A Randomized, Double-blind, Double-dummy, Multicenter, Adaptive Design, Dose Escalation (Part 1) and Dose-Response (Part 2) Study to Evaluate the Safety and Efficacy of Intravenous JNJ-64179375 Versus Oral Apixaban in Subjects Undergoing Elective Total Knee Replacement Surgery
Phase: PHASE2
Conditions: VTE Prophylaxis With Anticoagulation After Total Knee Replacement Surgery
Sponsor: Janssen Research & Development, LLC

1
Status: Approved, Date: 11 September 2017
Janssen Research & Development *
Clinical Protocol
A Randomized, Double-blind, Double-dummy, Multicenter, Adaptive Design, 
Dose-Escalation (Part 1) and Dose-Response (Part 2) Study to Evaluate the Safety and 
Efficacy of Intravenous JNJ-64179375 Versus Oral Apixaban in Subjects Undergoing 
Elective Total Knee Replacement Surgery
TEXT- Targeting EXosite-1 Thrombin Inhibition, TEXT – TKR
Protocol 64179375THR2001; Phase 2
AMENDMENT 1
JNJ-64179375
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International, NV; Janssen Pharmaceutica, NV; Janssen, Inc; Janssen 
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout 
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information 
page that accompanies the protocol.
This compound is being investigated in Phase 2 clinical studies.
EudraCT NUMBER: 2016-004550-15
Status:
Approved
Date:
11 September 2017
Prepared by:
Janssen Research & Development, LLC 
EDMS number:
EDMS-ERI-136897708, 2.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................... 8
TIME AND EVENTS SCHEDULE FOR PART 1 AND PART 2 ................................................................. 17
ABBREVIATIONS ...................................................................................................................................... 20
DEFINITIONS OF PHARMACOKINETIC TERMS..................................................................................... 21
1.
INTRODUCTION................................................................................................................................ 22
1.1.
Background .................................................................................................................................... 23
1.1.1.
Nonclinical Studies ..................................................................................................................... 23
1.1.1.1.
Nonclinical Pharmacology ....................................................................................................... 23
1.1.1.2.
Safety Pharmacology .............................................................................................................. 24
1.1.1.3.
Toxicology................................................................................................................................ 24
1.1.1.4.
Pharmacokinetic and Product Metabolism in Animals ............................................................ 25
1.1.2.
Clinical Studies ........................................................................................................................... 26
1.1.2.1.
Overall Study Design and Status............................................................................................. 26
1.1.2.2.
Part 1 ....................................................................................................................................... 26
1.1.2.2.1.
Demographic Characteristics............................................................................................... 26
1.1.2.2.2.
Safety and Tolerability.......................................................................................................... 27
1.1.2.2.3.
Pharmacokinetics................................................................................................................. 31
1.1.2.2.4.
Pharmacodynamics.............................................................................................................. 31
1.1.2.2.5.
Overall Summary ................................................................................................................. 32
1.1.2.3.
Parts 2 and 3 ........................................................................................................................... 33
1.2.
Comparator Drug ........................................................................................................................... 33
1.3.
Overall Rationale for the Study...................................................................................................... 36
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 37
2.1.
Objectives and Endpoints .............................................................................................................. 37
2.1.1.
Objectives ................................................................................................................................... 37
2.1.2.
Endpoints.................................................................................................................................... 38
2.2.
Hypothesis ..................................................................................................................................... 40
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 40
3.1.
Overview of Study Design.............................................................................................................. 40
3.1.1.
Part 1: Single-Ascending Dose................................................................................................... 42
3.1.2.
Part 2: Dose-Response Evaluation ............................................................................................ 42
3.2.
Study Design Rationale.................................................................................................................. 43
4.
SUBJECT POPULATION.................................................................................................................. 47
4.1.
Inclusion Criteria ............................................................................................................................ 47
4.2.
Exclusion Criteria ........................................................................................................................... 49
4.3.
Prohibitions and Restrictions ......................................................................................................... 50
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 51
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 52
7.
TREATMENT COMPLIANCE............................................................................................................ 54
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8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 54
9.
STUDY EVALUATIONS .................................................................................................................... 56
9.1.
Study Procedures........................................................................................................................... 56
9.1.1.
Overview..................................................................................................................................... 56
9.1.2.
Screening Phase ........................................................................................................................ 57
9.1.3.
Double-Blind Dosing Phase........................................................................................................ 58
9.1.4.
Follow-Up Phase ........................................................................................................................ 59
9.2.
Efficacy Evaluations....................................................................................................................... 59
9.2.1.
Assessments for DVT................................................................................................................. 60
9.2.2.
Assessments for PE ................................................................................................................... 60
9.2.3.
Assessments for Other Thrombotic Events................................................................................ 61
9.3.
Pharmacokinetics and Immunogenicity ......................................................................................... 62
9.3.1.
Evaluations ................................................................................................................................. 62
9.3.2.
Analytical Procedures................................................................................................................. 62
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 63
9.3.4.
Immunogenicity Assessments .................................................................................................... 63
9.4.
Pharmacodynamic/Biomarker Evaluations .................................................................................... 64
9.5.
Pharmacokinetic/Pharmacodynamic Evaluations.......................................................................... 65
9.6.
Health Resource Utilization............................................................................................................ 65
9.7.
Safety Evaluations ......................................................................................................................... 66
9.7.1.
Adverse Events........................................................................................................................... 66
9.7.2.
Adverse Events of Special Interest............................................................................................. 67
9.7.2.1.
Bleeding Events....................................................................................................................... 67
9.7.2.1.1.
Classification of Bleeding Events......................................................................................... 67
9.7.2.1.2.
Approach to Subjects With a Bleeding Event ...................................................................... 68
9.7.2.2.
Infusion or Hypersensitivity Reactions .................................................................................... 69
9.7.2.3.
Wound or Joint Complications................................................................................................. 70
9.7.3.
Clinical Laboratory Tests ............................................................................................................ 70
9.7.4.
Electrocardiogram....................................................................................................................... 71
9.7.5.
Vital Signs (temperature, heart rate, blood pressure) ................................................................ 71
9.7.6.
Physical Examination.................................................................................................................. 72
9.8.
Sample Collection and Handling.................................................................................................... 72
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY DRUG/ WITHDRAWAL FROM 
THE STUDY....................................................................................................................................... 73
10.1.
Completion ..................................................................................................................................... 73
10.2.
Discontinuation of Study Drug/Withdrawal from the Study............................................................ 73
11.
STATISTICAL METHODS................................................................................................................. 75
11.1.
Analysis Datasets........................................................................................................................... 75
11.2.
Sample Size Determination ........................................................................................................... 76
11.3.
Efficacy and Bleeding Analyses..................................................................................................... 78
11.4.
Pharmacokinetic Analyses............................................................................................................. 81
11.5.
Immunogenicity Analyses .............................................................................................................. 81
11.6.
Pharmacodynamic/Biomarker Analyses ........................................................................................ 82
11.7.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 82
11.8.
Health Resource Utilization Analyses............................................................................................ 82
11.9.
Safety Analyses ............................................................................................................................. 82
11.10.
Interim Analyses............................................................................................................................. 84
11.11.
Committees .................................................................................................................................... 84
11.11.1.
Operations Committee................................................................................................................ 84
11.11.2.
Independent Data Monitoring Committee................................................................................... 85
11.11.3.
Steering Committee.................................................................................................................... 85
11.11.4.
Clinical Events Committee.......................................................................................................... 85
12.
ADVERSE EVENT REPORTING ...................................................................................................... 86
12.1.
Definitions ...................................................................................................................................... 87
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12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 87
12.1.2.
Attribution Definitions.................................................................................................................. 88
12.1.3.
Severity Criteria .......................................................................................................................... 89
12.2.
Special Reporting Situations.......................................................................................................... 89
12.3.
Procedures..................................................................................................................................... 89
12.3.1.
All Adverse Events...................................................................................................................... 89
12.3.2.
Serious Adverse Events ............................................................................................................. 90
12.3.3.
Pregnancy................................................................................................................................... 91
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 91
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 92
13.1.
Procedures..................................................................................................................................... 92
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 92
14.
STUDY DRUG INFORMATION......................................................................................................... 92
14.1.
Physical Description of Study Drugs.............................................................................................. 92
14.2.
Packaging ...................................................................................................................................... 93
14.3.
Labeling.......................................................................................................................................... 93
14.4.
Preparation, Handling, and Storage............................................................................................... 93
14.5.
Drug Accountability ........................................................................................................................ 93
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 94
16.
ETHICAL ASPECTS ......................................................................................................................... 94
16.1.
Study-Specific Design Considerations........................................................................................... 94
16.2.
Regulatory Ethics Compliance....................................................................................................... 96
16.2.1.
Investigator Responsibilities ....................................................................................................... 96
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 96
16.2.3.
Informed Consent ....................................................................................................................... 98
16.2.4.
Privacy of Personal Data ............................................................................................................ 98
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 99
16.2.6.
Country Selection ....................................................................................................................... 99
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 99
17.1.
Protocol Amendments.................................................................................................................... 99
17.2.
Regulatory Documentation .......................................................................................................... 100
17.2.1.
Regulatory Approval/Notification .............................................................................................. 100
17.2.2.
Required Prestudy Documentation........................................................................................... 100
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 101
17.4.
Source Documentation................................................................................................................. 101
17.5.
Case Report Form Completion .................................................................................................... 102
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 102
17.7.
Record Retention ......................................................................................................................... 103
17.8.
Monitoring .................................................................................................................................... 103
17.9.
Study Completion/Termination..................................................................................................... 104
17.9.1.
Study Completion/End of Study................................................................................................ 104
17.9.2.
Study Termination..................................................................................................................... 104
17.10.
On-Site Audits .............................................................................................................................. 104
17.11.
Use of Information and Publication.............................................................................................. 105
REFERENCES.......................................................................................................................................... 107
INVESTIGATOR AGREEMENT ............................................................................................................... 113
LIST OF ATTACHMENTS
Attachment 1:
Sample Bleeding Risk History .................................................................................. 109
Attachment 2:
Definitions of Bleeding Events.................................................................................. 111
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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Most Frequent (>5% Incidence) Treatment-Emergent Adverse Events - by Body 
System and Preferred Term: Part 1; Safety Analysis Set (Study 64179375EDI1001)............. 28
Table 2: 
Treatment-Emergent Bleeding Adverse Events - by Body System and Preferred Term: 
Part 1; Safety Analysis Set (Study 64179375EDI1001) ........................................................... 30
Table 3:
Mean (±SD) Pharmacokinetic Parameters of JNJ-64179375 Following a Single 30-
minute IV Infusion (0.03 to 2.5 mg/kg, Part 1) in Healthy Male Subjects ................................. 31
Table 4:
ADVANCE-1 and ADVANCE-2 Safety Results ........................................................................ 35
Table 5:
ADVANCE-1 and ADVANCE-2 Efficacy Results...................................................................... 36
Table 6:
Volume of Blood to be Collected From Each Subject............................................................... 57
Table 7:
Assumed Efficacy and Safety Event Rates by Treatment Group in Sample Size 
Determination for Part 2............................................................................................................ 78
FIGURES
Figure 1:
Thrombin Time (s) Mean Ratio to Baseline by Treatment Group Central Specialty 
Laboratory; Safety Analysis Set (Study 64179375EDI1001).................................................... 32
Figure 2:
Probability to Flag a Higher Event Rate in the JNJ-64179375 Group Than in the 
Apixaban Group at a 1-Sided, 10% -Level............................................................................. 77
Figure 3:
Candidate Models for Total VTE (Efficacy) .............................................................................. 79
Figure 4:
Candidate Models for Any Bleeding (Safety)............................................................................ 80
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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
07 Jun 2017
Amendment 1
11 Sep 2017
Amendments below are listed beginning with the most recent amendment.
Amendment 1 (11 September 2017)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.  
The overall reason for the amendment: The overall reason for the amendment is to clarify the distribution of 
normal saline bags and to remove a laboratory test. Normal saline bags will not be provided by the sponsor to all 
sites because some sites will be providing their own or require local or central distribution. 
Applicable Section(s)
Description of Change(s)
Rationale: Removed the text specifying that the sponsor will supply normal saline bags to clarify that sites will 
provide the normal saline bags unless regulations require local or central distribution. 
14.2. Packaging
Removed the 50-mL normal saline bags.
Rationale: Removed the Hemoclot Thrombin Inhibitor assay because additional testing has now shown that the 
assay cannot measure levels of JNJ-64179375 below 20 ug/mL and most results will likely be less than this lower 
limit of quantitation so testing would be of limited value.
Synopsis, Exploratory Objectives, 
Synopsis, Exploratory Endpoints;
Synopsis, Pharmacodynamic/
Biomarker Evaluations; 
Synopsis, Statistical Methods; 
Time and Events Schedule; 
2.1.1. Objectives; 2.1.2. Endpoints; 
3.2. Study Design Rationale; 
9.1.1. Overview (Table 6); 
9.4. Pharmacodynamic/
Biomarker Evaluations; 
11.6. Pharmacodynamic/Biomarker 
Analyses; 11.7. Pharmacokinetic/
Pharmacodynamic Analyses
Removed references to the Hemoclot Thrombin Inhibitor assay.
Rationale: Corrected discrepancies in the number of laboratory samples collected between the Time and Events 
Schedule and Table 6.
9.1.1. Overview, 9.1.1. Overview 
(Table 6); 16.1 Study-Specific 
Design Considerations
Corrected the number of sparse and dense pharmacokinetic (PK) and 
pharmacodynamic (PD) samples to match the Time and Events Schedule, 
while separate samples for immunogenicity were removed as the testing can 
be done on the samples collected for PK. Minor adjustments were also made 
to the volume of each sample based on the final laboratory supplies to be 
provided. Total volume was recalculated and updated.
Rationale: Corrected a typographical error.
11.2. Sample Size Determination 
Corrected a typographical error in sample size determination assumptions.
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Applicable Section(s)
Description of Change(s)
Rationale: Included language for an impartial witness in the event a subject cannot read and/or write since it had 
been inadvertently omitted and subjects that cannot read and/or write are not excluded from the study.
16.2.3. Informed Consent
Included language for an impartial witness in the event a subject cannot read 
and/or write
Rationale: Modifications have been made for consistency with the current version of the protocol template.
Throughout the protocol 
Template changes have been applied, as appropriate.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or editorial changes were made for clarity.
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SYNOPSIS
A Randomized, Double-blind, Double-dummy, Multicenter, Adaptive Design, Dose-Escalation 
(Part 1) and Dose-Response (Part 2) Study to Evaluate the Safety and Efficacy of Intravenous 
JNJ-64179375 Versus Oral Apixaban in Subjects Undergoing Elective Total Knee Replacement 
Surgery
JNJ-64179375 is a first-in-class, recombinant, fully human immunoglobin (Ig) G4 monoclonal antibody 
that binds reversibly with high affinity and specificity to the exosite-1 region of thrombin. JNJ-64179375 
acts as an anticoagulant by blocking only exosite-1-mediated fibrinogen binding to thrombin (and also 
blocks proteinase-activated receptor-1 binding), but does not inhibit the catalytic activity of the protease. 
The mechanism of action is distinct from currently available direct thrombin inhibitors that block the 
active site only (eg, dabigatran, argatroban) or that block both the active site and exosite 1 
(eg, bivalirudin, hirudin) and from other mechanisms that inhibit thrombin generation (eg, Factor Xa 
[FXa] inhibitors). The primary goal of the clinical program will be to demonstrate noninferior efficacy 
with a reduced bleeding risk versus active comparators. However, the possibility of demonstrating 
superior efficacy may be considered based on better compliance with a once-monthly dosing regimen 
and/or the ability to achieve more effective drug levels due to a reduced risk of bleeding (ie, doses not 
limited by bleeding risk).
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives
Part 1
In men and women undergoing primary unilateral total knee replacement (TKR) surgery, after 
single-ascending intravenous (IV) doses of JNJ-64179375 or 10 to 14 days of oral apixaban:
Primary Objective
The primary objective is to assess the safety and tolerability of JNJ-64179375 for each dose level for dose 
escalation within Part 1 and any bleeding events (the composite of major, clinically relevant nonmajor, 
and minimal bleeding events) for the selection of doses for Part 2.
Secondary Objectives

To assess the dose response of JNJ-64179375 for the occurrence of the composite endpoint of any 
bleeding events, the composite endpoint of major or clinically relevant nonmajor bleeding events, 
and the individual components of the composite endpoint of any bleeding event

To assess the dose response of JNJ-64179375 for the prevention of total venous thromboembolism 
(VTE) (proximal and/or distal deep vein thrombosis [DVT, asymptomatic confirmed by venography 
assessment of the operated leg or objectively confirmed symptomatic], nonfatal pulmonary
embolism [PE], or any death) and the individual components of total VTE
Part 2
In men and women undergoing primary unilateral TKR surgery, after a single IV dose of JNJ-64179375 
or 10 to 14 days of oral apixaban:
Primary Objective
The primary objective is to assess the efficacy dose response of JNJ-64179375 for the prevention of total 
VTE (proximal and/or distal DVT [asymptomatic confirmed by venography assessment of the operated 
leg or objectively confirmed symptomatic], nonfatal PE, or any death).
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Key Secondary Objectives

To assess the dose response of JNJ-64179375 for the occurrence of the composite endpoint of any 
bleeding events, the composite endpoint of major or clinically relevant nonmajor bleeding events, 
and the individual components of the composite endpoint of any bleeding event

To assess the dose response of JNJ-64179375 for the prevention of major VTE (asymptomatic 
confirmed by venography assessment of the operated leg or objectively confirmed symptomatic 
proximal DVT, nonfatal PE, or any death) and the individual components of the total VTE endpoint
Common Objectives in Parts 1 and 2
Other Secondary Objectives

To assess the effect of individual doses of JNJ-64179375 compared with apixaban for both efficacy 
and safety endpoints, with the goal to identify a studied or model-predicted dose with the most 
promising benefit-risk profile for a more extensive evaluation in Phase 3

To assess the effect of JNJ-64179375 compared with apixaban on wound or joint complications in 
the operated leg
Exploratory Objectives

To assess the effect of JNJ-64179375 compared with apixaban on other thrombotic events 
(ie, myocardial infarction [MI], ischemic stroke, peripheral arterial embolism)

To evaluate the cost effectiveness of JNJ-64179375 compared with apixaban based on health 
resource utilization

To assess the pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships of 
JNJ-64179375 in men and women undergoing primary unilateral TKR surgery and the relation of 
these measures to efficacy and safety endpoints (eg, exposure-response analyses)

To evaluate the PD assays (thrombin time [TT], ecarin clotting time [ECT], prothrombin time [PT], 
activated partial thromboplastin time [aPTT], and D-dimer) to determine the most appropriate tests 
to measure the effect of JNJ-64179375
Endpoints
The endpoints of the study will be the same for Parts 1 and 2 although the focus of Part 1 will be 
primarily dose escalation based on safety while the focus of Part 2 will primarily be the assessment of 
dose response in both safety and efficacy.
Common Endpoints in Parts 1 and 2
Primary Safety Endpoint
The primary safety endpoint is any bleeding event defined as the composite of major, clinically relevant 
nonmajor, and minimal bleeding events assessed through the Day 10-14 visit.
Primary Efficacy Endpoint
The primary efficacy endpoint is total VTE, defined as the composite of proximal and/or distal DVT 
(asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed 
symptomatic), nonfatal PE, or any death assessed through the Day 10-14 visit.
Key Secondary Endpoints
The key secondary endpoints are the assessment of the primary endpoints through the Week 18 visit, and:
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
All individual components of the primary safety endpoint (major bleeding, clinically relevant 
nonmajor bleeding, and minimal bleeding)

Composite of major and clinically relevant nonmajor bleeding

Major VTE, a composite of proximal DVT (asymptomatic confirmed by venography assessment of 
the operated leg or objectively confirmed symptomatic), nonfatal PE, or any death

All individual components of the primary efficacy endpoint (ie, proximal and/or distal DVT 
[asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed 
symptomatic], nonfatal PE, any death)
Other Secondary Endpoints

Any wound or joint complication in the operated leg
Exploratory Endpoints

Other thrombotic events (ie, MI, ischemic stroke, peripheral arterial embolism)

The total length of the initial hospitalization, including the level of care and discharge destination

The incidence of rehospitalization for any reason

The number of scheduled and unscheduled visits, including the associated cost to healthcare 
providers for study outcomes, any other medical reasons, and the diagnostic procedures used in 
relation to study endpoints

Calculation of PK parameters, eg, total clearance of the drug after IV administration (CL), volume of 
distribution (Vd), terminal half-life (t1/2), area under the plasma concentration versus time curve from 
time 0 to infinity (AUCinf), and maximum concentration during a dosing interval (Cmax)

