonstrate DVT/PE, 
or if a distal DVT is demonstrated by ultrasound, then venography on 
 should be 
performed as specified in the protocol. 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 
 
, 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. 
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8.2.2.2. 
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. 
8.2.3. 
Safety Procedures  
8.2.3.1. 
Vital Signs 
Vital signs, including temperature, semi-recumbent blood pressure, pulse, and respiration rate will 
be collected time points according to Table 2. 
8.2.3.2. 
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. 
8.2.3.3. 
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. 
8.2.3.4. 
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.  
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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 4.3.1.  
8.2.3.5. 
Laboratory Testing 
Hematology, chemistry, urinalysis, and the coagulation panel will be analyzed. Plasma for PT and 
aPTT biomarkers will be analyzed (Section 8.2.6). 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 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/ 
bicarbonate 
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) 
• Calculation of GFR 
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• Coagulation panel: INR, aPTT are collected for confirming the enrollment criteria; 
separate samples are also collected for PT and aPTT for biomarkers (Section 8.2.6). 
• 
 
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 
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 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 9.1.1. 
8.2.4. 
Drug Concentration and Factor XI Measurements 
Samples for REGN7508 concentration measurement and FXI concentration measurements will be 
collected at visits listed in Table 2 and Table 3. Actual time of sample collection must be recorded. 
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 8.2.6.5 and Section 8.2.7. 
8.2.5. 
Immunogenicity Measurements and Samples 
Samples for ADA assessment will be collected in serum 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 8.2.6.5 and Section 8.2.7. 
8.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures 
This study includes measurements of aPTT, PT, as well as the 
 
. 
The main PD variable aPTT will be used to measure the anticipated anticoagulant effect of 
REGN7508. PT is a measure of extrinsic and/or common pathway function. 
 
.  
8.2.6.1. 
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 
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monitor REGN7508 effect in the healthy volunteer study R7508-HV-21102. 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. PT 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 R7508-HV-21102 suggest that REGN7508 
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. 
8.2.6.2. 
  
8.2.6.3. 
 
8.2.6.4. 
 
8.2.6.5. 
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 REGN7508, 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 CSR unless biomarker measurements are 
included in primary or secondary objectives. 
8.2.7. 
Future Biomedical Research (Optional) 
Participants who agree to participate in the FBR substudy will be required to consent to this 
optional substudy 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 
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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. 
8.2.8. 
Pharmacogenomic Analysis (Optional) 
Participants who agree to participate in the genomics substudy will be required to consent to this 
optional substudy 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. DNA 
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 
, 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 REGN7508, 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, 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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9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Recording and Reporting Adverse Events  
9.1.1. 
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 10.4.5.1). 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. AEs 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 9.2. 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 SAE (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 9.2 
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 9.1.3.  
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9.1.2. 
Reporting Procedure  
9.1.2.1. 
Individual Case Safety Reporting (ICSR) 
All events (serious and nonserious) must be reported with investigator’s assessment of the event’s 
seriousness, severity, and causality to the (when applicable: blinded) study drug. All SAEs and 
AESIs must be reported to the sponsor (or designee) by completing the AE eCRF immediately, 
but no later than 24 hours of learning of the event. 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.  
9.1.2.2. 
Aggregate Safety Reporting (Development Safety Update Report) 
Relevant safety information on the comparator will be addressed in the REGN7508 Development 
Safety Update Report. 
9.1.3. 
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 
 of the dose of REGN7508, and within 
 of the last dose of the 
comparator enoxaparin. Any complication of pregnancy affecting a female study 
participant or female partner of a male study participant, 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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9.2. 
Definitions 
9.2.1. 
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 PRO, the PRO data are generally not reportable as individual AEs and thus will 
not be reported or reconciled as such. 
9.2.2. 
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 inpatient 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.  
9.2.3. 
Adverse Events of Special Interest 
An AESI (serious or nonserious) 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.  
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9.2.4. 
Infusion Reactions 
Infusion reactions are defined as any relevant AE that occurs during the infusion or within 2 hours 
after the infusion is completed.  
9.2.5. 
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 participant’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 
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 
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9.2.6. 
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  
• Participant’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, participant’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, participant’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: 
− The AE follows a reasonable temporal sequence from a protocol specified 
procedure and cannot be reasonably explained by the nature of the reaction, 
participant’s clinical (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
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• 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, participant’s clinical 
state (eg, disease under study, concurrent diseases, and concomitant medications) 
or other external factors. 
9.3. 
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 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 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. 
9.4. 
Notifying Health Authorities, Institutional Review Board /Ethics 
Committee, and Investigators 
During the study, the sponsor and/or CRO will inform health authorities, IECs/IRBs, and the 
participating investigators of any SUSARs occurring in other study centers or other studies of the 
active study drug (REGN7508; 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 IRB/EC unless delegated to the sponsor. 
Event expectedness for REGN7508 is assessed against the Reference Safety Information section 
of the IB that is effective for expedited safety reporting.  
Event expectedness for enoxaparin 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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10. 
STATISTICAL PLAN 
10.1. 
Statistical Hypothesis  
The clinical hypothesis comparing the efficacy of REGN7508 to enoxaparin will be assessed 
through a Bayesian estimation framework. 
 