Changes in PD by dose: TT, ECT, PT, aPTT, and D-dimer

Changes in PD assays as listed above by concentration metrics (AUCinf, Cmax, or time-matched 
concentrations)
Refer to Section 9, Study Evaluations for related evaluations.
Hypothesis
In Part 1, a range of doses of JNJ-64179375 will be assessed to determine if it is sufficiently safe to 
proceed with Part 2 of the study. No formal hypothesis testing will be conducted for Part 1. In Part 2, the 
clinical hypothesis is to demonstrate proof-of-efficacy based on the total VTE endpoint. This can be 
achieved by either showing that JNJ-64179375 has a statistically significant dose-response trend with 
respect to the total VTE endpoint, or the combined dose groups of JNJ-64179375 have a total VTE event 
rate of less than 30%.
OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, double-dummy, active-controlled, multicenter, dose-escalation and 
dose-response study of JNJ-64179375. The study has 2 parts, dose-escalation and dose-response 
evaluation, and will be conducted in subjects undergoing primary unilateral elective TKR surgery. Part 1 
will assess the safety of single-ascending IV doses of JNJ-64179375 while Part 2 will confirm the safety 
of the doses selected from Part 1 and will assess the efficacy dose-response relationship with respect to 
the selected doses in the parallel groups. Subjects will participate in either Part 1 or Part 2 of the study 
only.
For each subject in each part, the study will be conducted in 3 phases: an up to 30-day screening phase 
before surgery, a 14-day double-blind dosing phase, and a 16-week follow-up phase. Unscheduled visits 
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may be performed at the discretion of the investigator for the assessment of any potential bleeding or 
efficacy endpoint events. The total duration of the subject’s participation in Part 1 or Part 2 after 
randomization will be approximately 18 weeks.
Screening for eligible subjects in Parts 1 and 2 may be done up to 30 days before randomization, pre- or 
postoperatively. Following primary unilateral elective TKR surgery, eligible subjects will be randomly 
assigned to treatment with either JNJ-64179375 or apixaban. All subjects will receive a single IV infusion 
of JNJ-64179375 or JNJ-64179375 placebo and oral apixaban or matching apixaban placebo the day after
TKR surgery (Day 1, 0 hours), while the subject is still hospitalized and within a minimum of 12 hours 
and a maximum of 24 hours after the end of the TKR surgery, defined as the time of wound closure.
Following discharge or transfer to an alternate facility, subjects in both parts will continue to take 
apixaban or matching apixaban placebo twice daily to complete a total of 10 to 14 days of dosing. 
Unilateral venography assessment of the operated leg will be performed after the last dose of apixaban or 
matching apixaban placebo is taken.
Subjects in both Parts 1 and 2 will return to the site for study-related procedures 5, 10, and 18 weeks after 
TKR surgery. Safety evaluations will include the monitoring of all nonserious and serious adverse events, 
(including adverse events of special interest: bleeding events, infusion reactions, hypersensitivity 
reactions, and wound or joint complications), clinical laboratory tests (ie, hematology, clinical chemistry, 
urinalysis), vital signs measurements (blood pressure, pulse/heart rate [HR], temperature), and physical 
examinations. Pharmacokinetics (dense and sparse), PD, and immunogenicity samples will be collected 
and health resource utilization will also be assessed.
An Operations Committee (OC), Independent Data Monitoring Committee (IDMC), Steering Committee 
(SC), and independent Clinical Events Committee (CEC) will be commissioned for this study.
The number of cohorts and the size of each cohort in Part 1 may be adjusted based on the ongoing 
unblinded data review by the OC. Additionally, an unblinded data review is planned for Part 1 after all 
subjects are expected to have completed the Day 10-14 visit to determine the dose range and doses of 
JNJ-64179375 for Part 2. An adaptive approach will be used to guide decisions to drop and/or add the 
doses of JNJ-64179375 and adjust the randomization ratio based on available efficacy, safety, PK, and 
PD data at 2 planned, unblinded interim analyses in Part 2. The sponsor will also be responsible for 
conducting an unblinded administrative interim analysis after all subjects are expected to have completed 
the Day 10-14-visit in Part 2 to facilitate additional study planning.
SUBJECT POPULATION
Subjects will be men and women of non-childbearing potential, at least 50 years of age or older who have 
undergone an elective primary unilateral TKR and are considered to be medically appropriate for 
postoperative anticoagulant prophylaxis as determined by the investigator on the basis of the physical 
examination, medical history, vital signs measurements, and clinical laboratory tests performed as part of 
screening for elective TKR surgery and any examinations performed as part of standard postoperative 
care following surgery. It is estimated that approximately 1,500 subjects will be randomly assigned to 
treatment in this study. Part 1 will include up to approximately 300 subjects and Part 2 is estimated to be
1,200 subjects. Subjects who are withdrawn early from the study will not be replaced.
DOSAGE AND ADMINISTRATION
In both Parts 1 and 2, subjects will be randomly assigned to receive an active single IV dose of 
JNJ-64179375 or apixaban 2.5 mg given orally twice daily for 10 to 14 days. The administration of the 
study drugs will begin the day after the TKR surgery (Day 1, 0 hours), while the subject is still 
hospitalized and within a minimum of 12 hours and a maximum of 24 hours after the end of the 
TKR surgery, defined as the time of wound closure. Within that timeframe, both the single IV infusion 
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and the oral study drug should be administered as close as possible to each other, with up to a maximum 
of 60 minutes between the start of the IV infusion and the first dose of the oral study drug. 
All study drug administrations of JNJ-64179375 must be calculated based on the subject’s weight on 
Day -1 or prior to dosing on Day 1. The single infusion of JNJ-64179375 or JNJ-64179375 placebo 
(saline) will be administered under the supervision of the investigator or his/her designee over a period of 
approximately 30 minutes by infusion pump or by gravity flow using a flow regulator. A physician must 
be immediately available at the study site at all times during the administration of the study drug infusion.
The first dose of apixaban or matching apixaban placebo will be administered as previously described. 
Subjects will receive apixaban or matching apixaban placebo twice a day while hospitalized and will be 
given a supply of apixaban or matching apixaban placebo at the time of discharge or transfer to an 
alternate facility, with instructions to take the study drug orally, twice a day at approximately the same 
times each day to complete a total of 10 to 14 days of dosing. Apixaban or matching apixaban placebo 
should be swallowed with water, with or without food. 
Part 1 Dosing
Eligible subjects in Part 1 will be randomly assigned to a single-ascending IV dose of JNJ-64179375 or 
apixaban 2.5 mg given orally twice daily for 10 to 14 days. Six cohorts of up to approximately 50 unique 
subjects per cohort (total of up to approximately 300 unique subjects) are planned but the number of 
cohorts and the size of each cohort may be adjusted based on the ongoing unblinded data review by the 
OC. Within each cohort, subjects will be randomized in a 4:1 ratio to JNJ-64179375 or apixaban, 
respectively (ie, approximately 40 subjects to JNJ-64179375: approximately 10 subjects to apixaban). 
JNJ-64179375 will be administered in a dose-escalation manner, with planned doses of 0.3, 0.6, and 
1.2 mg/kg in Cohorts 1, 2, and 3, respectively. 

Cohort 1: JNJ-64179375 0.3 mg/kg IV/JNJ-64179375 placebo (saline) IV infusion and matching 
apixaban placebo/apixaban, orally twice a day for 10 to 14 days

Cohort 2: JNJ-64179375 0.6 mg/kg IV/JNJ-64179375 placebo (saline) IV infusion and matching 
apixaban placebo/apixaban, orally twice a day for 10 to 14 days

Cohort 3: JNJ-64179375 1.2 mg/kg IV/JNJ-64179375 placebo (saline) IV infusion and matching 
apixaban placebo/apixaban, orally twice a day for 10 to 14 days
The doses of JNJ-64179375 to be used in the optional cohorts will be dependent on the available 
preliminary safety, tolerability, efficacy, PK, and PD data obtained from the preceding cohorts. Doses 
within the optional cohorts will either be new doses within the range of 0.1 to 1.8 mg/kg not previously 
administered in the preceding cohorts, or doses from the preceding cohorts, which may be repeated, as 
needed. 
After all of the subjects in Part 1 are expected to have completed the Day 10-14 visit, an unblinded data 
review will be conducted by the OC, SC, IDMC, and sponsor to determine the dose range and doses for 
Part 2.
Part 2 Dosing
Part 2 of this study has an adaptive design, with the intent to optimize data collection for the 
dose-response evaluation using multiple comparison procedure and modeling (MCP-Mod). Eligible 
subjects prior to the first interim analysis in Part 2 will be randomly assigned equally to 1 of up to 
5 parallel treatment groups, including up to 4 dose levels of JNJ-64179375, given as a single, active 
IV infusion, or oral apixaban 2.5 mg twice daily for 10 to 14 days. The number of doses and 
randomization ratio after the 2 interim analyses will depend on the interim analysis results. However, the 
number of ongoing doses of JNJ-64179375 in the study is not expected to exceed 4 doses.
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
Group A: JNJ-64179375 Dose A mg/kg IV and apixaban placebo orally twice a day for 
10 to 14 days

Group B: JNJ-64179375 Dose B mg/kg IV and apixaban placebo orally twice a day for 10 to 14 days

Group C: JNJ-64179375 Dose C mg/kg IV and apixaban placebo orally twice a day for 10 to 14 days

Group D: JNJ-64179375 Dose D mg/kg IV and apixaban placebo orally twice a day for 
10 to 14 days

Group E: JNJ-64179375 placebo (saline) IV and apixaban 2.5 mg orally twice a day for 
10 to 14 days
EFFICACY EVALUATIONS
Efficacy evaluations will include unilateral venography assessment of the operated leg and assessments of 
symptomatic DVT, PE, death, or other thrombotic events (ie, MI, ischemic stroke, and peripheral arterial 
embolism) to assess the primary, secondary, and exploratory efficacy outcomes.
Venography assessments of the operated leg will be performed by injecting contrast agent into a foot vein 
and obtaining x-ray images of the proximal and distal leg veins. Evaluable venography assessments
require the visualization of all of the deep veins except for the muscular, anterior tibial, and deep femoral 
veins. An ultrasound will be performed in those subjects with suspected symptomatic DVT prior to the 
Day 10-14 visit. In these cases, if the ultrasound confirms symptomatic proximal DVT, a subsequent 
venography assessment is not required. If the ultrasound is negative or confirms a distal DVT, the 
venography assessment should be conducted on the Day 10-14 visit.
For all subjects with symptoms of PE, spiral computed tomography (CT), pulmonary angiography, or 
perfusion/ventilation lung scintigraphy combined with chest radiography will be performed. If a subject is 
diagnosed with a PE meeting the specified definitions, a subsequent venography assessment of the 
operated leg is not required.
Other thrombotic events will include MI, ischemic stroke, and peripheral arterial embolism. In addition, 
events that appear suggestive of study endpoints (eg, transient ischemic attack [TIA], unstable angina) 
will be reported by the investigator and reviewed by the CEC to ascertain if a thrombotic event has 
occurred.
PHARMACOKINETIC EVALUATIONS
Samples for analysis of JNJ-64179375 plasma concentration will be collected for all subjects over time as 
specified in the Time and Events Schedule but will only be analyzed for subjects randomly assigned to 
JNJ-64179375. Dense PK sampling will be conducted at all sites for subjects at all visits in Part 1 until 
approximately up to the first 200 subjects have been randomized. Thereafter, the remaining subjects in 
Part 1 and all subjects in Part 2 will have PK blood samples collected at a limited number of visits 
(ie, sparse PK sampling). The exact date and time of each PK blood sample collection will be recorded
even if the time deviates slightly from the scheduled time of collection. Subjects who experience a 
bleeding event or symptomatic thrombotic event should have PK samples collected as soon as practically 
possible after the event occurs. 
The PK parameters to be calculated following the single IV dose of JNJ-64179375 will include, but are 
not limited to, the following: Cmax, AUCinf, t1/2, CL, and apparent volume of distribution in the terminal 
phase (VZ). Additional PK parameters may be determined, as appropriate.
A separate population PK modeling plan will be developed before the first subject is consented and the
population PK modeling results will be reported separately, in a document other than the clinical study 
report (CSR).
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IMMUNOGENICITY EVALUATIONS
Blood samples for antibodies to JNJ-64179375 will be collected from all subjects according to the Time 
and Events Schedule but will only be analyzed in plasma samples for subjects randomized to 
JNJ-64179375. The exact date and time of each blood sample collection will be recorded. Plasma samples 
will be screened for antibodies binding to JNJ-64179375 and the titer of confirmed positive samples will 
be reported. Other analyses (eg, neutralization capacity) may be performed to further characterize the 
immunogenicity of JNJ-64179375.
PHARMACODYNAMIC/BIOMARKER EVALUATIONS
All subjects will have plasma samples collected to assess PD markers as specified in the Time and Events 
Schedule. The assay plan is designed to assess target engagement and the mechanism of action with a 
battery of PD assessments. Pharmacodynamic evaluations will include the coagulation assays 
(ie, TT, ECT, PT, aPTT) and a D-dimer assessment. Subjects who experience a bleeding event or 
symptomatic thrombotic event should have PD samples (except D-dimer) collected as soon as practically 
possible after the event occurs. 
SAFETY EVALUATIONS
The safety and tolerability of JNJ-64179375 will be evaluated throughout the study according to the time 
points provided in the Time and Events Schedule by the assessment of adverse events, including serious 
adverse events, adverse events of special interest (ie, bleeding events, infusion reactions, hypersensitivity 
reactions, and wound or joint complications), clinical laboratory tests (ie, hematology, clinical chemistry, 
urinalysis), vital signs measurements (blood pressure, pulse/HR, temperature), and physical examinations. 
Safety evaluations may also be performed at unscheduled time points, if deemed by the investigator or 
appropriate designee as necessary to ensure the safety of the subject. All suspected symptomatic efficacy
(thrombotic) events will also be captured as adverse events of special interest.
STATISTICAL METHODS
A total of 1,500 subjects are planned for this study, of which up to 300 subjects will be enrolled in Part 1 
and the remainder for the entire study will be enrolled in Part 2. In Part 1, the sample size is not based on 
hypothesis testing but rather on making a preliminary assessment of the bleeding risk for the doses of 
JNJ-64179375. 
In Part 1, the intent is to escalate across the planned doses (0.3 to 0.6 to 1.2 mg/kg) of JNJ-64179375 
based on the OC review of the totality of the data but with a focus on bleeding events. Specific analyses 
to be reviewed (eg, continual reassessment or escalation with overdose control methods) and dose-
escalation decision guidelines will be included in the OC charter. After all subjects in Part 1 are expected 
to have completed the Day 10-14 visit, an unblinded data review is planned and the selection of the dose 
range and doses for Part 2 will be based on the evaluation of the totality of the data but with a focus on 
the any bleeding and total VTE endpoints. Analyses to aid in dose selection will be prespecified in the 
OC charter and the Part 1 statistical analysis plan (SAP). No formal hypothesis testing is planned for 
Part 1 due to the limited sample size. Historical apixaban bleeding and VTE event rates may also be 
considered in making decisions. 
In Part 2, this study will use an adaptive design intended to optimize data collection for dose-response 
modeling. In Part 2, the primary goal is to assess the efficacy (total VTE endpoint) dose-response 
relationship of JNJ-64179375. A hybrid methodology that combines aspects of multiple testing with 
modeling techniques (MCP-Mod) will be used for evaluating dose-response trends and estimating the 
dose-response relationships for the efficacy and bleeding endpoints for JNJ-64179375. The sample size 
for Part 2 may be adjusted based on the observed bleeding and total VTE event rates in Part 1.
Assuming that 80% of the venography assessments are evaluable and the true underlying total VTE event 
rates are 15%, 10%, 8%, and 6% at potential doses of JNJ-64179375 of 0.3, 0.6, 0.9, and 1.2 mg/kg, 
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Approved, Date: 11 September 2017
respectively, with a total sample size of 1,200 subjects, the study is expected to have over 90% power to 
declare proof-of-efficacy, which is defined as either a statistically significant dose-response trend or a
total VTE event rate lower than 30% in the pooled doses of JNJ-64179375 at a 1-sided, 2.5% -level. The 
exact power will vary because of the nature of the adaptive study design.
For comparison with apixaban in Part 2, if the true underlying total VTE and any bleeding event rates are 
as specified in the table below, a simulation study demonstrates that there will be approximately 
90% probability to identify a dose within the dose range of 0.3 to 1.2 mg/kg, of which both the 
model-predicted total VTE and any bleeding event rates met the prespecified noninferiority (NI) criterion 
(the 
upper 
bound 
of 
the 
1-sided 
90% 
confidence 
interval 
[CI]
for 
the 
odds 
ratio 
[JNJ-64179375 to apixaban] is equal to or lower than 1.5 for total VTE and any bleeding events).
Assumed Efficacy and Safety Event Rates by Treatment Group in Sample Size Determination for Part 2
JNJ-64179375
Apixaban
0.3 mg/kg
0.6 mg/kg
0.9 mg/kg
1.2 mg/kg
2.5 mg bid
Total VTE
(Efficacy)
15%
10%
8%
6%
15%
Any Bleeding
(Safety)
5%
6%
7%
8%
8%
bid=twice daily; VTE=venous thromboembolism
Two planned, unblinded interim analyses will be conducted in Part 2 by the IDMC as part of the adaptive 
approach that will be used to guide decisions to drop and/or add doses of JNJ-64179375 and adjust the 
randomization ratio based on available efficacy, safety, PK, and PD data. A futility analysis will also be 
included as part of both interim analyses. Further details related to the interim analyses and decision 
guidelines will be specified in the IDMC charter and Part 2 SAP. In addition, an unblinded administrative 
interim analysis is planned to be conducted by the sponsor after all subjects are expected to have 
completed the Day 10-14 visit in Part 2 to facilitate additional study planning.
Plasma concentrations of JNJ-64179375 will be listed for all subjects by time of collection and dose level. 
For each dose, descriptive statistics, including mean, median, standard deviation (SD), and coefficient of 
variation will be calculated for the plasma concentrations at each nominal sampling time. In addition, a 
population PK model will be developed and dependence of PK of JNJ-64179375 on population covariates 
(eg, demographics, laboratory variables) will be evaluated. 
The incidence of antibodies to JNJ-64179375 will be summarized for all subjects who receive a dose of 
JNJ-64179375 and have at least 1 appropriate sample obtained after study drug administration for the 
detection of antibodies to JNJ-64179375. A listing of subjects who are positive for antibodies to 
JNJ-64179375 will be provided. The maximum titers of antibodies to JNJ-64179375 will be summarized 
for subjects who are positive for antibodies to JNJ-64179375. Analyses of the impact of immunogenicity 
on PK, PD, PK/PD, efficacy, and safety endpoints will be performed to further characterize the immune 
responses that are generated.
Descriptive statistics including mean, median, SD, minimum, and maximum will be provided for the 
PD parameters of TT, ECT, PT, aPTT, and D-dimer. The parameters of TT, PT, and aPTT may be 
statistically analyzed using mixed models. Other PD parameters may be analyzed similarly.
The PK/PD relationships will be investigated graphically and, if appropriate, may be further analyzed 
using suitable statistical methods. Preliminary assessments of these relationships will be made available 
to the IDMC at both interim analyses to support their evaluations.
Health resource utilization will be descriptively summarized by treatment group.
All safety data will be fully listed. The reporting of the safety data of all subjects receiving at least 
1 active dose of JNJ-64179375 or apixaban will include the incidence and type of adverse events, plus 
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absolute values and changes in blood pressure (systolic and diastolic), HR, clinical laboratory data, and 
physical examinations from predose to the final postdose time point.
Based on the mechanism of action of JNJ-64179375 and given that it is a monoclonal antibody, adverse 
events of special interest will include bleeding events, infusion reactions, hypersensitivity reactions, and 
wound or joint complications. Subjects with adverse events of special interest may be counted or listed 
using standardized Medical Dictionary for Regulatory Activities (MedDRA) queries (SMQs)
(eg, hemorrhage excluding laboratory terms SMQ). All suspected symptomatic efficacy (thrombotic) 
events will also be captured as adverse events of special interest.
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TIME AND EVENTS SCHEDULE FOR PART 1 AND PART 2
Phase
Screeninga
Double-Blind Dosing
Follow-upb
Unscheduled 
Visitf
Up to
Day -30
Day 1
Day 
2
Day 
3d
Day 
7d
Day
10-14
(EOD/
EW)e
Week 5
(±1 wk)
Week 10
(±2 wk)
Week 18
(±2 wk)
Study Procedures
0 h
1 hc
4 h
Screening/Baseline/Administrative
Informed consentg
X
Inclusion/exclusion criteriah
X
X
Medical history and demographics
X
Bleeding risk history
X
Relevant prestudy therapy
X
ECG
X
Total knee replacement surgeryj
X
Study Drug Administration
Randomization 
X
Dispense/administer study drugk
X
X
X
X
X
Drug accountability
X
Safety Assessments
Physical examinationl
X
X
X
Vital signsm
X
Xi
X
X
X
X
X
X
X
Efficacy Assessments
Venography of the operated leg
Xn
Symptomatic thrombotic eventso
X
X
X
X
X
X
X
X
X
X
X
Clinical Laboratory Assessments
Hematology
Xi
X
X
X
X
Serum chemistry
Xi
X
X
X
X
Urinalysis
Xi
X
X
X
Pharmacokinetics/Immunogenicity
Dense PK sample collectionp
X
X
X
X
X
X
X
X
X
X
Sparse PK sample collectionq
X
X
X
X
X
Xr
X
ADA sample collection
Xi
X
X
X
X
Pharmacodynamics
PD coagulation sample collections
Xi
X
X
X
X
D-dimer
Xi
X
X
Ongoing Subject Review
Health resource utilization
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
NCT03251482

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Clinical Protocol 64179375THR2001 Amendment 1
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Approved, Date: 11 September 2017
Phase
Screeninga
Double-Blind Dosing
Follow-upb
Unscheduled 
Visitf
Up to
Day -30
Day 1
Day 
2
Day 
3d
Day 
7d
Day
10-14
(EOD/
EW)e
Week 5
(±1 wk)
Week 10
(±2 wk)
Week 18
(±2 wk)
Study Procedures
0 h
1 hc
4 h
Adverse events monitoring, including 
adverse events of special interest (ie, 
bleeding events, infusion reactions, 
hypersensitivity reactions, wound or joint 
complications)t
X
X
X
X
X
X
X
X
X
X
X
X
Key: ADA=antidrug antibody; ECG=electrocardiogram; EOD=end of dosing; EW=early withdrawal; h=hour; PD=pharmacodynamic(s); PK=pharmacokinetic(s); 
wk=week
a
Screening for eligible subjects in Parts 1 and 2 may be done up to 30 days before randomization, pre- or postoperatively. Final eligibility must be confirmed after 
surgery, prior to randomization.
b
Reasonable attempts should be made to conduct the follow-up visit(s) at the scheduled time points. If a subject withdraws from the study before the end of the
follow-up phase and is unwilling or unable to return for follow-up visits in person or have follow-up contacts, the study site should collect as much follow-up visit 
information as possible, including contacting the subject or subject’s representative or health care professional by telephone or mail.
c
One hour (10 minutes) from the start of the 30-minute infusion.
d
Study procedures will be conducted on Days 3 and 7 only for those subjects who are still hospitalized.
e
Subjects who do not receive the full infusion of JNJ-64179375 or prematurely discontinue dosing (ie, EW) with apixaban or matching apixaban placebo before the 
end of the double-blind dosing phase will be instructed to return to the study site at the originally scheduled Day 10-14 visit to conduct assessments, including the 
venography assessment of the operated leg (unless a pulmonary embolism [PE] or symptomatic proximal deep vein thrombosis [DVT] has been diagnosed), and to 
complete the remaining visits through the Week 18 assessments.
f
At the discretion of the investigator, subjects may return to the study site between scheduled visits. Subjects should return to the study site for the assessment of 
any potential bleeding or efficacy endpoint events. Unscheduled PK and PD samples (except D-dimer) should be collected as soon as practically possible for any 
subject who experiences symptomatic thrombotic or bleeding events.
g
At the time of informed consent, 2 alternative means of contact for the each subject will be collected (eg, contact information of the subject’s children, spouse,
significant other, caretaker, legal representative, or health care professional).
h
The investigator will need to determine if the subject is medically appropriate for postoperative anticoagulant prophylaxis on the basis of physical examination, 
medical history, vital signs measurements, and clinical laboratory tests performed as part of screening for elective TKR surgery and any examination performed as 
part of standard postoperative care following surgery.
i
Procedures should be conducted prior to the first dose of the study drug.
j
Details regarding the total knee replacement (TKR) surgery and the post-surgery management (eg, type of anesthesia, procedure duration, cement use, tourniquet 
use and duration, drain use and volume, use of all mechanical venous thromboembolism [VTE] prophylaxis methods) will be collected in the electronic case report 
form (eCRF).
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k
The day after TKR surgery (Day 1, 0 hours), while the subject is still hospitalized and within a minimum of 12 hours and a maximum of 24 hours after the end of 
the TKR surgery, defined as the time of wound closure, all subjects will receive a single IV infusion of JNJ-64179375 or JNJ-64179375 placebo and oral apixaban 
or matching apixaban placebo. The first dose of apixaban or matching apixaban placebo will be administered while the subject is hospitalized, with up to a 
maximum of 60 minutes between the start of the IV infusion and the first dose of oral study drug. Subjects will receive apixaban or matching apixaban placebo 
twice a day while hospitalized and will be given a supply of apixaban or matching apixaban placebo at the time of discharge or transfer to an alternate facility, with 
instructions to take the study drug orally, twice a day at approximately the same times each day to complete a total of 10 to 14 days of dosing.
l
Height and weight should be obtained at the screening visit, with weight only on Day -1 or prior to dosing on Day 1 and the final visit. An assessment of the wound 
will be made at all visits as part of the adverse event assessment and the final physical examination will assess the range of motion of the operated joint.
m
Blood pressure and pulse/heart rate (HR) measurements will be assessed with subjects in the supine position with a completely automated device and should be 
preceded by at least 5 minutes of rest. The subject’s temperature should also be obtained.
n
Subjects who complete dosing with apixaban or matching apixaban placebo will return to the study site for final EOD assessments (at the Day 10-14 visit, EOD), 
at which time a unilateral venography assessment of the operated leg will be performed within 24 hours of the last dose of apixaban or matching apixaban placebo. 
If dosing with apixaban or matching apixaban placebo is prematurely discontinued, the venography assessment should be completed on the originally scheduled 
Day 10-14 (EOD) visit, not earlier. If a subject has suspected symptomatic DVT prior to the Day 10-14 visit, an ultrasound will be performed. If the ultrasound 
confirms symptomatic proximal DVT, a subsequent venography assessment is not required. If the ultrasound is negative or confirms a distal DVT, the venography 
assessment should be conducted on the Day 10-14 visit. In addition, if the subject is diagnosed with a PE, a venography assessment of the operated leg is not 
required.
o
Suspected symptomatic efficacy (thrombotic) events (DVT, PE, death, myocardial infarction, ischemic stroke, peripheral arterial embolism) will be reported by the 
investigator and reviewed by the Clinical Events Committee to ascertain if a thrombotic event has occurred.
p
All sites in Part 1 will collect PK blood samples for subjects at all visits (hereafter referred to as dense PK sample collection) until approximately up to the first 
200 subjects have been randomized. The Day 1 samples will be drawn at 1 hour and 4 hours from the start of the IV infusion. The Day 2 blood sample will be 
drawn 24 hours after the start of the IV infusion and may be done with the subject as an inpatient or outpatient. The Day 3 (48 hours) and Day 7 (144 hours) blood 
samples are only required for those subjects who are still hospitalized. 
q
After approximately up to the first 200 randomized subjects in Part 1 have initiated dense PK sampling, the remaining subjects in Part 1 and all subjects in Part 2
will have PK blood samples collected at a limited number of visits (hereafter referred to as sparse PK sample collection). The Day 2 sample will be drawn 24 hours 
after the start of the IV infusion and may be done with the subject as an inpatient or outpatient.
r
The PK sample will only be collected at this visit if it was not collected at the Week 10 visit.
s
Pharmacodynamic evaluations will include the coagulation assays (ie, thrombin time [TT], ecarin clotting time [ECT], prothrombin time [PT], and activated partial 
thromboplastin time [aPTT]). Samples on Day 1 will be obtained before the study drug is administered and at 1 hour after the start of the study drug infusion. 
t
All adverse events, whether serious or nonserious, will be reported from the time a signed and dated informed consent form (ICF) is obtained until the completion 
of the subject’s last study-related procedure. Adverse events of special interest are bleeding events, infusion reactions, hypersensitivity reactions, and wound or 
joint complications). All suspected symptomatic efficacy (thrombotic) events will also be captured as adverse events of special interest. 
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ABBREVIATIONS
ADA
antidrug antibody
aPTT
activated partial thromboplastin time
AV
arteriovenous
CEC
Clinical Events Committee
CI
confidence interval
CSR
clinical study report
CT
computed tomography
CYP
cytochrome P450
DOAC
direct-acting oral anticoagulants
DVT
deep vein thrombosis
ECG
electrocardiogram
eCRF
electronic case report form
ECT
ecarin clotting time
eDC
electronic data capture
EOD
end of dosing
FeCl3
ferric chloride
FSH
follicle stimulating hormone
FXa
Factor Xa
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HaNDL
Headache and Neurological Deficits with cerebrospinal fluid Lymphocytosis
HR
heart rate
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
Ig
immunoglobin
IPPI
Investigational Product Preparation Instructions
IRB
Institutional Review Board
ITT
intent to treat
IV
intravenous
IWRS
interactive web response system
LMWH
low molecular-weight heparin
MCP-Mod
multiple comparison procedure and modeling
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
NI
noninferiority
NSAID
nonsteroidal anti-inflammatory drug
OC
Operations Committee
PCC
prothrombin complex concentrate
PD
pharmacodynamic(s)
PE
pulmonary embolism
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PQC
product quality complaint
PT
prothrombin time
QTcF
QT corrected according to Friderica’s formula
RBC
red blood cell
SAD
single-ascending dose
SAP
statistical analysis plan
SC
Steering Committee
SD
standard deviation
SMQ
standardized MedDRA queries
SQ
subcutaneous
SUSAR
suspected unexpected serious adverse reaction
NCT03251482