 and enoxaparin, 
as well as the OR of confirmed VTE in participants administered REGN7508 as compared to that 
of enoxaparin (ORRE). 
 
is lower in the REGN7508 arm compared to the enoxaparin arm. 
10.2. 
Justification of Sample Size 
Up to total of approximately 180 participants will be randomized in a 2:1 allocation ratio to 
REGN7508 and enoxaparin.  
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10.3. 
Analysis Sets 
10.3.1. 
Efficacy Analysis Sets 
The primary analysis will be conducted in the mITT population, consisting of randomized and 
treated participants that have either an evaluable venogram, a confirmed episode of venous 
thromboembolism, or both. It is based on the treatment received (as treated).  
10.3.2. 
Safety Analysis Set 
The 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. 
10.3.3. 
Pharmacokinetic Analysis Sets 
The PK analysis population includes all participants in the REGN7508 treatment group who 
received study drug and who had at least 1 non-missing result following the first dose of study 
drug. Analysis will be based on the treatment received. 
10.3.4. 
Immunogenicity Analysis Sets 
The ADA analysis set includes all participants who received any study drug and who had at least 
1 non-missing ADA result following the first dose of study drug.  
10.3.5. 
Pharmacodynamic Analysis Set  
The pharmacodynamic analysis set includes all randomized participants who received any study 
drug and who had at least 1 non-missing PD result following the first dose of study drug; it is based 
on the treatment received (as treated). 
10.4. 
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. 
10.4.1. 
Participant Disposition 
The number and percentage of participants screened, randomized, and the primary reasons for 
screening failure and discontinuation will be summarized. 
10.4.2. 
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 4.1 for a full list of demographic and baseline variables. No statistical hypothesis tests will 
be performed on these characteristics.  
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10.4.3. 
Efficacy Analyses 
10.4.3.1. Primary Efficacy Analysis 
The treatment effect will be estimated using the posterior distribution of ORRE. For comparison of 
REGN7508 vs 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) will be computed, along with 
the cumulative posterior distribution, which quantifies evidence for all possible treatment effects. 
. 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, SD, Q1, median, Q3, minimum, and maximum will be reported. 
10.4.4. 
Control of Multiplicity 
Not applicable. 
10.4.5. 
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. 
10.4.5.1. Adverse Events 
Definitions 
For safety variables, the 3 observation periods are defined in Section 8.1. 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 
preferred term 
• TEAEs by severity (according to the grading scale outlined in Section 9.2.5), presented 
by SOC and preferred term 
• Treatment-emergent AESIs  
• Treatment-emergent adverse events leading to permanent treatment discontinuation 
will be summarized by treatment group. 
10.4.5.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized. 
Laboratory Tests 
Laboratory test results will be summarized. 
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Number and percentage of participants with a potentially clinically significant value will be 
tabulated.  
10.4.5.3. 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 arm, exposure will be summarized by the 
number of days that the participant received enoxaparin administration. 
10.4.5.4. 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 REGN7508 arm, the number of planned 
administrations is one. 
10.4.6. 
Pharmacokinetics 
10.4.6.1. 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 REGN7508 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. 
No formal statistical hypothesis testing will be performed.  
10.4.7. 
Analysis of Immunogenicity Data 
Immunogenicity will be characterized by the ADA response observed:  
• 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. 
• Treatment-emergent ADA response: A negative result or missing result at baseline with 
at least one positive post baseline result in the ADA assay. 
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• Treatment boosted ADA response: A positive result at baseline in the ADA assay with 
at least one post baseline titer result ≥9-fold the baseline titer value. 
• 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. 
10.4.8. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
The PD biomarker population will consist of all participants in the PD analysis set. 
For biomarkers including 
 