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TEAE
treatment-emergent adverse event
TIA
transient ischemic attack
TK
toxicokinetic
TKR
total knee replacement
TT
thrombin time
TXA
tranexamic acid
VTE
venous thromboembolism
WBC
white blood cell
wk
week
DEFINITIONS OF PHARMACOKINETIC TERMS
AUC
area under the plasma concentration curve
AUCinf
area under the plasma concentration versus time curve from time 0 to infinity
AUCDay22-29
area under the concentration-time curve during the dosing interval between Days 22 and 29
CL
total clearance of drug after IV administration
Cmax
maximum concentration during a dosing interval
t1/2
terminal half-life
Tmax
time to reach the maximum observed plasma concentration
Vd
volume of distribution
VZ
apparent volume of distribution in the terminal phase
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1.
INTRODUCTION
JNJ-64179375 is a first-in-class, recombinant, fully human immunoglobin (Ig) G4 monoclonal 
antibody that binds reversibly with high affinity and specificity to the exosite-1 region of 
thrombin. JNJ-64179375 was engineered to mimic the pharmacologic effects of an IgA antibody 
that was found in a patient with markedly abnormal clotting times but with a lack of spontaneous 
bleeding episodes over a prolonged follow-up period, representing the profile of an anticoagulant 
that might have a beneficial therapeutic index in terms of anticoagulation efficacy with low 
bleeding risk.1 JNJ-64179375 acts as an anticoagulant by blocking only exosite-1-mediated 
fibrinogen binding to thrombin (and also blocks proteinase-activated receptor-1 binding), but 
does not inhibit the catalytic activity of the protease. The mechanism of action is distinct from 
currently available direct thrombin inhibitors that block the active site only (eg, dabigatran, 
argatroban) or that block both the active site and exosite 1 (eg, bivalirudin, hirudin) and from 
other mechanisms that inhibit thrombin generation (eg, Factor Xa [FXa] inhibitors). The primary 
goal of the clinical program will be to demonstrate noninferior efficacy with a reduced bleeding 
risk versus active comparators. However, the possibility of demonstrating superior efficacy may 
be considered based on better compliance with a once-monthly dosing regimen and/or the ability 
to achieve more effective drug levels due to a reduced risk of bleeding (ie, doses not limited by 
bleeding risk).
An estimated 920,000 patients in Japan and Europe experience venous thromboembolism (VTE) 
annually, which includes deep vein thrombosis (DVT) and pulmonary embolism (PE).6,19 Joint 
replacement surgery of the lower extremities carries a high risk of VTE due to prothrombotic 
processes such as soft tissue and bone injury during surgery, which causes coagulation activation
from thromboplastin release, venous stasis from peri- and postoperative immobilization, and 
inflammation from the healing process.32 This has led to recommendations in the guidelines that 
all patients undergoing total knee replacement (TKR) should receive pharmacologic and/or 
mechanical VTE prophylaxis.10,19 Low molecular-weight heparin (LMWH) and several 
direct-acting oral anticoagulants (DOACs), including apixaban, have been used in the prevention 
of VTE in patients undergoing TKR surgery. However, limitations of these drugs include once-
or twice-daily dosing regimens and the possibility of an increased bleeding risk at their 
recommended dosages.
JNJ-64179375 is being developed for multiple thrombosis-mediated conditions, including the 
prevention of VTE after TKR surgery, and may offer the potential for equivalent (or superior) 
efficacy to currently available anticoagulant drugs with a reduced risk of bleeding and a simpler
dosing regimen. A novel antithrombotic agent requires the demonstration of both efficacy and 
safety in relevant populations. Phase 2 studies are frequently performed in subjects undergoing 
TKR surgery because of the well-documented high incidence of DVT in the absence of adequate 
thromboprophylaxis, as well as the increased risk of bleeding after recent surgery.7 An 
assessment of the effect on efficacy and safety of JNJ-64179375 compared with apixaban in this 
study will be used to identify an appropriate dose for evaluation in the Phase 3 clinical 
development program.
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For the most comprehensive nonclinical and clinical information regarding JNJ-64179375, refer 
to the latest version of the Investigator's Brochure (IB) 17 and the Addendum to the IB18 for
JNJ-64179375.
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Background
1.1.1.
Nonclinical Studies
1.1.1.1.
Nonclinical Pharmacology
JNJ-64179375 binds to human, mouse, rat, and monkey thrombin with high affinity 
(ie, equilibrium dissociation constants <2 nM) and does not bind to prothrombin or other serine 
proteases. 
Spiking 
of 
JNJ-64179375 
in 
human 
plasma 
in 
vitro 
resulted 
in 
concentration-dependent prolongation of clotting in various coagulation assays (thrombin time 
[TT] [dilute and normal], ecarin clotting time [ECT], prothrombin time [PT], and activated 
partial thromboplastin time [aPTT]), with TT being the most sensitive for this compound. 
JNJ-64179375 inhibited thrombin-induced platelet aggregation in human platelet-rich plasma 
in vitro but did not affect platelet aggregation induced by other platelet agonists. 
The antithrombotic efficacy of JNJ-64179375 was evaluated in several different thrombosis 
models in rats and cynomolgus monkeys, and in a human translational ex-vivo flow-chamber
model (Badimon chamber). JNJ-64179375 inhibited thrombosis in rat ferric chloride (FeCl3) and 
arteriovenous (AV)-shunt models
of venous
thrombosis in a dose-dependent manner 
(0.1 to 1 mg/kg, intravenous [IV]). At 0.3 and 1 mg/kg, JNJ-64179375 produced antithrombotic 
efficacy accompanied by approximately 1.5- and 2-fold increases in TT ex vivo, respectively
(serum level approximately 7 and 23 μg/mL, respectively). JNJ-64179375 (0.3 and 1 mg/kg, IV) 
also inhibited thrombosis in a dose-dependent manner in a FeCl3 model of venous thrombosis in 
cynomolgus monkeys. At the 1-mg/kg dose, serum levels were approximately 40 μg/mL.
The Badimon chamber is a clinical ex-vivo model of thrombosis that mimics the arterial flow 
conditions within the coronary circulation. Under these conditions, higher concentrations of 
JNJ-64179375 added extracorporeally to the blood (approximately 250 g/mL) were required to 
demonstrate efficacy. Overall, the pharmacology data suggests that the therapeutic range of 
JNJ-64179375 for the prevention of venous thrombosis may be between approximately 7 μg/mL
and 40 μg/mL (ie, the concentrations in rats at the 0.3-mg/kg dose and in monkeys at the
1-mg/kg dose, respectively).
The ability of 4 marketed nonspecific reversal agents (Beriplex®, FEIBA, NovoSeven®, and 
tranexamic acid [TXA]) to reverse the bleeding induced by JNJ-64179375 was evaluated in the 
rat-tail transection model. JNJ-64179375 at a dose of 10 mg/kg IV, (ie, a 10-fold higher dose 
than the effective dose in the FeCl3 and AV-shunt models of venous thrombosis), resulted in 
increases in bleeding time and blood loss in this model; however, these increases in bleeding 
parameters were significantly attenuated by pretreatment with either Beriplex (a 4-factor 
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prothrombin complex concentrate [PCC]) or FEIBA (an activated PCC). In contrast, TXA and 
NovoSeven did not shorten the bleeding times after dosing with JNJ-64179375 at the doses 
studied.
1.1.1.2.
Safety Pharmacology
Safety pharmacology evaluations were incorporated into the 1-month repeat-dose Good 
Laboratory Practice (GLP) toxicology studies in rats (T-2016-006) and cynomolgus monkeys 
(T-2016-005). The results of the 1-month GLP toxicity study in monkeys with JNJ-64179375 
(3, 15, 50 mg/kg/week [wk]) IV and 30 mg/kg/wk subcutaneous [SQ]) indicated no 
treatment-related abnormalities in rhythm or waveform morphology at any dose level based on 
comparison of predose and postdose electrocardiogram (ECG) recordings, and the ECGs
evaluated in this study were qualitatively considered normal for cynomolgus monkeys. In the 
monkey study, there were no treatment-related changes in blood pressure, heart rate (HR), 
respiratory rate, or body temperature. Clinical observations from both the rat (up to 
30 mg/kg/wk) and monkey studies did not reveal any treatment-related neurobehavioral effects.
1.1.1.3.
Toxicology
A series of in-vitro and in-vivo nonclinical studies were conducted as part of the JNJ-64179375 
safety assessment in support of clinical studies with a treatment period up to 1 month. Both the 
rat and cynomolgus monkey are pharmacologically relevant species for toxicology testing. The 
maximum dose tested in the non-GLP studies in rats and monkeys was 100 mg/kg/wk IV, and in 
GLP studies, 30 mg/kg/wk and 50 mg/kg/wk in rats and monkeys, respectively. In these 1-month 
repeat-dose studies, animals did not demonstrate any overt or target organ toxicities upon 
administration of JNJ-64179375 other than those related to an extension of the intended 
pharmacology, including dose-dependent prolongation in PT, aPTT, and TT, bruises and 
hemorrhage at the site of administration (rats only), increased hold-off times (bleeding stop time) 
after venipuncture (monkeys), and mortality (rat only).
Five of 8 mortalities observed in the non-GLP and GLP rat studies occurred in the toxicokinetic 
(TK) animals that had blood samples collected from the jugular vein repeatedly throughout the 
in-life phases. The 2 main study rats in the non-GLP study died either on the day of or the 
morning after blood sampling. In the GLP study (no blood sampling in main study animals), the 
death of 1 main study rat in the 10-mg/kg dose group represented 1 in 90 rats at the same or 
higher doses (10-mg/kg IV, 30-mg/kg IV, and SQ groups). However, there were no 
histopathological findings in any of the tissues and organs examined. In addition, there were no 
histopathological findings in any rats examined at the end-of-dosing phase. Therefore, it can be 
concluded that the mortalities in rats are most likely related to study procedures in anticoagulated 
animals and not directly due to treatment with JNJ-64179375.
Excluding the pharmacological effects, the no-observable-adverse-effect-level was defined at the 
highest doses tested in the 1-month GLP studies; 30 mg/kg/wk IV for the rat and 
50 mg/kg/wk IV for the monkey, respectively. The corresponding exposures were: rat maximum 
concentration during a dosing interval (Cmax) at 1,241 µg/mL and area under the 
concentration-time curve during the dosing interval between Day 22 and Day 29 (AUCDay22-29) at 
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4,607 µg•day/mL; monkey Cmax at 2,853 µg/mL and AUCDay22-29 at 11,962 µg•day/mL (both area 
under the plasma concentration curve [AUC] values were from the last dose interval, 
Days 22-29).
1.1.1.4.
Pharmacokinetic and Product Metabolism in Animals
Single-dose pharmacokinetic (PK) studies were conducted in rats and cynomolgus monkeys and 
multiple-dose TKs were assessed in the 1-month non-GLP and GLP rat and cynomolgus monkey 
toxicology studies. In the single-dose PK studies in rats, the drug exposure increased with dose 
in an approximately dose-proportional manner following a single IV dose in the dose range from 
0.1 to 10 mg/kg. In cynomolgus monkeys, the Cmax increased with dose in an approximately 
dose-proportional manner, but the dose-normalized area under the concentration-time curve from 
time zero to infinity (AUCinf) increased with dose in a more than dose-proportional manner 
following a single IV dose ranging from 0.3 to 10 mg/kg. The maximum concentration occurred 
at 3 to 5 days postdose and the estimated absolute bioavailability was 61.40% to 70.40% 
following administration of a single SQ dose of JNJ-64179375 of 1 mg/kg and 3 mg/kg, 
respectively, in rats. Following administration of a single SQ dose of JNJ-64179375 (3 mg/kg) in 
monkeys, the maximum concentration occurred at 3 days postdose, and the absolute 
bioavailability was nearly complete.
In the single-dose PK studies in rats, the mean total clearance of drug after IV administration 
(CL) of JNJ-64179375 from the 0.1- to 10-mg/kg IV-dose groups ranged from 3.95 to 
6.44 mL/day/kg, and the mean terminal half-life (t1/2) ranged from 9.64 to 13.44 days across all 
dose groups. The mean CL of JNJ-64179375 from the IV-dose groups ranged from 1.81 to 
4.82 mL/day/kg, and the mean values of t1/2 ranged from 7.2 to 17.3 days across all dose groups 
in monkeys. The mean apparent volume of distribution in the terminal phase (Vz) of 
JNJ-64179375 ranged from 53.07 to 94.46 mL/kg across the 0.1- to 10-mg/kg single IV dose 
groups in rats. The mean Vz of JNJ-64179375 following a single IV dose ranged from 26.32 to 
62.26 mL/kg across all dose groups in monkeys. The Vz of JNJ-64179375 in rats and 
cynomolgus monkeys was similar to the blood volume in each species, suggesting that 
JNJ-64179375 was mainly distributed in the intravascular space in rats and monkeys.
In the 1-month non-GLP and GLP repeat-dose studies in rats and monkeys, the drug exposure 
increased with dose in an approximately dose-proportional manner following weekly 
IV administration of JNJ-64179375 (3 to 100 mg/kg). The mean drug accumulation ratios ranged 
from approximately 1.5- to 3-fold in the systemic circulation following weekly IV or 
SQ administration of JNJ-64179375 in rats and monkeys,
indicating moderate drug 
accumulation.
Some rats and cynomolgus monkeys exhibited faster decreases in serum concentrations of 
JNJ-64179375 during the terminal phase following single or repeated administration of 
JNJ-64179375. It is likely that the relatively rapid clearance and short half-life in some rats and 
cynomolgus monkey was due to the impact of antidrug antibodies (ADAs) on PK but the formal 
analysis has not yet been completed. No apparent differences in drug exposure were observed 
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between female and male rats following weekly IV or SQ doses of JNJ-64179375 in both non-
GLP and GLP toxicology studies.
1.1.2.
Clinical Studies
The safety, tolerability, PK, immunogenicity, and pharmacodynamics (PD) of single-ascending
IV and SQ doses of JNJ-64179375 are currently being evaluated in a first-in-human study 
(Protocol 64179375EDI1001). Interim data from this study are included in the Addendum to the 
IB.18 The study was initiated in November 2016 and is being conducted at a single study site in 
Belgium.
1.1.2.1.
Overall Study Design and Status
The study is ongoing, has 3 parts, and is being conducted in healthy male subjects: Part 1 
assesses the safety, tolerability, PK, immunogenicity, and PD of single-ascending IV doses of 
JNJ-64179375; Part 2 assesses the reversibility of the PD effects of JNJ-64179375 following a 
single IV dose of a 4-factor PCC, as well as safety, tolerability, PK, and immunogenicity; and 
Part 3 assesses the safety, tolerability, PK, immunogenicity, and PD of a single SQ dose of 
JNJ-64179375.
In Part 1, up to 6 cohorts of 8 subjects each were to be enrolled to evaluate successively 
increasing doses of JNJ-64179375 over a dose range of 0.03 to 5.0 mg/kg (planned doses of 
0.03, 0.1, 0.3, 1.0, 2.5, and 5.0 mg/kg). Up to 2 additional optional cohorts could be enrolled to 
repeat a dose or examine other doses. In Parts 2 and 3, 1 cohort of 8 subjects was to be enrolled
in each.
In Parts 1 and 3 of the study, 6 of the 8 subjects to be enrolled in each cohort were to be 
randomly assigned to treatment with JNJ-64179375 and 2 subjects were to be randomly assigned 
to treatment with placebo. In Part 2, all 8 subjects were to receive JNJ-64179375 followed by 
either 4-factor PCC (n=6) or placebo (n=2). For each subject in each part, the study consists of a 
screening period (up to 28 days), an in-house period (15 days/14 nights), and an outpatient 
period (approximately 99 days), with the total study duration up to approximately 22 weeks for 
each subject.
1.1.2.2.
Part 1
The preliminary results presented below are based on unblinded data from a planned interim 
analysis that was conducted after all Part 1 subjects completed the in-house period (data cutoff 
5 April 2017).
1.1.2.2.1.
Demographic Characteristics
In Part 1, the mean age of the subjects was 32.7 years (range 19 to 45 years) and the mean weight 
was 81.24 kg (range 60.2 to 100.3 kg). Over 90% of the subjects were Caucasian. There were no 
meaningful differences between the cohorts for any demographic parameter.
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1.1.2.2.2.
Safety and Tolerability
The actual dose sequence in Part 1 (8 cohorts) was 0.03, 0.1, 0.3, 1.0, 2.5, repeat 2.5, 1.75, and 
2.125 mg/kg (total n=63 subjects: JNJ-64179375=48 subjects, placebo=15 subjects). After the 
dose was escalated to 2.5 mg/kg of JNJ-64179375 or placebo as planned, an increased frequency 
and severity of bleeding-related adverse events were observed, which suggested a potential 
bleeding-risk signal. To further characterize the safety/tolerability of the 2.5-mg/kg dose of 
JNJ-64179375, an additional 8 subjects were enrolled to repeat the JNJ-64179375 2.5-mg/kg or 
placebo dose cohort. Based on the safety and tolerability data pooled from the two 2.5-mg/kg 
cohorts (Cohorts 5 and 6), 2.5 mg/kg of JNJ-64179375 was assessed as a dose with a bleeding 
signal and therefore the planned 5-mg/kg dose of JNJ-64179375 was not studied. Instead, the 
2.5-mg/kg dose was de-escalated to 1.75 mg/kg (Cohort 7) and then a dose of 2.125 mg/kg 
(Cohort 8) was completed as the last dose cohort studied in Part 1.
Single-ascending IV doses of JNJ-64179375 have been generally well tolerated in healthy male 
subjects over the dose range of 0.03 to 2.5 mg/kg. No subject has withdrawn from the study due 
to an adverse event. A summary of the most frequent treatment-emergent adverse event (TEAE) 
preferred terms (>5% incidence for placebo and the JNJ-64179375 groups combined) is provided 
in Table 1. Overall, most subjects experienced
at least 1 TEAE (placebo, 80%;
JNJ-64179375 dose groups combined, approximately 90%), with no clear dose relationship for 
nonbleeding adverse events. The most frequent
nonbleeding TEAEs were headache 
(placebo 33.3%, JNJ-64179375 22.9%), laceration (placebo 6.7%, JNJ-64179375 20.8%), and 
diarrhoea (placebo 13.3%, JNJ-64179375 12.5%). Most TEAEs were assessed by the 
investigator as mild in intensity. Three events were assessed as severe in intensity 
(meningitis viral, subsequently diagnosed as Headache and Neurological Deficits with 
cerebrospinal fluid Lymphocytosis [HaNDL] syndrome, metabolic acidosis, and pneumonia 
aspiration) in the 2 subjects with serious adverse events as described below. 
Three serious adverse events considered doubtfully related to the study drug were reported for 
2 subjects. Metabolic acidosis and panic attack were reported for 1 subject who had personal 
problems related to a relationship. The subject had a prior history of anxiety and alcohol abuse
that were not disclosed at the screening visit. The subject was hospitalized on Study Day 18 after 
drinking a liter of vodka. He was admitted to the intensive care unit for the treatment of 
metabolic acidosis and aspiration pneumonia. After transferring to the psychiatric unit for 
alcohol treatment, he signed himself out against medical advice. The second subject was 
hospitalized on Study Day 82, with a headache, fever, neurological symptoms, and a preliminary 
diagnosis of viral meningitis. The majority of the workup was negative (clinical laboratory 
reports, polymerase chain reaction for herpes virus, magnetic resonance imaging, and 
electroencephalogram) except for the lumbar puncture, which revealed white blood cells (WBCs) 
(330 per µl) and protein. The subject received symptomatic treatment and was discharged. 
Five days later (Study Day 91), the subject was readmitted and a diagnosis of HaNDL syndrome 
was made (after the interim analysis data cutoff date). The symptoms improved and the subject 
was discharged.
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Table 1:
Most Frequent (>5% Incidence) Treatment-Emergent Adverse Events - by Body System and Preferred Term: Part 1; Safety Analysis Set 
(Study 64179375EDI1001)
JNJ-64179375
Plc 
0.03mg/kg
0.1mg/kg
0.3mg/kg
1.0mg/kg
1.75 mg/kg
2.125 mg/kg
2.5mg/kg
Active Total
Subjects treated
15
6
6
6
6
6
6
12
48
Subjects with 1 or more AEs
12 (80%)
5 (83.3%)
6 (100%)
6 (100%)
5 (83.3%)
4 (66.7%)
6 (100%)
11 (91.7%)
43 (89.6%)
Body System or Organ Class/
Dictionary-Derived Term
General disorders and administration site conditions
8 (53.3%)
2 (33.3%)
3 (50%)
2 (33.3%)
2 (33.3%)
4 (66.7%)
6 (100%)
9 (75%)
28 (58.3%)
Vessel puncture-site bruise
2 (13.3%)
0
2 (33.3%)
2 (33.3%)
2 (33.3%)
4 (66.7%)
6 (100%)
7 (58.3%)
23 (47.9%)
Fatigue
2 (13.3%)
1 (16.7%)
1 (16.7%)
0
0
0
0
0
2 (4.2%)
Influenza like illness
3 (20%)
0
1 (16.7%)
0
0
0
0
0
1 (2.1%)
Gastrointestinal disorders
5 (33.3%)
4 (66.7%)
3 (50%)
2 (33.3%)
0
0
3 (50%)
7 (58.3%)
19 (39.6%)
Gingival bleeding
2 (13.3%)
2 (33.3%)
1 (16.7%)
2 (33.3%)
0
0
2 (33.3%)
3 (25%)
10 (20.8%)
Diarrhoea
2 (13.3%)
2 (33.3%)
2 (33.3%)
0
0
0
0
2 (16.7%)
6 (12.5%)
Abdominal pain
0
2 (33.3%)
1 (16.7%)
0
0
0
1 (16.7%)
1 (8.3%)
5 (10.4%)
Nausea
1 (6.7%)
1 (16.7%)
0
0
0
0
2 (33.3%)
0
3 (6.3%)
Injury, poisoning and procedural complications
2 (13.3%)
1 (16.7%)
4 (66.7%)
2 (33.3%)
3 (50%)
1 (16.7%)
1 (16.7%)
6 (50%)
18 (37.5%)
Laceration
1 (6.7%)
0
2 (33.3%)
0
3 (50%)
1 (16.7%)
1 (16.7%)
3 (25%)
10 (20.8%)
Contusion
2 (13.3%)
0
1 (16.7%)
2 (33.3%)
0
0
0
1 (8.3%)
4 (8.3%)
Nervous system disorders
5 (33.3%)
1 (16.7%)
3 (50%)
2 (33.3%)
1 (16.7%)
3 (50%)
2 (33.3%)
3 (25%)
15 (31.3%)
Headache
5 (33.3%)
1 (16.7%)
1 (16.7%)
2 (33.3%)
0
2 (33.3%)
2 (33.3%)
3 (25%)
11 (22.9%)
Respiratory, thoracic and mediastinal disorders
6 (40%)
4 (66.7%)
0
1 (16.7%)
1 (16.7%)
1 (16.7%)
1 (16.7%)
4 (33.3%)
12 (25%)
Epistaxis
3 (20%)
1 (16.7%)
0
1 (16.7%)
1 (16.7%)
0
0
2 (16.7%)
5 (10.4%)
Cough
2 (13.3%)
2 (33.3%)
0
0
0
0
0
0
2 (4.2%)
Infections and infestations
5 (33.3%)
2 (33.3%)
5 (83.3%)
0
1 (16.7%)
0
1 (16.7%)
0
9 (18.8%)
Nasopharyngitis
2 (13.3%)
0
2 (33.3%)
0
1 (16.7%)
0
1 (16.7%)
0
4 (8.3%)
Investigations
1 (6.7%)
2 (33.3%)
2 (33.3%)
1 (16.7%)
1 (16.7%)
0
0
3 (25%)
9 (18.8%)
Blood creatine phosphokinase increased
1 (6.7%)
1 (16.7%)
0
0
1 (16.7%)
0
0
1 (8.3%)
3 (6.3%)
AEs= adverse events; Plc=placebo
Note: Percentages calculated with the number of subjects in each group as denominator.
Note: Incidence is based on the number of subjects, not the number of events.
Reported dictionary version: MedDRA 19.1.
[TSFAE01P1.RTF] [JNJ-64179375\EDI1001\DBR_IA_SEQUESTERED\RE_IA_SEQUESTERED\PREPROD\TSFAE01P1.SAS] 25APR2017, 15:30
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Table 2 shows all treatment-emergent bleeding adverse events selected using the Medical 
Dictionary for Regulatory Activities (MedDRA) standardized MedDRA queries (SMQ) term 
hemorrhage (excluding laboratory terms). In the placebo group, 46.7% of the subjects had 1 or 
more events compared with 72.9% for the combined JNJ-64179375 groups. This difference was 
mostly due to the increased incidence of treatment-emergent bleeding adverse events observed in 
the 2.125- (100%) and 2.5- (91.7%) mg/kg groups.
The most common bleeding adverse events observed were vessel puncture-site bruises 
(placebo, 13.3%;
JNJ-64179375,
47.9%), 
gingival 
bleeding 
(placebo, 
13.3%; 
JNJ-64179375, 20.8%), 
and 
epistaxis 
(placebo,
20%;
JNJ-64179375, 
10.4%). 
Most 
treatment-emergent bleeding adverse events were associated with mild trauma (ie, venipuncture, 
brushing teeth/gums, blowing nose) and all resolved. All were considered mild in intensity 
except for 6 events considered to be of moderate intensity (1 event of epistaxis at 1 mg/kg, 
1 event of ecchymosis at 2.125 mg/kg, and 4 skin-bruising or hematoma events at 2.5 mg/kg). 
The criteria for moderate intensity were defined as an episode of epistaxis lasting more than 
5 minutes or a skin bruise event with a maximum dimension of 10 cm or larger.
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Table 2: 
Treatment-Emergent Bleeding Adverse Events - by Body System and Preferred Term: Part 1; Safety Analysis Set (Study 64179375EDI1001)
JNJ-64179375
Plc
0.03 mg/kg
0.1 mg/kg
0.3 mg/kg
1.0 mg/kg
1.75 mg/kg
2.125 mg/kg
2.5 mg/kg
Active Total
Subjects treated
15
6
6
6
6
6
6
12
48
Subjects with 1 or more Bleeding AEs
7 (46.7%)
3 (50%)
5 (83.3%)
4 (66.7%)
2 (33.3%)
4 (66.7%)
6 (100%)
11 (91.7%)
35 (72.9%)
Body System or Organ Class
Dictionary-Derived Term
General disorders and administration site conditions
3 (20%)
0
2 (33.3%)
2 (33.3%)
2 (33.3%)
4 (66.7%)
6 (100%)
8 (66.7%)
24 (50%)
Vessel puncture site bruise
2 (13.3%)
0
2 (33.3%)
2 (33.3%)
2 (33.3%)
4 (66.7%)
6 (100%)
7 (58.3%)
23 (47.9%)
Infusion site bruising
1 (6.7%)
0
0
0
0
0
0
2 (16.7%)
2 (4.2%)
Catheter site haemorrhage
0
0
0
0
0
0
0
1 (8.3%)
1 (2.1%)
Infusion site haematoma
0
0
0
0
0
0
0
1 (8.3%)
1 (2.1%)
Injection site bruising
0
0
0
0
0
0
0
1 (8.3%)
1 (2.1%)
Vessel puncture site haematoma
0
0
0
0
0
0
1 (16.7%)
0
1 (2.1%)
Gastrointestinal disorders
2 (13.3%)
3 (50%)
1 (16.7%)
2 (33.3%)
0
0
2 (33.3%)
4 (33.3%)
12 (25%)
Gingival bleeding
2 (13.3%)
2 (33.3%)
1 (16.7%)
2 (33.3%)
0
0
2 (33.3%)
3 (25%)
10 (20.8%)
Haematochezia
0
0
0
0
0
0
0
1 (8.3%)
1 (2.1%)
Mouth haemorrhage
0
1 (16.7%)
0
0
0
0
0
0
1 (2.1%)
Injury, poisoning and procedural complications
2 (13.3%)
1 (16.7%)
1 (16.7%)
2 (33.3%)
0
0
0
2 (16.7%)
6 (12.5%)
Contusion
2 (13.3%)
0
1 (16.7%)
2 (33.3%)
0
0
0
1 (8.3%)
4 (8.3%)
Procedural haemorrhage
0
1 (16.7%)
0
0
0
0
0
0
1 (2.1%)
Traumatic haemorrhage
0
0
0
0
0
0
0
1 (8.3%)
1 (2.1%)
Respiratory, thoracic and mediastinal disorders
3 (20%)
1 (16.7%)
0
1 (16.7%)
1 (16.7%)
0
0
2 (16.7%)
5 (10.4%)
Epistaxis
3 (20%)
1 (16.7%)
0
1 (16.7%)
1 (16.7%)
0
0
2 (16.7%)
5 (10.4%)
Skin and subcutaneous tissue disorders
2 (13.3%)
0
0
0
0
0
1 (16.7%)
1 (8.3%)
2 (4.2%)
Ecchymosis
1 (6.7%)
0
0
0
0
0
1 (16.7%)
0
1 (2.1%)
Blood blister
1 (6.7%)
0
0
0
0
0
0
0
0
Skin haemorrhage
0
0
0
0
0
0
0
1 (8.3%)
1 (2.1%)
Investigations
0
1 (16.7%)
1 (16.7%)
0
0
0
0
1 (8.3%)
3 (6.3%)
Blood urine present
0
1 (16.7%)
1 (16.7%)
0
0
0
0
1 (8.3%)
3 (6.3%)
Ear and labyrinth disorders
0
0
0
0
0
0
1 (16.7%)
0
1 (2.1%)
Ear haemorrhage
0
0
0
0
0
0
1 (16.7%)
0
1 (2.1%)
AE=adverse event; Plc=placebo
Note: Percentages calculated with the number of subjects in each group as denominator.
Note: Incidence is based on the number of subjects, not the number of events.
Reported dictionary version: SMQ19.1, HAEMORRHAGE TERMS (EXCL LABORATORY TERMS) (SMQ)
[TSFAE02P1.RTF] [JNJ-64179375\EDI1001\DBR_IA_SEQUESTERED\RE_IA_SEQUESTERED\PREPROD\TSFAE02P1.SAS] 25APR2017, 15:30
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Clinical Laboratory, Vital Signs, and ECG Assessments
Clinical safety laboratory tests (clinical chemistry, hematology, coagulation, and urinalysis), vital 
signs, and ECGs were collected at specified times before and after study drug dosing.
There were no apparent group-mean trends or dose-related effects in these assessments with 
JNJ-64179375, with the exception of dose-related increases in PT, aPTT, and TT levels 
consistent with the mechanism of action of JNJ-64179375 (see Section 1.1.2.2.4, 
Pharmacodynamics). Individual ECGs did not show any clinically significant changes from 
baseline; no subject had a QT corrected according to Fridericia’s formula (QTcF) >450 msec or 
an increase from baseline in QTcF >30 msec.
1.1.2.2.3.
Pharmacokinetics
The results presented below are based on preliminary bioanalytical data and nominal sampling 
times from the subjects who received at least 1 dose of JNJ-64179375 in Part 1. Plasma samples 
were analyzed to determine concentrations of JNJ-64179375 using a validated, selective, and 
sensitive immunoassay method (lower limit of quantification 0.01 µg/mL). Interim preliminary 
PK results were determined using noncompartmental methods and are summarized in Table 3.
Table 3:
Mean (±SD) Pharmacokinetic Parameters of JNJ-64179375 Following a Single 30-minute 
IV Infusion (0.03 to 2.5 mg/kg, Part 1) in Healthy Male Subjects
Cohort
JNJ-64179375 
mg/kg IV
Cmax
μg/mL
Tmax
a
h
AUCinf
day*μg/mL
CL
mL/day/kg
Vz
mL/kg
t1/2
day
1
0.03
0.707 (0.196)
1 (0.5-1)
15.4 (3.87)
2.07 (0.628)
73.3 (21.8)
24.7 (3.6)
2
0.1
2.15 (0.183)
1 (0.5-8)
47.2 (6.74)
2.16 (0.361)
76.3 (5.67)
24.8 (3.2)
3
0.3
6.86 (1.30)
1 (0.5-4)
145 (22.3)
2.11 (0.286)
78.8 (19.1)
26.0 (5.3)
4
1
28.4 (3.90)
1 (0.5-4)
514 (71.3)
1.98 (0.285)
83.0 (11.5)
29.2 (3.1)
5+6
2.5
58.0 (12.7)
2.5 (0.5-8)
1266 (266)
2.06 (0.487)
80.5 (12.4)
27.8 (5.2)
7
1.75
44.3 (8.90)
2.5 (0.5-4)
813 (124)
2.20 (0.328)
68.7 (9.64)
21.8 (2.1)
8
2.125
42.9 (3.62)
1 (0.5-4)
970 (209)
2.28 (0.499)
73.5 (15.3)
23.2 (6.9)
AUCinf=area under the concentration curve from zero to infinity; CL= total clearance of drug after IV administration; 
Cmax= maximum concentration during a dosing interval; h=hour; IV=intravenous; SD=standard deviation; 
t1/2=terminal half-life; Tmax=time to reach the maximum observed plasma concentration; Vz=apparent volume of 
distribution in the terminal phase
aData presented as Median (Minimum-Maximum)
The median time to reach the maximum observed plasma concentration (Tmax) was 1 to 2.5 hours 
postdose. The mean Cmax and AUCinf increased in an approximately dose-proportional manner. 
The mean t1/2 ranged from approximately 21.8 to 29.2 days.
1.1.2.2.4.
Pharmacodynamics
Prothrombin time, aPTT, and TT demonstrated dose-dependent increases whether measured 
locally or at a central specialty laboratory, with TT being the most sensitive test and PT the least 
sensitive test. A plot of mean ratio to baseline for TT from the central specialty laboratory is 
provided in Figure 1. For TT, the 2 highest dose groups showed similar prolongations for the 
early timepoints (an approximately 7-fold increase) as some subjects in both groups exceeded the 
laboratory upper reporting limit of 120 seconds. At 14 days, the prolongation in TT was about 
5-fold for the highest dose group. At the 0.3-mg/kg dose level, the peak prolongation in TT was 
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approximately 2.7-fold and it was approximately 1.7-fold at 14 days. For aPTT, the assay upper 
reporting limit was not approached for any subject but the maximum prolongation appears to be 
an approximately 1.6-fold increase from baseline for each of the 3 highest dose groups. For PT, 
the maximum-fold increase was approximately 1.3-fold at the highest dose. These data are 
consistent with the in-vitro data and with the mechanism of action of JNJ-64179375. Local
laboratory results demonstrated a similar pattern.
Figure 1:
Thrombin Time (s) Mean Ratio to Baseline by Treatment Group Central Specialty Laboratory; 
Safety Analysis Set (Study 64179375EDI1001)
Baseline is defined as the last valid measurement prior to dosing.
[GSFEPDC1.RTF] [JNJ-64179375\EDI1001\DBR_IA_SEQUESTERED\RE_IA_SEQUESTERED\PREPROD\GSFEPDC1.SAS] 30MAY2017, 12:09
1.1.2.2.5.
Overall Summary
In this single-ascending dose (SAD), randomized, double-blind, placebo-controlled study in 
healthy male subjects (Part 1), JNJ-64179375 was generally well tolerated at all doses. All 
observed bleeding events were of mild or moderate intensity, mostly related to local trauma 
(eg, venipuncture, brushing teeth, blowing nose), and none were severe or serious. At the 
2 highest doses (2.125 and 2.5 mg/kg), an increased frequency (and severity at 2.5 mg/kg) of 
bleeding events was observed compared with placebo.
With the exception of the bleeding adverse events, there was no evidence of dose-dependent 
adverse events over the studied dose range. As hypersensitivity reactions have been observed 
with the administration of monoclonal antibodies, infusion or allergic reactions were closely 
monitored for this study. One subject in the 2.5-mg/kg cohort developed mild urticaria that 
started prior to receiving the study drug. The urticaria spread and was assessed as moderate in 
severity at approximately 4 hours postdose. The urticaria resolved spontaneously 24 hours later 
and was considered doubtfully related to the study drug.
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JNJ-64179375 administered as an IV infusion exhibited a favorable PK profile in healthy 
subjects, and the observed PK parameters were close to those predicted based on the animal 
PK data. Mean Cmax and AUCinf values increased in an approximately dose-proportional manner 
in the studied dose range. Mean t1/2 ranging from 21.8 to 29.2 days is consistent with the 
expected t1/2 of human IgG4. Importantly, variations of the PK concentration and parameters 
(Cmax and AUCinf) of JNJ-64179375 were low, indicating PK predictability.
Consistent with the nonclinical findings, JNJ-64179375 produced a dose-dependent prolongation 
of the coagulation parameters (PT, aPTT, and TT) over the studied dose range. Based on 
fold-changes from baseline observed in this study, TT was the most sensitive assay for 
JNJ-64179375, which is consistent with its mechanism of action and direct effect on 
thrombin-mediated clot formation. The effect-time curves for all coagulation parameters seemed
parallel to the plasma drug concentration-time curves of JNJ-64179375 with no apparent lag 
time.
1.1.2.3.
Parts 2 and 3
Parts 2 and 3 of the study (1 single cohort in each part) had also completed dosing as of
21 April 2017. A blinded data review as of 02 May 2017 is briefly summarized below; however, 
this data was not included in the unblinded interim analysis as it was not available until after the 
cutoff date. Eight subjects were dosed intravenously with 1.0 mg/kg of JNJ-64179375 in Part 2 
followed by either placebo (n=2) or 50 IU/kg of the 4-factor PCC Confidex(n=6). Confidex did 
not appear to reverse the effects of JNJ-64179375 on either aPTT or TT. In Part 3, 8 subjects 
were dosed subcutaneously with either 1.0 mg/kg of JNJ-64179375 (n=6) or placebo (n=2). The 
PK data showed the expected delay to peak drug levels. For both cohorts, the bleeding adverse 
events were mostly mild skin-site events as observed in Part 1. One moderate intensity epistaxis
bleeding event was reported in Part 2.
In the nonclinical studies, 4-factor PCC and activated PCC were able to normalize rat-tail 
bleeding times after the administration of JNJ-64179375 but did not reverse TT or aPTT 
prolongation (data on file). Therefore, the lack of reversal of TT and aPTT with 4-factor PCC in 
Part 2 of the Phase 1 study was not unexpected and likely reflects the insensitivity of these 
coagulation assays for measuring the potential hemostatic effects of PCC administration.
1.2.
Comparator Drug
Eliquis(apixaban)
The following information, taken from the European Union Summary of Product Characteristics, 
is intended to provide a brief, representative overview of apixaban.8
Eliquis(apixaban) is a potent, oral, reversible, direct and highly selective active-site inhibitor of 
FXa. Apixaban does not require antithrombin III for antithrombotic activity. It inhibits free and 
clot-bound FXa and prothrombinase activity. Apixaban has no direct effects on platelet 
aggregation but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, 
apixaban prevents thrombin generation and thrombus development. Apixaban does not have any 
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effects on TT but does prolong PT and aPTT although the changes in these assays are small and 
variable at therapeutic doses.
Apixaban is indicated in the European Union for the prevention of VTE in adult patients who 
have undergone elective hip or knee replacement surgery. For the prevention of VTE after 
TKR surgery, the recommended dose of apixaban is 2.5 mg taken orally twice daily, with the 
initial dose taken 12 to 24 hours after surgery. The recommended duration of treatment is 
10 to 14 days.
The ADVANCE-1 and ADVANCE-2 studies included subjects who had undergone a TKR for 
one or both knees.
In the ADVANCE-1 study, which included 3,195 randomized subjects and 3,184 subjects in the 
safety population, apixaban 2.5 mg twice daily following TKR was compared with enoxaparin 
30 mg twice daily. Both medications were started 12 to 24 hours after surgery and continued for 
10 to 14 days. The primary efficacy endpoint was total VTE defined as the composite of 
adjudicated asymptomatic and symptomatic DVT, nonfatal PE, or all-cause death. The primary 
safety outcome was major bleeding during the treatment period or within 2 days after the last 
dose of the study drug. The total VTE rates were similar for apixaban and enoxaparin although 
statistically apixaban did not meet 1 of the 2 prespecified criteria for noninferior efficacy. 
Bleeding events were lower in the apixaban group.23 (Table 4 and Table 5)
In the ADVANCE-2 study, which included 3,057 randomized subjects and 3,009 subjects in the 
safety population undergoing elective TKR surgery, subjects received either apixaban 2.5 mg 
given orally twice daily or enoxaparin 40 mg SQ once daily. Apixaban was started 12 to 
24 hours after surgery, while enoxaparin was started 9 to 15 hours before surgery, with both 
drugs given for 10 to 14 days. The primary efficacy endpoint was total VTE and the primary 
safety outcome was major bleeding reported during the treatment period. Apixaban demonstrated 
a statistically superior reduction in total VTE and in the major VTE endpoint, a composite of 
proximal DVT, nonfatal PE, and VTE-related death, compared with enoxaparin. The safety 
endpoints of major bleeding, the composite of major and clinically relevant nonmajor bleeding, 
and all bleeding were not statistically different but were numerically lower for subjects treated 
with apixaban 2.5 mg twice daily compared with enoxaparin 40 mg SQ once daily.24 (Table 
4 and Table 5)
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Table 4:
ADVANCE-1 and ADVANCE-2 Safety Results
Oral Apixaban 
2.5 mg BID
SQ Enoxaparin
30 mg BID
Difference in Risk 
(95% CI)
p-value
ADVANCE-1
N=1,596
95% CI
N=1,588
95% CI
Major Bleeding
11 (0.7)
0.4-1.3
22 (1.4)
0.9-2.1
-0.81 (-1.5 to 0.1)
0.05
CRNM
35 (2.2)
1.6-3.1
47 (3.0)
2.2-3.4
-0.77 (-1.8 to 0.3)
Surgical site†
22 (1.4)
35 (2.2)
Major or CRNM bleeding
46 (2.9)
2.2-3.8
68 (4.3)
3.4-5.4
-1.46 (-2.8 to 0.2)
0.03
All bleeding events
85 (5.3)
4.3-6.6
108 (6.8)
5.7-8.2
-1.52 (-3.2 to 0.1)
0.08
Minor bleeding events
39 (2.4)
40 (2.5)
Oral Apixaban 
2.5 mg BID
SQ Enoxaparin
40 mg QD
ADVANCE-2
N=1,501
N=1,508
Absolute Risk 
Difference
p-value
Major Bleeding
9 (0.6)
14 (0.9)
-0.3 (-1.0 to 0.3)
0.3
CRNM
44 (2.9)
58 (3.8)
-0.9 (-2.2 to 0.4)
0.17
Surgical site†
32 (2.1)
44 (2.9)
Major + CRNM bleeding
53 (3.5)
72 (4.8)
-1.2 (-2.7 to 0.2)
0.09
All bleeding events
104 (6.9)
126 (8.4)
-1.4 (-3.3 to 0.5)
0.14
Minor bleeding events
51 (3.4)
54 (3.6)
BID=twice daily; CI=confidence interval; CRNM=clinically relevant nonmajor; N=number; QD=once daily; 
SQ=subcutaneous
†Numbers are from investigator reports
Source: Lassen 200923; Lassen 201024
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Table 5:
ADVANCE-1 and ADVANCE-2 Efficacy Results
Intended 
Treatment Period
Oral Apixaban 2.5 mg BID
SQ Enoxaparin 30 mg BID
Relative Risk 
(95% CI)
Difference in 
Risk (95% CI)
ADVANCE-1
n/N
95% CI
n/N
95% CI
Total VTE 
104/1157
9.0
(7.47-10.79)
100/1130
8.8
(7.33-10.66)
1.02
(0.78-1.32)
0.11
(-2.22-2.44)
Major VTE
26/1269
2.0
(1.39-3.01)
20/1216
1.6
(1.06-2.55)
1.25
(0.70-2.23)
0.36 
(-0.68-1.40)
Symptomatic VTE 
and VTE-related 
death
19/1599
1.2
(0.75-2.95)
13/1596
0.8
(0.46-1.41)
1.46
(0.72-2.95)
0.38
(-0.30-1.06)
All DVT
89/1142
7.8
(6.37-9.51)
92/1122
8.2
(6.73-9.97)
---
---
All PE
16/1599
1.0
0.61-1.64
7/1596
0.4
(0.20-0.93)
---
---
ADVANCE-2
n/N
Rate
SQ Enoxaparin 40 mg QD
Relative Risk 
(95% CI)/
p-value
Absolute risk 
difference (%)
n/N
Rate
Total VTE 
147/976
15.0
(12.95-17.46)
243/997
24.37
(21.81-27.14)
0.62
(0.51-0.74)/
0.0001
-9.27%
(-12.74-[-5.79])
Major VTE
13/1195
1.09
(0.62-1.88)
26/1199
2.17
(1.47-3.18)
0.5
(0.26-0.97)/
0.0186
-1.04%
(-2.03-[-0.05])
Symptomatic VTE 
and VTE-related 
death
7/1528
0.46%
(0.20 - 0.97)
7/1529
0.46
(0.20-0.97)
1.00
(0.35-2.85)/
---
0.00%
(-0.48-0.48)
All DVT
142/971
14.6%
(12.5 - 17.0)
243/997
24.4
(21.8-27.1)
---/---
---
All PE
4/1528
0.26%
(0.08 – 0.70)
0/1529
0.00
(0.00-0.31)
---/---
---
BID=twice daily; CI=confidence interval; DVT=deep vein thrombosis; n/N=number; PE=pulmonary embolism; 
QD=once daily; SQ=subcutaneous; VTE=venous thromboembolism
Source: Lassen 200923; Lassen 201024
1.3.
Overall Rationale for the Study
Low molecular-weight heparins have a long and well-established role in the prevention of VTE 
in subjects undergoing TKR surgery, and while very effective with an acceptable bleeding risk, 
SQ dosing once or twice a day is required. More recently, several DOACs (eg, apixaban, 
rivaroxaban, dabigatran, edoxaban) have been approved for use in TKR, based on comparisons 
with the LMWH, enoxaparin, and their use has become more widespread in this patient 
population. Apixaban starting 12 to 24 hours after TKR surgery demonstrated superior efficacy 
compared with enoxaparin 40 mg once daily and similar efficacy to enoxaparin 30 mg twice 
daily, with numerically less bleeding than both enoxaparin regimens.23,24 Apixaban was chosen 
as the active comparator for this study because it is orally administered and compares favorably 
with enoxaparin for both efficacy and bleeding endpoints.
JNJ-64179375 is a first-in-class, recombinant, fully human IgG4 monoclonal antibody that binds 
reversibly with high affinity and specificity to the exosite-1 region on thrombin. By only 
blocking exosite-1, the catalytic activity of the protease is maintained. Therefore, this unique 
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mechanism of action of JNJ-64179375 may offer the potential for noninferior (or superior) 
efficacy compared with currently available anticoagulant drugs (eg, vitamin K antagonists, 
enoxaparin, and DOACs) with a reduced risk of bleeding.
Given that TKR surgery carries a high risk of VTE combined with the hemostatic challenges of 
surgery, it provides a good setting to evaluate the relative efficacy and safety (bleeding) 
characteristics of novel anticoagulants.7 As a monoclonal antibody, JNJ-64179375 has an 
expected duration of action of approximately 4 weeks, thereby allowing for the postoperative 
administration of a single IV dose to be used for VTE prophylaxis after TKR surgery. Based on 
the preclinical and Phase 1 studies conducted to date, JNJ-64179375 is anticipated to have a 
favorable safety profile with respect to bleeding risk. Therefore, JNJ-64179375 offers the 
potential for an efficacious treatment that has limited bleeding, with a simpler dosing regimen 
compared with currently available oral or parenteral treatments.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Part 1
In men and women undergoing primary unilateral TKR surgery, after single-ascending IV doses 
of JNJ-64179375 or 10 to 14 days of oral apixaban:
Primary Objective
The primary objective is to assess the safety and tolerability of JNJ-64179375 for each dose level 
for dose escalation within Part 1 and any bleeding events (the composite of major, clinically 
relevant nonmajor, and minimal bleeding events) for the selection of doses for Part 2.
Secondary Objectives

To assess the dose response of JNJ-64179375 for the occurrence of the composite endpoint 
of any bleeding events, the composite endpoint of major or clinically relevant nonmajor 
bleeding events, and the individual components of the composite endpoint of any bleeding 
event

To assess the dose response of JNJ-64179375 for the prevention of total VTE 
(proximal and/or distal DVT [asymptomatic confirmed by venography assessment of the 
operated leg or objectively confirmed symptomatic], nonfatal PE, or any death) and the 
individual components of total VTE
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Part 2
In men and women undergoing primary unilateral TKR surgery, after a single IV dose of 
JNJ-64179375 or 10 to 14 days of oral apixaban:
Primary Objective
The primary objective is to assess the efficacy dose response of JNJ-64179375 for the prevention 
of total VTE (proximal and/or distal DVT [asymptomatic confirmed by venography assessment 
of the operated leg or objectively confirmed symptomatic], nonfatal PE, or any death).
Key Secondary Objectives

To assess the dose response of JNJ-64179375 for the occurrence of the composite endpoint 
of any bleeding events, the composite endpoint of major or clinically relevant nonmajor 
bleeding events, and the individual components of the composite endpoint of any bleeding 
event

To assess the dose response of JNJ-64179375 for the prevention of major VTE 
(asymptomatic confirmed by venography assessment of the operated leg or objectively 
confirmed symptomatic proximal DVT, nonfatal PE, or any death) and the individual 
components of the total VTE endpoint
Common Objectives in Parts 1 and 2
Other Secondary Objectives

To assess the effect of individual doses of JNJ-64179375 compared with apixaban for both 
efficacy and safety endpoints, with the goal to identify a studied or model-predicted dose 
with the most promising benefit-risk profile for a more extensive evaluation in Phase 3

To assess the effect of JNJ-64179375 compared with apixaban on wound or joint 
complications in the operated leg
Exploratory Objectives

To assess the effect of JNJ-64179375 compared with apixaban on other thrombotic events 
(ie, myocardial infarction [MI], ischemic stroke, peripheral arterial embolism)

To evaluate the cost effectiveness of JNJ-64179375 compared with apixaban based on 
health resource utilization

To assess the PK, PD, and PK/PD relationships of JNJ-64179375 in men and women 
undergoing primary unilateral TKR surgery and the relation of these measures to efficacy 
and safety endpoints (eg, exposure-response analyses)

To evaluate the PD assays (TT, ECT, PT, aPTT, and D-dimer) to determine the most 
appropriate tests to measure the effect of JNJ-64179375
2.1.2.
Endpoints
The endpoints of the study will be the same for Parts 1 and 2 although the focus of Part 1 will be 
primarily dose escalation based on safety while the focus of Part 2 will primarily be the 
assessment of dose response in both safety and efficacy.
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Clinical Protocol 64179375THR2001 Amendment 1
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Approved, Date: 11 September 2017
Common Endpoints in Parts 1 and 2
Primary Safety Endpoint
The primary safety endpoint is any bleeding event defined as the composite of major, clinically 
relevant nonmajor, and minimal bleeding events assessed through the Day 10-14 visit.
Primary Efficacy Endpoint
The primary efficacy endpoint is total VTE, defined as the composite of proximal and/or distal 
DVT (asymptomatic confirmed by venography assessment of the operated leg or objectively 
confirmed symptomatic), nonfatal PE, or any death assessed through the Day 10-14 visit.
Key Secondary Endpoints
The key secondary endpoints are the assessment of the primary endpoints through the 
Week 18 visit, and:

All individual components of the primary safety endpoint (major bleeding, clinically 
relevant nonmajor bleeding, and minimal bleeding)

Composite of major and clinically relevant nonmajor bleeding

Major VTE, a composite of proximal DVT (asymptomatic confirmed by venography 
assessment of the operated leg or objectively confirmed symptomatic), nonfatal PE, or any
death

All individual components of the primary efficacy endpoint (ie, proximal and/or distal DVT
[asymptomatic confirmed by venography assessment of the operated leg or objectively 
confirmed symptomatic], nonfatal PE, any death)
Other Secondary Endpoints

Any wound or joint complication in the operated leg
Exploratory Endpoints

Other thrombotic events (ie, MI, ischemic stroke, peripheral arterial embolism)

The total length of the initial hospitalization, including the level of care and discharge 
destination

The incidence of rehospitalization for any reason

The number of scheduled and unscheduled visits, including the associated cost to healthcare 
providers for study outcomes, any other medical reasons, and the diagnostic procedures used 
in relation to study endpoints

Calculation of PK parameters, eg, CL, volume of distribution (Vd), t1/2, AUCinf, and Cmax