, 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. 
10.5. 
Interim Analysis  
Interim analyses may be conducted either to address requests from regulatory authorities or for 
internal decision-making purposes. The IA will not be used to make any decisions regarding the 
conduct of this study, eg, to stop the study. Investigators and participants will not be informed 
about the results of the IA, unless required by law. 
10.6. 
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 14.1. 
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11. 
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. The 
planned quality assurance and quality control procedures for the study are described in this section.  
11.1. 
Data Management and Electronic Systems 
11.1.1. 
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 EDC, Medidata Rave. 
11.1.2. 
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 
11.2. 
Study Monitoring  
11.2.1. 
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. 
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 may include: reduced 
source data verification, targeted source data review, the use of off-site and remote monitoring 
visits (as allowed by law), 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 may perform targeted source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
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. 
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11.2.2. 
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. 
11.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic 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. 
11.3. 
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 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. 
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11.4. 
Study Documentation 
11.4.1. 
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. 
11.4.2. 
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.  
11.4.3. 
Recruitment Strategy 
Potential study participants may be identified by the investigator through a variety of means, such 
as publicizing the trial or using existing participant 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 participant-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 participant identifiable 
information as part of recruitment efforts.  
11.4.4. 
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 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
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• 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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12. 
ETHICAL AND REGULATORY CONSIDERATIONS  
12.1. 
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. 
12.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
An ICF can be defined as either a paper consent form or an electronically-delivered consent 
(eConsent). An eConsent may be provided only where allowable by local laws and regulations and 
by site policies. 
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. 
12.3. 
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. 
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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. 
12.4. 
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. 
12.5. 
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 EOS (Section 5.1.2). 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, then 
only final results will be disclosed. 
 
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13. 
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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14. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
14.1. 
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. 
14.2. 
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. 
15. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
16. 
FINANCING AND INSURANCE  
Financing and insurance information is provided as a separate agreement. 
17. 
PUBLICATION POLICY  
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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18. 
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. 
 
Chen M-H,Ibrahim JG. Power prior distributions for regression models. Statistical Science 2000; 
15(1):46-60, 15. 
 
CLEXANE [SmPC].   2022; Sanofi Aventis, SA, Barcelona, Spain. 
 
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. 
 
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. 
 
Ibrahim JG, Chen MH, Gwon Y,Chen F. The power prior: theory and applications. Stat Med 2015; 
34(28):3724-3749. 
 
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 
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non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015; 
13(11):2119-2126. 
 
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. 
 
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. 
 
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. 
 
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. 
 
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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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19. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Phase 2, Multicenter, Randomized, Open-Label, Active 
Control Study of REGN7508, a Factor XI Monoclonal Antibody, for Prevention of Venous 
Thromboembolism after Elective, Unilateral, Total Knee Arthroplasty (ROXI-VTE II) 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 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 
REGN7508, a Factor XI Monoclonal Antibody, for Prevention of Venous Thromboembolism after 
Elective, Unilateral, Total Knee Arthroplasty (ROXI-VTE II) 
Protocol Number: 
R7508-DVT-2360 Amendment 1 
 
See appended electronic signature page 
Sponsor’s Responsible Medical 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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                                        VV-RIM-00353910-1.0 Approved - 12 Jun 2024 GMT-5:00