Changes in PD by dose: TT, ECT, PT, aPTT, and D-dimer

Changes in PD assays as listed above by concentration metrics (AUCinf, Cmax, or 
time-matched concentrations)
Refer to Section 9, Study Evaluations for evaluations related to endpoints.
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2.2.
Hypothesis
In Part 1, a range of doses of JNJ-64179375 will be assessed to determine if it is sufficiently safe 
to proceed with Part 2 of the study. No formal hypothesis testing will be conducted for Part 1. In 
Part 2, the clinical hypothesis is to demonstrate proof-of-efficacy based on the total 
VTE endpoint. This can be achieved by either showing that JNJ-64179375 has a statistically 
significant dose-response trend with respect to the total VTE endpoint, or the combined dose 
groups of JNJ-64179375 have a total VTE event rate of less than 30%. 
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This 
is 
a
randomized, 
double-blind, 
double-dummy,
active-controlled,
multicenter,
dose-escalation and dose-response
study
of JNJ-64179375. The study has
2 parts, 
dose-escalation and dose-response evaluation, and will be conducted in subjects undergoing 
primary unilateral elective TKR surgery. Part 1 will assess the safety of single-ascending 
IV doses of JNJ-64179375 while Part 2 will confirm the safety of the doses selected from Part 1 
and will assess the efficacy dose-response relationship with respect to the selected doses in the 
parallel groups. Subjects will be men or women of non-childbearing potential 50 years of age, 
considered medically appropriate for postoperative anticoagulant prophylaxis based on the 
study- and local standard-of-care-required assessments for pre- and postoperative evaluation. 
Subjects will participate in either Part 1 or Part 2 of the study only. A total of approximately 
1,500 subjects combined for Parts 1 and 2 are planned to be enrolled. Part 1 will include 
approximately 300 subjects and Part 2 will include approximately 1,200 subjects as described in 
Section 3.1.1, Part 1: Single-Ascending Dose and Section 3.1.2, Part 2: Dose-Response 
Confirmation, respectively.
For each subject in each part, the study will be conducted in 3 phases: an up to 30-day screening 
phase before surgery, a 14-day double-blind dosing phase, and a 16-week follow-up phase. 
Unscheduled visits may be performed at the discretion of the investigator for the assessment of 
any potential bleeding or efficacy endpoint events. The total duration of the subject’s 
participation in Part 1 or Part 2 after randomization will be approximately 18 weeks.
Screening for eligible subjects in Parts 1 and 2 may be done up to 30 days before randomization,
pre- or postoperatively. Following primary unilateral elective TKR surgery, eligible subjects will 
be randomly assigned to treatment with either JNJ-64179375 or apixaban. All subjects will 
receive a single IV infusion of JNJ-64179375 or JNJ-64179375 placebo and oral apixaban or 
matching apixaban placebo the day after TKR surgery (Day 1, 0 hours), while the subject is still 
hospitalized and within a minimum of 12 hours and a maximum of 24 hours after the end of the 
TKR surgery, defined as the time of wound closure. Details regarding the timing of oral dosing 
in relation to the start of the IV infusion are provided in Section 6, Dosage and Administration. 
Following discharge or transfer to an alternate facility, subjects in both parts will be reminded to 
continue to take apixaban or matching apixaban placebo twice daily to complete a total of 
10 to 14 days of dosing as described in Section 6, Dosage and Administration. Unilateral 
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venography assessment of the operated leg will be performed after the last dose of apixaban or 
matching apixaban placebo is taken as described in Section 9.2.1, Assessments for DVT.
Subjects in both Parts 1 and 2 will return to the site for study-related procedures 5, 10, and 
18 weeks after TKR surgery as described in the Time and Events Schedule that follows the 
Synopsis. Safety evaluations will include the monitoring of all nonserious and serious adverse 
events, (including adverse events of special interest: bleeding events, infusion reactions,
hypersensitivity reactions, and wound or joint complications), clinical laboratory tests
(ie, hematology, clinical chemistry, urinalysis), vital signs measurements (blood pressure, 
pulse/HR, temperature), and physical examinations. Pharmacokinetics (dense and sparse), PD, 
and immunogenicity samples will be collected and health resource utilization will also be 
assessed at the time points indicated in the Time and Event Schedule.
An Operations Committee (OC), Independent Data Monitoring Committee (IDMC), 
Steering Committee (SC), and independent Clinical Events Committee (CEC) will be 
commissioned for this study. Refer to Section 11.11, Committees.
An unblinded data review is planned for Part 1 after all subjects are expected to have completed 
the Day 10-14 visit to determine the dose range and doses of JNJ-64179375 for Part 2. Two 
planned, unblinded interim analysis will be conducted in Part 2 by the IDMC as part of the
adaptive approach that will be used to guide decisions to drop and/or add doses of JNJ-64179375 
and adjust the randomization ratio based on the available efficacy, safety, PK, and PD data. 
Additional details are provided in Section 11.10, Interim Analyses. An unblinded administrative 
interim analysis is planned after all subjects are expected to have completed the Day 10-14 visit
in Part 2 to facilitate additional study planning as described in Section 11.10, Interim Analyses.
A diagram of the study design is provided below.
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Schematic Overview of the Study
3.1.1.
Part 1: Single-Ascending Dose
Eligible subjects in Part 1 will be randomly assigned to a single-ascending IV dose of 
JNJ-64179375 or apixaban 2.5 mg given orally twice daily for 10 to 14 days. Six cohorts of up to 
approximately 50 unique subjects per cohort (total of up to approximately 300 unique subjects) 
are planned but the number of cohorts and the size of each cohort may be adjusted based on the 
ongoing unblinded data review by the OC. Within each cohort, subjects will be randomized in a 
4:1 ratio to JNJ-64179375 or apixaban, respectively (ie, approximately 40 subjects to 
JNJ-64179375: approximately 10 subjects to apixaban). JNJ-64179375 will be administered in a 
dose-escalation manner, with planned doses of 0.3, 0.6, and 1.2 mg/kg in Cohorts 1, 2, and 3, 
respectively. In Part 1, the OC will be responsible for reviewing ongoing safety and efficacy data 
by unblinded subject treatment assignments approximately every 1 to 3 weeks. Subjects enrolled 
in the 3 optional cohorts will receive doses of JNJ-64179375 in the range of 0.1 to 1.8 mg/kg, 
which will be dependent on the available preliminary safety, tolerability, efficacy, PK, and PD 
data obtained from the preceding cohorts (refer to Section 6, Dosage and Administration for 
additional details). After all of the subjects in Part 1 are expected to have completed the 
Day 10-14 visit, an unblinded data review will be conducted by the OC, SC, IDMC, and sponsor 
to determine the dose range and doses for Part 2.
3.1.2.
Part 2: Dose-Response Evaluation
Part 2 of this study has an adaptive design, with the intent to optimize data collection for the 
dose-response evaluation using multiple comparison procedure and modeling (MCP-Mod). 
Eligible subjects prior to the first interim analysis in Part 2 will be randomly assigned equally to 
1 of up to 5 parallel treatment groups, including up to 4 dose levels of JNJ-64179375, given as a 
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single, active IV infusion, or oral apixaban 2.5 mg twice daily for 10 to 14 days. The number of 
doses and randomization ratio after the 2 interim analyses will depend on the interim analysis 
results. However, the number of ongoing doses of JNJ-64179375 in the study is not expected to 
exceed 4 doses. The Part 2 sample size is estimated to be 1,200 subjects. In Part 2, the IDMC 
will be responsible for monitoring ongoing safety and efficacy and for conducting the 2 planned 
interim analyses to apply the adaptive design rules. Subjects will be randomized to 1 of the 
treatment groups with a balanced randomization ratio until the first interim analysis. After the 
review of each planned interim analysis, the IDMC will make a recommendation to declare 
futility, adjust the study drug doses, or modify the randomization ratio (see Section 11.10, 
Interim Analyses for details). The SC and sponsor will make a decision whether to implement 
the IDMC’s recommendation. The interim analyses will be performed after approximately 
400 and 800 subjects are enrolled and are expected to have completed the Day 10-14 visit. The 
final number of subjects in each dose group will depend on the results of the interim analyses.
3.2.
Study Design Rationale
Blinding, Control, Study Phase/Periods, Treatment Groups
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (eg, demographic and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity 
of statistical comparisons across treatment groups. Blinded treatment will be used to reduce 
potential bias during data collection and evaluation of clinical endpoints.
The treatment phase duration of up to 14 days is the approved duration of therapy with apixaban 
after TKR surgery. JNJ-64179375 has an estimated human plasma t½ of approximately 25 days 
based on preliminary data in healthy subjects. The 16-week follow-up duration (18 weeks from 
dosing) in this study is approximately 5 times the calculated t1/2 of JNJ-64179375, and is 
therefore adequate for PK analysis and is consistent with the safety reporting period.
The dose-escalation design in Part 1 will allow for a careful stepwise approach to assess bleeding 
risk in subjects undergoing TKR surgery to determine the dose range for the parallel design in 
Part 2, which will confirm the safety and efficacy dose response of JNJ-64179375.
Study Population
The risk of VTE following major orthopedic surgery, specifically joint replacement surgery, has 
been well documented and the use of postoperative prophylactic anticoagulant therapy is widely 
accepted as standard of care.10,19 Over the past 20 years, Phase 2 studies of injectable 
anticoagulants 
(LMWH, 
fondaparinux) 
and 
all 
of 
the 
newer 
oral 
anticoagulants
(apixaban, rivaroxaban, dabigatran, and edoxaban) were conducted in this population using 
venography to detect asymptomatic DVT. Subsequently, all of these oral medications were
evaluated in large, similarly designed Phase 3 studies and have been approved by regulatory 
agencies for the prevention of VTE in TKR surgery because they were found to be at least as 
effective as LMWH, have a similar or improved bleeding profile, and have the convenience of 
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easy administration.9,13,15,23,24,30 Therefore, the TKR study population is appropriate to evaluate 
the efficacy and safety of JNJ-64179375.
Total knee replacement surgery is most commonly performed due to arthritic disease of the joint, 
which occurs primarily in older men and women. The risks of VTE and bleeding also increase 
with age. Therefore, the intended population, which includes both men and women who are at 
least 50 years of age, is also appropriate. Women of childbearing potential are excluded from this 
study because reproductive toxicology testing of JNJ-64179375 has not been conducted. 
Dose Selection
The Part 1 planned doses of JNJ-64179375 (0.3, 0.6, or 1.2 mg/kg) were chosen based on 
preclinical 
data
and 
data
from 
the 
Phase 
1
study 
in 
healthy 
subjects
(Protocol 64179375EDI1001). In preclinical venous thrombosis models in both rats and 
monkeys, JNJ-64179375 at a dose of 0.3 mg/kg demonstrated good efficacy, which increased 
even further at 1 mg/kg. In healthy subjects, the 0.3-mg/kg dose was associated with a maximum 
mean blood level of approximately 7 g/mL and TT prolongation of approximately 3-fold from 
baseline while the 1-mg/kg dose had maximum mean blood levels of about 30 g/mL, with 
TT prolongations of greater than approximately 5-fold from baseline. Both doses demonstrated 
an acceptable safety profile. Therefore, the starting dose of 0.3 mg/kg was selected as it should 
be effective for VTE prevention after TKR surgery and provides a wide safety margin from the 
Phase 1 doses that showed a bleeding signal (2.125 and 2.5 mg/kg). Dose escalation will then be 
guided by the OC based on accumulating data for both safety and efficacy. The highest planned 
dose in Part 1 of 1.2 mg/kg has been selected because it is similar to the 1-mg/kg dose studied in 
the Phase 1 study and is approximately 50% of the lowest dose with a bleeding signal 
(ie, 2.125 mg/kg) in healthy subjects. If the 0.3-mg/kg dose appears to be fully effective in 
Part 1, there is the option to study a lower dose (as low as 0.1 mg/kg); likewise, if the 1.2-mg/kg 
dose appears well tolerated and incremental benefit is expected from a higher dose, there is the 
option to study a higher dose (up to 1.8 mg/kg). The dose selection in Part 2 will be based on the 
safety and efficacy results/comprehensive analyses from Part 1, with the goal being to study the 
widest possible dose range supported by the data.
Choice of Comparator
An active control (apixaban) will be used because pharmacologic VTE prophylaxis is considered 
standard-of-care in subjects undergoing TKR surgery. Given that VTE and bleeding event rates 
vary across studies, the active control will also provide an internal reference for comparison with 
JNJ-64179375 in this study.
Apixaban was chosen as the comparator in this study because it is an approved oral drug for this 
indication, has a start time after surgery that is preferred by many surgeons, and has 
demonstrated favorable efficacy and safety (ie, bleeding) results compared with enoxaparin.
Refer to Section 1.2, Comparator Drug for additional details regarding apixaban.
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The 2.5-mg dose of apixaban, taken twice daily for 10 to 14 days beginning 12 to 24 hours after 
the end of TKR surgery will be used in this study as it is the approved dosage regimen 
(in approved countries) for the indication being studied.8
Choice of Efficacy Measures
Total VTE is a standard efficacy measure for Phase 2 TKR VTE prophylaxis studies. The use of 
venography to detect asymptomatic DVT and standardized definitions to assess bleeding events 
are specifically recommended as the best approach for the Phase 2 orthopedic surgery setting.7
The assessment time between Days 10-14 is appropriate given that it is the approved duration of 
therapy for apixaban.
Ultrasound is a noninvasive, widely available technique, with a high sensitivity and specificity 
for symptomatic DVT that has replaced venography in clinical practice for the diagnosis of 
DVT events (all DVT sensitivity 88%, specificity 96%).20 However, ultrasound has repeatedly
been shown to have very low sensitivity compared with venography for detecting asymptomatic 
DVT in the postoperative setting.20,27 In a meta-analysis of 15 studies, the sensitivity of 
ultrasound compared with venography for detecting asymptomatic DVT was 47%.20 More recent 
data are from the Phase 2 studies of rivaroxaban in DVT prophylaxis following hip and knee 
replacement surgeries, where a substudy (VENUS study) was conducted comparing venography 
to ultrasound. Despite rigorous methodology, including separate adjudication sites for each 
technique and a large number of matching pairs of evaluable venography assessments and
ultrasounds, the authors concluded that ultrasound cannot replace venography for DVT diagnosis 
in this setting. The observed frequency of any DVT was 18.9% with venography and 11.5% with 
ultrasound. 
The 
sensitivity 
of 
ultrasound
compared 
with 
venography 
was 
31.1% (95% confidence interval [CI]: 23.4, 38.9) for any DVT, 21.0% (95% CI: 2.7, 39.4) for 
proximal DVT, and 30.8% (95% CI: 23.1, 38.6) for distal DVT. The results for specificity were 
93.0% (95% CI: 91.0, 95.1), 98.7% (95% CI: 98.0, 99.5), and 93.3% (95% CI: 91.5, 95.3), 
respectively.27
Therefore, venography is still considered the gold standard and the only reliable method for 
diagnosing asymptomatic DVT after TKR surgery. The most likely explanations for the poor 
performance of ultrasound compared with venography in this setting are the nature of the clots 
that form early after surgery (small and compressible) compared with symptomatic clots 
(larger and noncompressible) and the distortion of the veins produced by the postoperative 
swelling.
Although research into new anticoagulants has slowed in recent years, all proof-of-concept 
studies using the postoperative orthopedic model have continued to use venography to assess the 
primary endpoint.5,22,31 Venography produces plausible and reliable results in clinical 
studies7,14,29 and no anticoagulant has been approved by a health authority for postoperative 
orthopedic DVT prophylaxis without venography data. Despite the challenges with performing
venography, it remains the standard for detecting DVT after TKR surgery and is the most 
appropriate method for use in this study. 
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Bilateral venography has been used in most but not all previous Phase 3 studies.11,13 However, as 
unilateral venography of the operated leg detects over 90% of DVTs after TKR surgery12 and 
exposes subjects to less risk (radiation, contrast dye, venipuncture) and less discomfort, only 
venography of the operated leg will be performed in this study.
Suspected symptomatic efficacy (thrombotic) events (ie, DVT, PE, death, MI, stroke, peripheral 
arterial embolism) will also be specifically assessed in this study as these are clinically important 
events from the perspective of both the subject and the surgeon.
Choice of Safety Measures/Assessments
Bleeding events are the standard primary safety endpoint in studies of anticoagulant 
VTE prophylaxis after TKR surgery. Because the occurrence of major bleeding events is 
infrequent and previous dose-ranging studies have demonstrated that all categories of bleeding 
events increase with dose in a similar manner, the any bleeding event composite will be the 
primary safety endpoint in this study.21 Published guidelines that describe how to define major 
bleeding events after major orthopedic surgery will be followed.28 For nonmajor bleeding events,
standardized definitions, as utilized in the Phase 3 studies of apixaban, will be followed.23,24 All
wound or joint complications will also be specifically assessed in this study as these are 
important from the perspective of both the subject and the surgeon.
Choice of PK and Immunogenicity Measures
Pharmacokinetic blood samples will be collected from all subjects and analyzed for subjects who 
are randomly assigned to treatment
with JNJ-64179375 to further understand the 
PK characteristics and variability of JNJ-64179375 in the TKR patient population. The 
combination of dense and sparse PK samples in this patient population will be sufficient for the
development of a population PK model and predicted concentrations from such a model will 
allow for the development of exposure-response models for various endpoints related to safety 
and efficacy. Immunogenicity blood samples will be collected from all subjects and analyzed for 
subjects randomly assigned to JNJ-64179375 to assess for the development of any ADAs.
Choice of Pharmacodynamic/Biomarker and PK/PD
The PD assays (TT, ECT, PT, aPTT, and D-dimer) will be used to evaluate the mechanism of 
action and pharmacologic activity of JNJ-64179375. A battery of coagulation assays with 
different inhibition profiles for JNJ-64179375 has been chosen to evaluate those assays that 
might be most appropriate for assessing both pharmacologic activity and any relationships with 
PK and/or efficacy and/or safety endpoints. The goal of the PD analyses is to evaluate the PD 
effects of JNJ-64179375, the PK/PD relationship, and PD outcome relationships. Additional 
details regarding the collection of the PD assessment blood samples and the test procedures will 
be included in the laboratory manuals. It is expected that apixaban will have no effect or minimal 
effects on all of the coagulation assays and therefore, analysis of the apixaban samples is not 
planned.
Biomarker samples may be used to help address emerging issues and enable the development of 
safer, more effective, and ultimately individualized therapies. An exploratory objective will be to 
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evaluate and compare the performance of the various PD assays. A central specialty laboratory 
will be used to provide more robust quality control for these assays by performing them in 
batches and to maintain the study blind. No local PD sample collection is planned. Detailed 
descriptions of each of the assays are provided in Section 9.4, Pharmacodynamic/Biomarker 
Evaluations.
Choice of Health Resource Utilization Data Collection
With the growing demand on limited healthcare resources and concern about healthcare 
expenditures, the collection of health resource utilization data will be integrated into the study. 
Health resource utilization endpoints collected from this study will be key inputs for conducting 
exploratory cost-effectiveness analyses.
4.
SUBJECT POPULATION
It is estimated that approximately 1,500 subjects will be randomly assigned to treatment in this 
study as described in Section 3.1.1, Part 1: Single-Ascending Dose and Section 3.1.2, Part 2: 
Dose-Response Evaluation. Subjects who are withdrawn early from the study will not be 
replaced. For a discussion of the statistical considerations of subject selection, refer to 
Section 11.2, Sample Size Determination.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed.
Screening for eligible subjects in Parts 1 and 2 may be done up to 30 days before randomization, 
pre- or postoperatively. Subjects will be eligible for rescreening only in those cases when 
TKR surgery is rescheduled outside of the 30-day window. Subjects may only be rescreened on 
1 occasion.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
Male or female of non-childbearing potential
2.
At least 50 years of age or older
3.
Weight 40 kg to 150 kg
4.
Medically appropriate for postoperative anticoagulant prophylaxis as determined by the 
investigator on the basis of the physical examination, medical history, and vital signs
measurements performed as part of screening for elective TKR surgery and any 
examinations performed as part of standard postoperative care following surgery
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5.
Medically appropriate for postoperative anticoagulant prophylaxis on the basis of 
clinical laboratory tests performed as part of screening for elective TKR surgery and any 
examinations performed as part of standard postoperative care following surgery. If the 
results of the laboratory tests are outside the normal reference ranges, the subject may 
be included only if the investigator judges the abnormalities or deviations from normal 
to be not clinically significant or to be appropriate and reasonable for the population 
under study. This determination must be recorded in the subject's source documents.
6.
Has undergone an elective primary unilateral TKR
7.
Must sign an informed consent form (ICF) indicating that he or she understands the 
purpose of, and procedures required for, the study and is willing to participate in the 
study.
8.
Before randomization, a woman must not be of childbearing potential defined as:
o
Postmenopausal
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level 
(>40 IU/L or mIU/mL) 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.
o
Permanently sterile
Permanent 
sterilization 
methods 
include 
hysterectomy, 
bilateral 
salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral 
oophorectomy.
If reproductive status is questionable, additional evaluation should be considered in 
consultation with the sponsor. 
9.
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study
10.
Contraceptive use by men should be consistent with local regulations regarding the use 
of contraceptive methods for subject participating in clinical studies.
During the study from Day 1 through the Week 18 visit, a man

Who is sexually active with a woman of childbearing potential must agree to use a 
barrier 
method 
of 
contraception 
(eg, 
condom 
with 
spermicidal 
foam/gel/film/cream/suppository)

Who is sexually active with a woman who is pregnant must use a condom

Must agree not to donate sperm

Must agree not to father a child
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11.
Willing and able to adhere to the prohibitions and restrictions specified in this protocol.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:
1.
Any condition for which the use of apixaban is not recommended in the opinion of the 
investigator (eg, spinal anesthesia procedure with bleeding or significant trauma, 
postoperative epidural analgesia with an epidural catheter within 5 hours of oral or 
IV study drug administration, previous allergic reaction, creatinine clearance 
<15 mL/minute or on dialysis)
2.
Bilateral, revision or unicompartmental procedure
3.
Known or suspected hypersensitivity or intolerance to any biologic medication or 
known allergies or clinically significant reactions to murine, chimeric, or human 
proteins, monoclonal antibodies or antibody fragments, or any of the excipients of 
JNJ-64179375 (refer to Investigator's Brochure)17
4.
Unable to undergo venography (eg, due to contrast agent allergy, poor venous access, or 
impaired renal function that would increase the risk of contrast-induced nephropathy)
5.
Known previous DVT in either lower extremity
6.
Chronic anticoagulation therapy for any condition (eg, atrial fibrillation, mechanical
heart valve) is required
7.
Any preplanned invasive procedure (eg, surgery, colonoscopy) up to Week 18 for which 
anticoagulant or antiplatelet therapy would be interrupted
8.
Planned use of intermittent pneumatic compression after randomization
9.
Received an investigational drug (including investigational vaccines, experimental 
antibody or biologic therapy) within the previous 6 months or 5 half-lives, whichever is 
longer, or received any other experimental therapy, or used an invasive investigational 
medical device within 60 days before the planned first dose of study drug or is currently 
enrolled in an investigational study
10.
Previous randomized subject in this study or participated in previous studies with 
JNJ-64179375
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11.
Any condition for which, in the opinion of the investigator, participation would not be 
in the best interest of the subject (eg, compromise the well-being) or that could prevent, 
limit, or confound the protocol-specified assessments
12.
Employee of the investigator or study site, with direct involvement in the proposed 
study or other studies under the direction of that investigator or study site, as well as 
family members of the employees or the investigator
13.
At the time of informed consent, the subject does not agree to following up with 
scheduled study visits or allowing a telephone contact to the subject’s alternative means 
of contact (eg, subject’s children, spouse, significant other, caretaker, legal 
representative, or healthcare professional), as necessary, until the end of the study,
should he or she discontinue prematurely
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study drug is given such 
that he or she no longer meets all eligibility criteria, then the subject should be excluded from 
participation in the study. Section 9.1.2, Screening Phase, describes options for retesting. 
Section 17.4, Source Documentation, describes the required documentation to support meeting 
the enrollment criteria.
4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation. Additionally, for 
apixaban, investigators should follow the prohibitions and restrictions in the Summary of 
Product Characteristics.
1.
Refer to Section 8, Prestudy and Concomitant Therapy for details regarding prohibited 
and restricted therapy during the study.
2.
Agree to follow all requirements that must be met during the study as noted in the 
Section 4.1, Inclusion Criteria and Section 4.2, Exclusion Criteria.
3.
A man who is sexually active must agree to use a barrier method of contraception 
method as described in Section 4.1, Inclusion Criteria. All men must also not donate 
sperm through the Week 18 visit.
4.
Subjects who are given permission by the treating physician to resume normal activity 
following TKR surgery should avoid activities that could produce significant trauma, 
and when participating in low-risk sports (eg, biking), proper safety gear 
(eg, helmet, gloves) should be worn through the Week 18 visit. In addition, subjects 
should be more cautious when using sharp objects (eg, razors, scissors, and knives) 
through the Week 18 visit.
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5.
Subjects should not donate blood or blood products for the duration of the study and for 
at least 4 weeks after the Week 18 visit.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. In Part 1, within each of the up to 
6 planned cohorts, subjects will be randomly assigned to 1 of 2 treatment groups based on a 
computer-generated randomization schedule prepared by or under the supervision of the sponsor. 
The randomization will be balanced by using randomly permuted blocks and in Part 2 will also
be stratified by region. The interactive web response system (IWRS) will assign a unique 
treatment code, which will dictate the treatment assignment for the subject. The requestor must 
use his or her own user identification and personal identification number when contacting the 
IWRS, and will then give the relevant subject details to uniquely identify the subject.
In Part 2, subjects will be randomly assigned to 1 of the treatment groups based on a 
computer-generated randomization schedule as previously described for Part 1. Separate 
randomization schedules will be used for Part 1 and Part 2 of the study.
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
Data that may potentially unblind the treatment assignment (ie, coagulation testing, study drug 
concentrations, antibodies to JNJ-64179375, study drug preparation/accountability data, 
treatment allocation, and biomarker laboratory data) will be handled with special care to ensure 
that the integrity of the blind is maintained and the potential for bias is minimized. This can 
include making special provisions, such as segregating the data in question from view by the 
investigators, clinical team, or others as appropriate until the time of database lock and 
unblinding. To maintain the blind of the study, the investigator should not measure coagulation 
assays locally unless considered necessary for subject clinical care. In addition, the investigator 
will not receive the results of the PD parameters from the central specialty laboratory during the 
conduct of the study.
Under normal circumstances, the blind should not be broken until all subjects have completed 
the study and the database is finalized. Otherwise, the blind should be broken only if specific 
emergency treatment/course of action would be dictated by knowing the treatment status of the 
subject. In such cases, the investigator may in an emergency determine the identity of the 
treatment by contacting the IWRS. While the responsibility to break the blind in emergency 
situations resides solely with the investigator, it is recommended that the investigator contact the 
sponsor or its designee if possible to discuss the particular situation, before breaking the blind.
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Telephone contact with the sponsor or its designee will be available 24 hours per day, 7 days per 
week. In the event the blind is broken, the sponsor must be informed as soon as possible. The 
date and time for the unblinding must be documented by the IWRS and the reason for the 
unblinding must be documented in the source document. The documentation received from the 
IWRS indicating the code break must be retained with the subject's source documents in a secure 
manner.
Subjects who have had their treatment assignment unblinded may continue on study drug unless 
the subject meets a study drug discontinuation criterion. Investigators should not disclose the 
treatment assignment to the subject whenever possible, even in a special situation where the 
treatment assignment has been unblinded to the investigator. Subjects who have had their 
treatment assignment unblinded should continue to return for scheduled evaluations.
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. However, the randomization codes and the translation of 
randomization codes into treatment and control groups will be disclosed to those authorized
individuals of the OC for the ongoing data reviews in Part 1 and of the IDMC for data reviews 
and interim analyses in Part 2. Refer to Section 11.10, Interim Analysis, Section 11.11.1,
Operations Committee, and Section 11.11.2, Independent Data Monitoring Committee for 
additional details.
JNJ-64179375 (Parts 1 and 2)
Using the randomization code, an unblinded pharmacist or other appropriately licensed and 
authorized health professional at each study site will prepare an individual study drug dose of 
JNJ-64179375 or JNJ-64179375 placebo (0.9% normal saline) for each subject in a 
50-mL normal saline IV bag as per the directions in the Investigational Product Preparation 
Instructions (IPPI). Subjects randomized to apixaban will receive a 0.9% normal saline IV bag 
with no active study drug. All study drugs will have a blinded label applied prior to dispensing.
Apixaban (Parts 1 and 2)
Using the randomization code, the pharmacist or other appropriately licensed and authorized 
health professional will dispense a bottle of blinded oral study drug (over-encapsulated apixaban 
tablets or matching apixaban placebo capsules) to each subject at the time of randomization. The 
subject will be administered the capsules from the bottle while hospitalized and will be given the 
bottle for outpatient use at the time of discharge from the hospital. Refer to Section 6, Dosage 
and Administration for additional details regarding subject dosing.
6.
DOSAGE AND ADMINISTRATION
In both Parts 1 and 2, subjects will be randomly assigned to receive an active single IV dose of 
JNJ-64179375 or apixaban 2.5 mg given orally twice daily for 10 to 14 days. The administration 
of the study drugs will begin the day after the TKR surgery (Day 1, 0 hours), while the subject is 
still hospitalized and within a minimum of 12 hours and a maximum of 24 hours after the end of 
the TKR surgery, defined as the time of wound closure. Within that timeframe, both the single 
IV infusion and the oral study drug should be administered as close as possible to each other, 
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with up to a maximum of 60 minutes between the start of the IV infusion and the first dose of the 
oral study drug. Subjects will be randomly assigned to the treatment groups as follows:
Part 1

Cohort 1: JNJ-64179375 0.3 mg/kg IV/JNJ-64179375 placebo (saline) IV infusion and 
matching apixaban placebo/apixaban, orally twice a day for 10 to 14 days

Cohort 2: JNJ-64179375 0.6 mg/kg IV/JNJ-64179375 placebo (saline) IV infusion and
matching apixaban placebo/apixaban, orally twice a day for 10 to 14 days

Cohort 3: JNJ-64179375 1.2 mg/kg IV/JNJ-64179375 placebo (saline) IV infusion and 
matching apixaban placebo/apixaban, orally twice a day for 10 to 14 days
Optional Cohorts (JNJ-64179375 in the Range of 0.1 to 1.8 mg/kg)
The doses of JNJ-64179375 to be used in the optional cohorts will be dependent on the available 
preliminary safety, tolerability, efficacy, PK, and PD data obtained from the preceding cohorts as 
described in Section 3.1.1, Part 1, Single-Ascending Dose. Doses within the optional cohorts will 
either be new doses within the range of 0.1 to 1.8 mg/kg not previously administered in the 
preceding cohorts, or doses from the preceding cohorts, which may be repeated, as needed.

Cohort 4: JNJ-64179375 Dose to be determined (TBD) mg/kg IV/JNJ-64179375 placebo 
(saline) IV infusion and matching apixaban placebo/apixaban, orally twice a day for 
10 to 14 days

Cohort 5: JNJ-64179375 Dose TBD mg/kg IV/JNJ-64179375 placebo (saline) IV infusion 
and matching apixaban placebo/apixaban, orally twice a day for 10 to 14 days

Cohort 6: JNJ-64179375 Dose TBD mg/kg IV/JNJ-64179375 placebo (saline) IV infusion 
and matching apixaban placebo/apixaban, orally twice a day for 10 to 14 days
Part 2

Group A: JNJ-64179375 Dose A mg/kg IV and apixaban placebo orally twice a day for 
10 to 14 days

Group B: JNJ-64179375 Dose B mg/kg IV and apixaban placebo orally twice a day for 
10 to 14 days

Group C: JNJ-64179375 Dose C mg/kg IV and apixaban placebo orally twice a day for 
10 to 14 days

Group D: JNJ-64179375 Dose D mg/kg IV and apixaban placebo orally twice a day for 
10 to 14 days

Group E: JNJ-64179375 placebo (saline) IV and apixaban 2.5 mg orally twice a day for
10 to 14 days
Doses of JNJ-64179375 may change after the interim analyses in Part 2 as described in 
Section 11.10, Interim Analyses.
For both parts, JNJ-64179375 will be prepared according to the subject’s weight and treatment 
assignment by the pharmacist or other appropriately licensed and authorized health professional 
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who is not blinded to the treatment assignment. All study drug administrations of JNJ-64179375
must be calculated based on the subject’s weight on Day -1 or prior to dosing on Day 1. The 
single infusion of JNJ-64179375 or JNJ-64179375 placebo (saline) will be administered under 
the supervision of the investigator or his/her designee over a period of approximately 30 minutes 
by infusion pump or by gravity flow using a flow regulator. A physician must be immediately 
available at the study site at all times during the administration of the study drug infusion. 
Detailed instructions for dose preparation, dosing procedures, and storage conditions of the study 
drug will be provided to the study site in the IPPI. These documents may be revised as needed 
and should be maintained in the study files.
The first dose of apixaban or matching apixaban placebo will be administered as previously 
described. Subjects will receive apixaban or matching apixaban placebo twice a day while 
hospitalized and will be given a supply of apixaban or matching apixaban placebo at the time of 
discharge or transfer to an alternate facility, with instructions to take the study drug orally, twice 
a day at approximately the same times each day to complete a total of 10 to 14 days of dosing. 
Apixaban or matching apixaban placebo should be swallowed with water, with or without food. 
If a dose of apixaban or matching apixaban placebo is missed, the missed dose should be taken 
as soon as possible and then the subject should continue with the twice-daily intake as previously 
instructed. The dose should not be doubled to make up for a missed dose and more than 2 doses 
should not be taken on the same day.
Refer to Section 14, Study Drug Information for details regarding a physical description of the 
study drugs, packaging, labeling, and preparation, handling, and storage.
7.
TREATMENT COMPLIANCE
Drug supplies will be inventoried and accounted for throughout the study. The IWRS will track 
the study drug dispensed to (JNJ-64179375 or apixaban/matching apixaban placebo) and 
returned by (apixaban or matching apixaban placebo only) subjects.
JNJ-64179375 or JNJ-64179375 placebo will be administered as a single IV infusion by 
qualified study site personnel and the details of the administration will be recorded. For apixaban 
or matching apixaban placebo, subjects will be required to return empty study drug containers 
and unused study drug at their Day 10-14 visit, at which time study drug accountability will be 
performed.
8.
PRESTUDY AND CONCOMITANT THERAPY
Modification of an effective preexisting therapy should not be made for the explicit purpose of 
entering a subject into the study.
The use of the following medications/therapies is not permitted from randomization through 
Week 18:
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
Additional anticoagulant(s) (eg, vitamin K antagonists, Factor IIa or FXa inhibitors). The 
blinded study drug (apixaban) will be discontinued in subjects who develop any condition 
that requires long-term anticoagulation (eg, DVT, atrial fibrillation). Refer to Section 9.2, 
Efficacy Evaluations for details regarding the management approach for subjects who 
develop a symptomatic VTE event or who have asymptomatic DVT detected by 
venography.

Antiplatelet therapies (eg, platelet adenosine diphosphate P2Y12 receptor antagonist
[eg, clopidogrel, ticagrelor]) during the study except for aspirin 100 mg/day

Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided, if possible, during the 
study because their use can increase the risk of bleeding and may interfere with collagen 
formation. If NSAID use is necessary, it is recommended that the minimum dose is used for 
the shortest possible duration.

Intermittent 
pneumatic 
compression 
after 
randomization 
(all 
other 
mechanical 
VTE prevention methods such as foot pumps, graduated compression stockings and 
continuous passive motion devices are permitted)
In addition, the use of the following medications is not permitted concomitantly with apixaban or 
matching apixaban placebo:

Concomitant systemic treatment with strong inhibitors of both cytochrome P450 (CYP) 3A4 
and P-glycoprotein (P-gp), such as azole-antimycotics (eg, ketoconazole, itraconazole, 
voriconazole, and posaconazole) and human immunodeficiency virus protease inhibitors 
(eg, ritonavir). These medicinal products may increase apixaban exposure by 2-fold or 
greater in the presence of additional factors that increase apixaban exposure (eg, severe 
renal impairment).8

Strong CYP3A4 and P-gp inducers (eg, rifampicin, phenytoin, carbamazepine, 
phenobarbital, or St. John’s Wort). The concomitant use with apixaban may lead to an 
approximately 50% reduction in apixaban exposure.8
Only selected medications administered up to 7 days before randomization will be recorded in 
the electronic case report form (eCRF) as prestudy therapies (eg, TXA, antiplatelet therapies, 
anticoagulant therapies, and NSAIDs).
All concomitant pharmacologic
therapies,
including prescription or over-the-counter 
medications, products to manage bleeding, vaccines, vitamins, and herbal supplements different 
from the study drug must be recorded throughout the study from the time of randomization 
through the last follow-up visit on Week 18.
All non-pharmacologic therapies such as intermittent pneumatic compression devices, foot pump 
devices, continuous passive motion devices, compression stockings, electrical stimulation, 
acupuncture, special diets, exercise regimens, including physical and occupational therapy must 
also be recorded in the eCRF.
Recorded information will include a description of the type of therapy, duration of use, dosing 
regimen, route of administration, and its indication.
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The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy, PK, 
immunogenicity, PD/biomarker, health resource utilization, and safety measurements applicable 
to this study. The Time and Events Schedule, and the description of the study phases that 
follows, are applicable to subjects participating in either Part 1 or Part 2 of the study, unless 
otherwise noted.
If multiple assessments are scheduled for the same time point, it is recommended that procedures 
be performed in the following order: ECG (as applicable), vital signs, and blood draw. 
Blood collections for PK and PD assessments should be kept as close to the specified time as 
possible. Other measurements may be done earlier than specified time points, if needed. Actual 
dates and times of assessments will be recorded in the source documentation. Blood samples for 
PK and PD assessments on Day 1 postdose should be collected in the opposite arm as the 
infusion of JNJ-64179375 or placebo. Blood samples will be collected in the following order: 
safety (serum chemistry, hematology), PK, immunogenicity, and PD.
Venous blood will be collected for all blood-based analysis. Blood will be drawn using a cannula 
or by venipuncture. Only saline (not heparin) can be used for flushing the cannula. If blood 
samples are collected via an indwelling cannula, an appropriate amount (ie, 1 mL) of fluid 
slightly greater than the dead space volume of the lock will be removed from the cannula and 
discarded before blood samples are taken.
The total blood volume to be collected from each subject will be approximately 95.4 mL for 
subjects with dense PK sampling and approximately 80.4 mL for subjects with sparse 
PK sampling as described in Table 6. It is important to record the exact date and time for 
PK sample collection even if the time deviates slightly from the scheduled time of collection.
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Table 6:
Volume of Blood to be Collected From Each Subject
Type of Sample
Volume per 
Sample (mL)a
No. of Samples 
per Subject
Approximate 
Total Volume of 
Blood (mL)b,c
Safety (including follow-up assessments)
Hematology
2.0
5
10.0
Serum chemistry
2.5
5
12.5
PK samples, including ADA, where required
Dense
5.0
9
45.0
Sparse
5.0
6
30.0
PD/Biomarker samples
TT, PT, aPTT
4.5
4
18.0
ECT (alone)
1.8
1
1.8
ECT including D-dimer
2.7
3
8.1
Approximate Totalc for Dense PK subjects
95.4
Approximate Totalc for Sparse PK subjects
80.4
ADA=antidrug antibody; aPTT=activated partial thromboplastin time; ECT=ecarin clotting time; No.=number; 
PD = pharmacodynamics; PK=pharmacokinetic, PT = prothrombin time; TT = thrombin time
a
Some sample volumes will vary slightly for subjects in Japan (due to customs requirements for laboratory 
tubes).
b
Calculated as number of samples per subject multiplied by volume of blood per sample.
c
Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples.
Note: An indwelling IV cannula may be used for blood sample collection.
Additional blood samples may be collected, if necessary, for additional safety, PK, or 
PD assessments based on emerging data, but the total blood volume collected from an individual 
subject during this study will not exceed 200 mL without prior Independent Ethics Committee 
(IEC) or Institutional Review Board (IRB) and health authority approvals. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples
and do not require prior IEC/IRB and health authority approvals.
Health resource utilization data will be collected. Refer to Section 9.6, Health Resource 
Utilization for details.
9.1.2.
Screening Phase
The screening phase will occur up to 30 days before randomization, pre- or postoperatively. 
Potential subjects may be evaluated for eligibility before or after their unilateral elective 
TKR surgery. Final eligibility must be confirmed after surgery, prior to randomization.
Prior to conducting any study-related procedure, the investigator (or designated study personnel) 
will review and explain the written ICF to each subject. No study procedures can be performed 
until the subject signs the ICF. At the time of informed consent, 2 alternative means of contact 
for the each subject will be collected (eg, contact information of the subject’s children, spouse,
significant other, caretaker, legal representative, or health care professional). Details regarding 
the TKR surgery and the post-surgery management (eg, type of anesthesia, procedure duration, 
cement use, tourniquet use and duration, drain use and volume, and use of all mechanical 
VTE prophylaxis methods) will be collected in the eCRF. In addition, the subject will respond to 
questions (see Attachment 1) regarding his or her family and personal bleeding history, including 
any bleeding from previous surgical procedures.
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Subjects will be eligible for rescreening only in those cases when TKR surgery is rescheduled
outside of the 30-day window. Subjects may only be rescreened on 1 occasion.
9.1.3.
Double-Blind Dosing Phase
Day 1/Day of Randomization
On Day 1, subjects who meet all of the eligibility criteria will be randomly assigned to study 
drug, either JNJ-64179375 or apixaban as described in Section 6, Dosage and Administration.
JNJ-64179375 or JNJ-64179375 placebo will be administered under the supervision of the 
investigator or his/her designee. Subjects will also begin to take oral apixaban or matching 
apixaban placebo twice daily. All procedures specified for the 0-hour time point should be 
conducted prior to the first dose of the study drug. The postdose samples will be drawn at 1 hour 
(10 minutes) and 4 hours from the start of the IV infusion.
Dosing Visits
Subjects will be discharged from the hospital or transferred to an alternate facility at an 
appropriate time as determined by the managing physician. The Day 2 blood sample will be 
drawn 24 hours after the start of the IV infusion and may be done with the subject as an inpatient 
or outpatient. Study procedures will be conducted on Days 3 (48 hours) and 7 (144 hours) only 
for those subjects who are still hospitalized. At the time of hospital discharge or transfer to an 
alternate facility, the subject will be reminded to continue to take the oral apixaban or matching 
apixaban placebo twice daily to complete a total of 10 to 14 days of dosing, the duration of 
which will be determined by the managing physician. Subjects who complete dosing with 
apixaban or matching apixaban placebo will return to the study site for final assessments in the 
double-blind dosing phase (Day 10-14 visit, end of dosing [EOD]), at which time a unilateral 
venography assessment of the operated leg will be performed within 24 hours of the last dose of 
apixaban or matching apixaban placebo. Further details regarding the venography are provided
in Section 9.2.1, Assessments for DVT.
Unscheduled Visits
At the discretion of the investigator, subjects may return to the study site between scheduled 
visits. Subjects should return to the study site for the assessment of any potential bleeding or 
efficacy endpoint events. Unscheduled PK and PD samples (except D-dimer) should be collected 
as soon as practically possible for any subject that experiences symptomatic thrombotic or 
bleeding events.
Early Withdrawal
Subjects who do not receive the full infusion of JNJ-64179375 or prematurely discontinue 
dosing with apixaban or matching apixaban placebo before the end of the double-blind dosing
phase will be instructed to return to the study site at the originally scheduled Day 10-14 visit
(not earlier) to conduct assessments, including the venography assessment of the operated leg. If 
a subject has a suspected symptomatic DVT prior to the Day 10-14 visit, an ultrasound will be 
performed. If the ultrasound confirms symptomatic proximal DVT, a subsequent venography 
assessment is not required. In addition, if the subject is diagnosed with a PE as defined in 
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Section 9.2.2, Assessments for PE, a venography assessment is not required. Refer to 
Section 9.2, Efficacy Evaluations for further details regarding anticoagulation treatment. If the 
ultrasound is negative or confirms a distal DVT, the venography assessment should be conducted 
on the Day 10-14 visit. Subjects should complete the remaining visits through the 
Week 18 assessments as indicated in the Time and Events Schedule. 
If a subject withdraws from the study before the end of the follow-up phase and is unwilling or 
unable to return for follow-up visits in person or have follow-up contacts, the study site should 
collect as much follow-up visit information as possible, including contacting the subject or the 
subject’s representative or health care professional by telephone or by mail to determine vital 
status and to collect medical information related to endpoint events, as agreed to by the subject 
during the initial informed consent process. For subjects who withdraw consent from study 
participation, the reasons for the withdrawal of consent should be documented in the source 
documents and entered in the eCRF. If applicable, vital status may be obtained by reviewing the 
subject’s medical or public records unless this contact is not permitted per local regulations.
Refer to Section 10.2, Discontinuation of Study Drug/Withdrawal from the Study for additional 
details.
9.1.4.
Follow-Up Phase
The first follow-up visit will occur approximately 3 weeks following the Day 10-14 visit, with 
subsequent follow-up visits occurring until Week 18 as described in the Time and Events 
Schedule. Reasonable attempts, as defined in Section 10.2, Discontinuation of Study 
Drug/Withdrawal from the Study should be made to conduct the follow-up visit(s) at the 
scheduled time points. Subjects will continue to be monitored for safety, including bleeding 
events and efficacy events, according to the time points indicated in the Time and Events 
Schedule.
9.2.
Efficacy Evaluations
Efficacy evaluations, including the unilateral venography assessment of the operated leg and 
assessments of symptomatic DVT, PE, death, or other thrombotic events (ie, MI, ischemic 
stroke, and peripheral arterial embolism) will be performed according to the time points in the 
Time and Events Schedule to assess the primary, secondary, and exploratory efficacy outcomes. 
All venography assessments, ultrasound evaluations for suspected symptomatic DVT, as 
applicable, and evaluations for suspected PE or other thrombotic events will be performed and 
read locally and sent for central adjudication by the independent CEC. The central adjudication 
evaluations will not be provided to the local sites.
The CEC-adjudicated and 
investigator-reported results on efficacy and safety outcomes will be provided for the unblinded 
data reviews and the interim analyses. The CEC-adjudicated events will be used in the final 
analysis. Refer to Section 11.11.4, Clinical Events Committee for additional details on the 
composition of the CEC and their responsibilities.
If an event or condition requiring anticoagulant treatment occurs during the double-blind dosing
phase then the blinded apixaban or matching apixaban placebo should be discontinued. 
Antithrombotic therapy management for conditions requiring anticoagulation (eg, new onset 
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atrial fibrillation, symptomatic DVT, or symptomatic PE) will be at the discretion of the local 
investigator. It is recommended that the event be treated with either a DOAC only or LMWH 
with a transition to a DOAC. If knowledge of the likely treatment group would change the 
planned event management strategy then local laboratory coagulation testing may also be 
considered, with a normal TT likely indicating the absence of JNJ-64179375. For asymptomatic 
distal DVT detected by venography, a possible management approach would be to use serial 
ultrasound to assess for any proximal progression and withhold anticoagulant therapy unless 
proximal progression is observed. If it is decided that treatment is to be given, the same approach 
as suggested for proximal DVT or PE is recommended.
In this study, all suspected symptomatic efficacy (thrombotic) events will also be captured as 
adverse events of special interest, which are defined in Section 9.7.2, Adverse Events of Special 
Interest.
9.2.1.
Assessments for DVT
Unilateral Venography
Venography assessments of the operated leg will be performed by injecting contrast agent into a 
foot vein and obtaining x-ray images of the proximal and distal leg veins consistent with the 
technique described by Rabinov and Paulin.26 Evaluable venography assessments require the 
visualization of all of the deep veins except for the muscular, anterior tibial, and deep femoral 
veins. A diagnosis of DVT will be made if a constant intraluminal filling defect is observed in at 
least 2 images. An ultrasound will be performed in those subjects with suspected symptomatic
DVT prior to the Day 10-14 visit. In these cases, if the ultrasound confirms symptomatic
proximal DVT, a subsequent venography assessment is not required. If the ultrasound is negative
or confirms a distal DVT, the venography assessment should be conducted on the 
Day 10-14 visit. Details regarding the timing of the venography assessment are provided in 
Section 9.1.3, Double-Blind Dosing Phase.
Study-specific venography assessment training will be provided to each study site. Each study 
site will be responsible for identifying at least 1 primary person to perform the venography 
assessments for subjects. Evaluability of the venography assessments based on centrally 
adjudicated data will be monitored for each site on an ongoing basis. If venography assessment 
performance is considered not acceptable, then further randomization by the investigator may be 
suspended until additional training or retraining is provided. Additional details regarding the 
venography procedure and study-specific training requirements will be provided in a venography 
manual, which will be provided separately to the study sites.
9.2.2.
Assessments for PE
For all subjects with symptoms of PE, spiral computed tomography (CT), pulmonary 
angiography, or perfusion/ventilation lung scintigraphy combined with chest radiography will be 
performed. A diagnosis of PE will be made only if the subject has symptoms of PE (eg, sudden 
onset of dyspnea, chest pain, or fainting), and 1 of the following criteria is met:
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
Positive spiral CT scan of the chest

Positive direct pulmonary arteriogram

High probability ventilation/perfusion lung scan (defined as 1 or more segmental or large 
[>75% of a segment] subsegmental perfusion defects associated with ventilation mismatch)

Intermediate probability ventilation/perfusion lung scan and ultrasound or venographic 
evidence of DVT

Autopsy confirmation
If a subject is diagnosed with a PE meeting the above definitions, a subsequent venography 
assessment of the operated leg is not required.
9.2.3.
Assessments for Other Thrombotic Events
Other thrombotic events will include MI, ischemic stroke, and peripheral arterial embolism. In 
addition, events that appear suggestive of study endpoints (eg, transient ischemic attack [TIA], 
unstable angina) will be reported by the investigator and reviewed by the CEC to ascertain if a 
thrombotic event has occurred. The investigator will use his/her medical judgment based upon 
the definitions below to determine if a thrombotic event has occurred.
Myocardial Infarction
The diagnosis of MI requires the combination of: 

Evidence of myocardial necrosis (either changes in cardiac biomarkers or postmortem
pathologic findings); and 

Supporting information derived from the clinical presentation, ECG changes, or myocardial 
or coronary artery imaging. 
Stroke
Stroke is defined as a new, sudden, focal neurologic deficit resulting from a presumed
cerebrovascular cause and not due to a readily identifiable cause such as trauma, a tumor, or 
seizure.
If an event matching this definition lasts less than 24 hours it will be considered a TIA unless 
imaging confirmation of infarction is obtained. Investigators will further classify the strokes 
based upon imaging studies.

Primary ischemic infarction – stroke without focal collections of intracranial blood
confirmed by imaging. The occurrence of hemorrhagic conversion of a primary ischemic 
infarction will be recorded.

Primary hemorrhagic – stroke with focal collections of intraparenchymal blood. The
diagnosis of primary hemorrhagic stroke can only be made with imaging studies. It may
include intraventricular hemorrhage.

Subarachnoid hemorrhage – the diagnosis requires documentation by an imaging study

Uncertain – no imaging or autopsy available
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Other events of intracranial bleeding such as subdural hematoma and epidural hematoma will not 
be considered to be a stroke as they are usually traumatic in nature.
Peripheral Arterial Embolism
A peripheral arterial embolism is defined as an abrupt vascular insufficiency associated with 
clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms 
(eg, trauma, atherosclerosis, instrumentation). In the presence of atherosclerotic peripheral 
vascular disease, diagnosis of embolism to the lower extremities should be made with caution 
and requires angiographic demonstration of abrupt arterial occlusion.
9.3.
Pharmacokinetics and Immunogenicity
Plasma samples will be used to evaluate the PK of JNJ-64179375, as well as the development of 
ADAs to JNJ-64179375 (immunogenicity).
9.3.1.
Evaluations
Samples for analysis of JNJ-64179375 plasma concentration will be collected for all subjects 
over time as specified in the Time and Events Schedule but will only be analyzed for subjects 
randomly assigned to JNJ-64179375. Dense PK sampling will be conducted at all sites for 
subjects at all visits in Part 1 until approximately up to the first 200 subjects have been 
randomized. Thereafter, the remaining subjects in Part 1 and all subjects in Part 2 will have 
PK blood samples collected at a limited number of visits (ie, sparse PK sample collection). The 
exact date and time of each PK blood sample collection will be recorded even if the time 
deviates slightly from the scheduled time of collection. Subjects who experience a bleeding event 
or symptomatic thrombotic event should have PK samples collected as soon as practically 
possible after the event occurs.
The timing of PK samples may be changed to ensure thorough PK monitoring; however, the total 
number of samples and/or the volume of blood drawn will not exceed the amount stated in 
Section 9.1.1, Overview without prior IEC/IRB and health authority approvals. Of note, 
additional blood samples may be collected for immediate safety monitoring of a subject and do 
not require prior IEC/IRB and health authority approvals. 
Samples collected for analyses of JNJ-64179375 plasma concentration and antibodies to
JNJ-64179375 may additionally be used to evaluate safety or efficacy aspects that address 
concerns arising during or after the study period, or for further characterization of 
immunogenicity. Genetic analyses will not be performed on these plasma samples. Subject 
confidentiality will be maintained. Additional information about the collection, handling, and 
shipment of biological samples will be provided in the laboratory manual.
9.3.2.
Analytical Procedures
Pharmacokinetics
Blood samples will be collected from all subjects according to the Time and Events Schedule 
and analyzed to determine plasma concentrations of JNJ-64179375 in appropriate samples using 
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a validated, specific, and sensitive immunoassay method by or under the supervision of the 
sponsor.
Immunogenicity
The detection and characterization of antibodies to JNJ-64179375 will be performed using a 
validated assay method by or under the supervision of the sponsor. All samples collected for 
detection of antibodies to JNJ-64179375 will also be evaluated for JNJ-64179375 plasma
concentration to enable interpretation of the antibody data. The Day 1, 0 hours (predose) 
ADA sample may be used for baseline characterization for both the PK and immunogenicity 
assays.
9.3.3.
Pharmacokinetic Parameters
The PK parameters to be calculated following the single IV dose of JNJ-64179375 will include, 
but are not limited to, the following:
Cmax
maximum concentration during a dosing interval
AUCinf
area under the plasma concentration versus time curve from time 0 to infinity
t1/2
terminal half-life
CL
total clearance of drug after IV administration
VZ
apparent volume of distribution in the terminal phase
Additional PK parameters may be determined, as appropriate.
Based on the individual plasma concentration-time data using the actual dose taken and the 
actual sampling times, PK parameters and exposure information of JNJ-64179375 will be 
derived using population PK modeling. Baseline covariates (eg, body weight, age, sex, creatinine 
clearance, race) may be included in the model, if relevant. A separate population PK modeling 
plan will be developed before the first subject is consented and the population PK modeling 
results will be reported separately, in a document other than the clinical study report (CSR).
9.3.4.
Immunogenicity Assessments
Blood samples for antibodies to JNJ-64179375 will be collected from all subjects according to 
the Time and Events Schedule but will only be analyzed in plasma samples for subjects 
randomized to JNJ-64179375. The exact date and time of each blood sample collection will be 
recorded. Additionally, samples should also be collected at the final visit from subjects who are 
discontinued from treatment or withdrawn from the study. These samples will be tested by the 
sponsor or sponsor's designee.
Plasma samples will be screened for antibodies binding to JNJ-64179375 and the titer of 
confirmed positive samples will be reported. Other analyses (eg, neutralization capacity) may be 
performed to further characterize the immunogenicity of JNJ-64179375. 
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9.4.
Pharmacodynamic/Biomarker Evaluations
All subjects will have plasma samples collected to assess PD markers as specified in the 
Time and Events Schedule. The assay plan is designed to assess target engagement and the 
mechanism of action with a battery of PD assessments. Pharmacodynamic evaluations will 
include the coagulation assays (ie, TT, ECT, PT, aPTT) and a D-dimer assessment. Subjects who 
experience a bleeding event or symptomatic thrombotic event should have PD samples (except 
D-dimer) collected as soon as practically possible after the event occurs. Samples on Day 1 will 
be obtained before the study drug is administered and at 1 hour after the start of the IV infusion 
and all assays will be performed by a central specialty laboratory. Additional information about 
the collection, processing, storage, and shipment of PD samples will be provided in a separate 
laboratory manual. It is expected that apixaban would have no effect or minimal effects on all of 
the coagulation assays and therefore, analysis of the apixaban samples is not planned.
To maintain the blind of the study, the investigator should not measure coagulation assays
locally unless considered necessary for subject clinical care. In addition, the investigator will not 
receive the results of the PD parameters from the central specialty laboratory during the conduct 
of the study.
Thrombin Time
The thrombin clotting time (designated TT) is a simple test that measures the time for clot 
formation in citrated plasma after the addition of thrombin. It reflects the effect of thrombin to 
cleave fibrinogen to form fibrin. Heparin and direct thrombin inhibitors such as hirudin, 
argatroban, and dabigatran are inhibitory, LMWH is partially inhibitory, and apixaban is 
inactive. 
Ecarin Clotting Time
The ECT test is based on the cleavage of prothrombin by ecarin, a highly purified 
metalloprotease isolated from the venom of the saw-scaled viper Echis carinatus. Ecarin 
generates meizothrombin from prothrombin, which is proteolytically active and can cleave
fibrinogen to form a fibrin clot. Meizothrombin, like thrombin, is inactivated by hirudin and 
other direct thrombin inhibitors, but is unaffected by heparin (as the heparin-antithrombin 
complex cannot inhibit meizothrombin due to steric hindrance). JNJ-64179375 is able to block 
the binding of meizothrombin to fibrinogen and therefore inhibit clot formation. This assay may 
offer potential advantages in sensitivity and useful range over the TT test.
Prothrombin Time
Prothrombin time is a global clotting test that is used for the assessment of the extrinsic pathway 
of the blood coagulation cascade. It is a 1-stage test based upon on the time required for a fibrin 
clot to form after the addition of Tissue Factor (historically known as tissue thromboplastin), 
phospholipid, and calcium to decalcified, platelet-poor plasma. The test is sensitive for 
deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X 
and less pronounced for Factor II. Prothrombin time and the normalized version, international 
normalized ratio, have been used to monitor warfarin therapy. It should be noted that currently, 
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3 types of PT reagents are used: recombinant thromboplastins, tissue thromboplastins (which are 
usually 
from 
rabbit 
brain 
or 
human 
placenta), 
or 
combined 
thromboplastins 
(tissue thromboplastin diluted into fibrinogen). These reagents differ in factor sensitivity, heparin 
responsiveness, lot-to-lot consistency, and absolute value of the clotting times.
Activated Partial Thromboplastin Time
Activated partial thromboplastin time is a measure of the intrinsic and final common pathways of 
the coagulation cascade. It represents the time, in seconds, for plasma to clot after addition of 
phospholipid, an intrinsic pathway activator, and calcium. The name 'Activated Partial 
Thromboplastin Time’ comes from the original form of the test in which only the phospholipid 
concentration of the test was controlled (as opposed to the phospholipid and the surface activator 
concentrations) and the name 'partial thromboplastin' was applied at the time to phospholipid 
preparations that accelerated clotting but did not correct the prolonged clotting times of 
hemophilic plasma. The term 'partial' means phospholipid is present but no tissue factor. The 
normal and reference ranges vary depending on reagent and instrument combinations, 
particularly with the phospholipid composition. It is used to evaluate the coagulation Factors XII, 
XI, IX, VIII, X, V, II (prothrombin), and I (fibrinogen) as well as prekallikrein and high 
molecular weight kininogen. Heparin and direct thrombin inhibitors, including hirudin, 
argatroban, and dabigatran have an effect on the assay.
D-dimer
The various states of coagulation activation that occur in vivo lead to the production of thrombin 
and then, fibrin. What follows is a reactive fibrinolysis, during which plasmin breaks down 
fibrin. The D-dimer is the ultimate degradation product of fibrin. The presence of D-dimer in 
plasma is an indirect marker of a coagulation activation followed by a reactive thrombolysis. 
Increased levels can be found in patients with DVT, PE, disseminated intravascular coagulation, 
hemorrhages, surgery, cancers, and severe infections. The D-dimer assay is an enzyme 
immunoassay procedure for the quantitative determination of D-dimer. 
9.5.
Pharmacokinetic/Pharmacodynamic Evaluations
The PD variables that will be evaluated for possible PK/PD relationships are TT, PT, and aPTT
(refer to Section 9.4, Pharmacodynamic/Biomarker Evaluations for a description of the 
PD variables). The PK of JNJ-64179375 to be used as predictor variables are Cmax and AUCinf
(but not limited to) obtained by population PK analysis as described in Section 9.3.3, 
Pharmacokinetic Parameters. The relationship between TT, PT, and aPTT and plasma exposure 
metrics (Cmax and AUCinf) will be evaluated using models that will further be detailed in a 
separate population PK modeling plan. 
9.6.
Health Resource Utilization
Health resource utilization data, associated with medical encounters, will be collected in the 
eCRF by the investigator and study-site personnel for all subjects throughout the study. 
Protocol-mandated procedures, tests, and encounters are excluded. Key parameters of healthcare 
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resource utilization will be collected for all subjects and compared between the treatment groups. 
The data collected will include the following:

Total length of initial hospitalization and length of stay for each specialized unit by level of 
care (eg, ward type, intensive care unit and cardiac care unit stays)

Rehospitalization for any reason through 18 weeks of follow up

Any scheduled and unscheduled visits to healthcare providers for study outcomes, any other 
medical reasons, and diagnostic procedures used in relation to study outcomes through 
18 weeks of follow up

Discharge destination from the initial or subsequent hospitalization(s) (eg, home, 
rehabilitation)

Details related to the management of any bleeding complications, (eg, procedures, extension 
of hospital stay, blood and/or plasma products)

Details regarding the management of subjects who develop symptomatic VTE
9.7.
Safety Evaluations
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule: adverse events, including serious adverse 
events, adverse events of special interest (ie, bleeding events, infusion reactions, hypersensitivity 
reactions, and wound or joint complications), clinical laboratory tests (ie, hematology, clinical 
chemistry, urinalysis), vital signs measurements (blood pressure, pulse/HR, temperature), and 
physical examinations. Safety evaluations may also be performed at unscheduled time points, if 
deemed by the investigator or appropriate designee as necessary to ensure the safety of the 
subject.
Any clinically relevant changes occurring during the study must be recorded on the adverse 
event section of the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached.
9.7.1.
Adverse Events
Adverse events, including serious adverse events, will be reported by the subject (or, when 
appropriate, by a caregiver, surrogate, or the subject's legally acceptable representative) for the 
duration of the study. Adverse events will be followed by the investigator as specified in 
Section 12, Adverse Event Reporting.
All adverse events, whether serious or nonserious, will be reported from the time a signed and 
dated ICF is obtained until the completion of the subject’s last study-related procedure. Refer to 
Section 12.3.1, All Adverse Events for additional details.
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Any wound or joint complications occurring after the TKR surgery will be specifically evaluated
as described in Section 9.7.2.3, Wound or Joint Complications. In addition, knee joint range of 
motion will be evaluated at Week 18 as described in Section 9.7.6, Physical Examination.
9.7.2.
Adverse Events of Special Interest
In this study, adverse events of special interest are:

Bleeding events (Section 9.7.2.1, Bleeding Events)

Infusion or hypersensitivity reactions (Section 9.7.2.2, Infusion or Hypersensitivity 
Reactions)

Wound or joint complications (Section 9.7.2.3, Wound or Joint Complications)
As previously noted in Section 9.2, Efficacy Evaluations, all suspected symptomatic efficacy
(thrombotic) events will also be captured as adverse events of special interest.
9.7.2.1.
Bleeding Events
9.7.2.1.1.
Classification of Bleeding Events
All subjects will be observed for signs and symptoms of bleeding events throughout the study 
and at each study visit as indicated in the Time and Events Schedule.
The investigator’s classification of bleeding events according to the protocol classification will 
be collected in the eCRF (refer to Attachment 2). In addition, Guidelines for Reporting Bleeding 
Event Verbatim Terms will be provided as noted in Section 15, Study-Specific Materials.
Additional information, including but not limited to the list below, will be collected for subjects 
with bleeding events and entered into the eCRF:

Location of the bleeding

Provocation of the bleeding

Association with any procedure

Action taken regarding the study drug

Concomitant or additional treatment given for this bleeding event

Any associated hemoglobin (and/or hematocrit) levels

Any associated blood transfusions and products

Hospitalization (or prolonged hospitalization) due to bleeding events

Outcome
All available information related to the classification of bleeding events will be collected and 
adjudicated by the independent CEC (refer to Section 11.11.4, Clinical Events Committee for 
additional details).
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9.7.2.1.2.
Approach to Subjects With a Bleeding Event
There is no antidote for either study drug. If a subject has a bleeding event requiring intervention 
during the study, the following measures should be considered for both study drugs:

Discontinue the study drug (refer to Section 10.2, Discontinuation of Study Drug/
Withdrawal from the Study)

Usual treatment measures for bleeding events, including local pressure, fluid replacement 
and hemodynamic support, blood transfusion, and fresh frozen plasma, if physical 
examination and laboratory testing suggest that benefit could be obtained

Other causes besides antithrombotic medication can be contributory to the seriousness of the 
bleeding event (ie, rule out disseminated intravascular coagulation, thrombocytopenia, and 
other coagulopathies, kidney and liver dysfunction, concomitant medications) and should be 
treated accordingly

Depending on local availability, consultation with a coagulation expert should be considered
If bleeding cannot be controlled by these measures, consider administration of 1 of the following 
procoagulants according to the dosages and dosing schedules that are recommended in their 
respective package inserts (Note: consultation with a coagulation expert is recommended before 
use):

PCC

Activated PCC

Factor VIIa
Of note, protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of 
either study drug. In a rat-tail transection bleeding model, Beriplex (4-factor PCC) and FEIBA 
(activated 4-factor PCC) returned bleeding times to control levels while TXA and activated 
Factor VIIa (NovoSeven) did not shorten the bleeding times after dosing with JNJ-64179375 at 
the doses studied. See Section 1.1.2.3, Parts 2 and 3 for reversal of PD effects for JNJ-64179375. 
Reversal of the PD effects of apixaban, as demonstrated by changes in the thrombin generation 
assay, was evident at the end of the infusion and reached baseline values within 4 hours after the 
start of a 30-minute infusion of 4-factor PCC in healthy subjects. However, there is little clinical 
experience with the use of 4-factor PCC products to reverse bleeding in individuals who have 
received apixaban. Currently, there is no experience with the use of recombinant Factor VIIa in 
individuals receiving apixaban. 
Due to its high molecular weight, JNJ-64179375 is not expected to be dialyzable. Hemodialysis
decreased the AUC of apixaban by 14% in subjects with end-stage renal disease when a single 
dose of apixaban 5 mg was administered orally. Therefore, hemodialysis is unlikely to be an 
effective means of managing an overdose with apixaban or to manage bleeding with 
JNJ-64179375.8
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In those cases where approaches to reduce the blood levels of the study drug are being 
considered:

In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of a 
20-mg dose of apixaban reduced mean AUC of apixaban by 50% and 27%, respectively, and 
had no impact on Cmax.·The mean half-life of apixaban decreased from 13.4 hours when 
apixaban was administered alone to 5.3 hours and 4.9 hours, respectively, when activated 
charcoal was administered 2 and 6 hours after apixaban. Therefore, administration of 
activated charcoal may be useful in the management of an overdose with apixaban or 
accidental ingestion.8

JNJ-64179375 has a plasma half-life of approximately 25 days as estimated from 
preliminary PK data in healthy subjects. Administration of IV immunoglobulins would be 
expected to increase the clearance of JNJ-64179375 by saturation of neonatal Fc receptors. 
A therapeutic plasma exchange to remove JNJ-64179375 could also be considered 
(estimated removal would be about 60% to 70% with 1 plasma volume exchange).33
9.7.2.2.
Infusion or Hypersensitivity Reactions
Infusion reactions or hypersensitivity reactions (eg, anaphylaxis, urticaria, dyspnea, hypotension) 
have been observed with the administration of monoclonal antibodies and may occur at any time 
during the administration of the IV study drug or within the first few hours after administration. 
Serum sickness-like reactions (also known as delayed hypersensitivity reactions) have been 
observed between 1 to 14 days after treatment. Symptoms associated with these reactions include 
fever, rash, headache, sore throat, myalgia, polyarthralgia, hand and facial edema, and/or 
dysphagia.
The IV study drug must not be administered to individuals with known or suspected intolerance 
or hypersensitivity to any biologic medication or known allergies or clinically significant 
reactions to murine, chimeric, or human proteins, monoclonal antibodies or antibody fragments, 
or to any of the excipients of the JNJ-64179375 formulation used in this study (refer to 
Section 4.2, Exclusion Criteria).
A physician must be immediately available at the site at all times during the administration of the 
study drug infusion as noted in Section 6, Dosage and Administration. All subjects will be 
carefully observed for symptoms of an infusion reaction during the infusion and for at least 
90 minutes after the start of the IV infusion and for the development of any allergic reaction 
during the study. The investigator should use clinical judgment in assessing the intensity of any 
infusion reactions. If an infusion reaction is observed, treatment such as oral 
paracetamol/acetaminophen and/or oral antihistamines may be administered. Details regarding 
the infusion reaction, including any medications administered, should be captured in the eCRF.
The following precautions should be applied during a study infusion:

Before an infusion is started, the appropriate personnel, medications (eg, epinephrine, 
inhaled -agonists, antihistamines, and corticosteroids), and other requirements to treat 
allergic reactions, including anaphylaxis, must be readily available.
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
If a subject has a moderate or severe infusion reaction, the infusion should be terminated 
immediately and the subject should be treated appropriately according to institutional 
guidelines.

Subjects discontinuing the study drug due to an infusion reaction will be asked to return for 
required assessments at all scheduled visits through the Week 18 visit. Refer to Section 10.2, 
Discontinuation of Study Drug/Withdrawal from the Study for additional details regarding 
subject discontinuation.
9.7.2.3.
Wound or Joint Complications
All subjects will be observed for signs and symptoms of wound or joint complications 
throughout the study and at each study visit as indicated in the Time and Events Schedule. The 
wound will be evaluated by the investigator for any abnormal bleeding, swelling, redness, 
drainage, or infection. Any joint complications such as bleeding/hematoma, infection, or 
prosthesis malfunction (eg, limited range of motion) will also be recorded as adverse events of 
special interest. Any medical or surgical treatments for wound or joint complications will be 
recorded as well.
9.7.3.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology and a urine sample for urinalysis will be 
collected. The investigator or appropriate designee must review the laboratory results, document 
this review, and record any clinically relevant changes occurring during the study in the adverse 
event section of the eCRF. The laboratory reports must be filed with the source documents.
At screening, the investigator will need to determine that the subject is medically appropriate for 
postoperative anticoagulant prophylaxis on the basis of clinical laboratory tests performed as part 
of local standard-of-care as part of screening for elective TKR surgery and as part of standard
postoperative care following surgery. Hematology and chemistry laboratory tests and a urine 
sample for urinalysis will be obtained before dosing (0 hour) and performed by the central 
laboratory. The following tests will be performed by the central laboratory:

Hematology Panel
-hemoglobin
-platelet count
-hematocrit
-mean corpuscular hemoglobin 
(MCH)
-red blood cell (RBC) count
-mean corpuscular hemoglobin 
concentration (MCHC)
-WBC count with differential
Mean corpuscular volume (MCV)
Note: A WBC evaluation may include any abnormal cells, which will then be reported by 
the laboratory. A RBC evaluation may include abnormalities in the RBC count, 
RBC parameters, or RBC morphology, which will then be reported by the laboratory.
In addition, any other abnormal cells in a blood smear will also be reported.
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
Serum Chemistry Panel
-sodium
-alkaline phosphatase
-potassium
-creatine kinase (CK) with myocardial band
fractionation, if elevated
-chloride
-lactic acid dehydrogenase (LDH)
-bicarbonate
-uric acid
-blood urea nitrogen (BUN)
-calcium
-creatinine
- phosphate
-glucose
-albumin
-aspartate aminotransferase (AST)
-total protein
-alanine aminotransferase (ALT)
-cholesterol
-gamma-glutamyltransferase (GGT)
-triglycerides
-total, direct and indirect bilirubin
-magnesium
-globulin

Urinalysis
Dipstick
Sediment (if dipstick result is
-specific gravity
abnormal)
-pH
-RBCs
-glucose
-WBCs
-protein
-epithelial cells
-blood
-crystals
-ketones
-casts
-bilirubin
-bacteria
-urobilinogen
-nitrite
-leukocyte esterase
If dipstick result is abnormal, flow cytometry will be used to measure sediment. In case of 
discordance between the dipstick results and the flow cytometric results, the sediment will 
be examined microscopically.
9.7.4.
Electrocardiogram
A 12-lead ECG will be performed during screening. During the collection of ECGs, subjects 
should be in a quiet setting without distractions (eg, television, cell phones). Subjects should rest 
in a supine position for at least 5 minutes before ECG collection and should refrain from talking 
or moving arms or legs. If blood sampling or vital signs measurements are scheduled for the 
same time point as ECG recording, it is recommended that the procedures be performed in the 
following order: ECG, vital signs, and blood draw.
9.7.5.
Vital Signs (temperature, heart rate, blood pressure)
Vital signs measurements will be obtained at the time points indicated in the Time and Events 
Schedule.
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Blood pressure and pulse/HR measurements will be assessed with subjects in the supine position
with a completely automated device. Manual techniques will be used only if an automated device 
is not available. Single measurements at each time point will be made. However, if any clinically 
significant abnormal values are detected (systolic blood pressure >160 or <90 mmHg, diastolic 
blood pressure >100 mmHg, HR <40 or >100 beats per minute) then repeat measurements will 
be performed at the discretion of the investigator.
Blood pressure and HR measurements should be preceded by at least 5 minutes of rest in a quiet 
setting without distractions (eg, television, cell phones).
The subject’s temperature should also be obtained.
9.7.6.
Physical Examination
The physical examination consists of a routine medical examination that includes general 
appearance and a review of the following systems: neurologic, eyes/ears/nose/throat, thyroid, 
cardiovascular, 
respiratory, 
abdominal/gastrointestinal, 
hepatic, 
musculoskeletal, 
and 
dermatologic. Any bleeding observed during the examination (eg, skin, gingiva, nares) will be 
recorded as a potential bleeding event as described in Section 9.7.2.1.1, Classification of 
Bleeding Events.
Additional body systems or further detailed physical examinations 
(eg, rectal examinations) should be performed if considered clinically appropriate by the 
investigator. Physical examinations will be performed by the investigator or a designated health 
care professional who is licensed and/or certified in accordance with applicable local laws to 
perform physical examinations.
Height and weight should be obtained at the screening visit, with weight only on Day -1 or prior 
to dosing on Day 1 and the final visit. Scales used should be calibrated according to the standard 
operating procedures at the study site to assure weight is accurate.
The physical examination will be conducted at the time points indicated in the Time and Events 
Schedule. An assessment of the wound will be made at all visits as part of the adverse event 
assessment and the final physical examination will assess the range of motion of the operated 
joint. Any new, clinically significant findings (in the opinion of the investigator) that were not 
noted at the time of the screening visit must be captured as adverse events and will be followed 
to resolution.
9.8.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded on the laboratory requisition 
form. If blood samples are collected via an indwelling cannula, an appropriate amount (1 mL) of 
serosanguineous fluid slightly greater than the dead space volume of the lock will be removed 
from the cannula and discarded before each blood sample is taken. After blood sample 
collection, the cannula will be flushed with 0.9% sodium chloride, United States Pharmacopeia 
(USP) (or equivalent) and charged with a volume equal to the dead space volume of the lock. 
Blood samples for PK and PD assessments on Day 1 post dosing should be collected in the 
opposite arm as the infusion of JNJ-64179375 or placebo.
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Refer to the Time and Events Schedule for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of all blood and urine samples are 
found in the separate laboratory manual that will be provided. Collection, handling, storage, and 
shipment of samples must be under the specified, and where applicable, controlled temperature 
conditions as indicated in the laboratory manual.
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY DRUG/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will be considered to have completed the study if he or she has completed the 
Week 18 visit of the follow-up phase.
Subjects who prematurely discontinue the study drug for any reason before completion of the 
double-blind dosing phase will be considered to have completed the study if they have completed 
the Week 18 visit. A subject who dies will be considered to have completed the study.
10.2.
Discontinuation of Study Drug/Withdrawal from the Study
It is imperative for the integrity of the study and results to have complete data. If a subject 
withdraws from the study before the end of the follow-up phase and is unwilling or unable to 
return for follow-up visits in person, the study site should collect as much follow-up visit 
information as possible, by contacting the subject by telephone or by mail. If applicable, vital 
status may be obtained by reviewing the subject’s medical or public records unless this contact is 
not permitted per local regulations.
Study drug assigned to a subject that discontinues study drug or withdraws may not be assigned 
to another subject. Subjects who withdraw will not be replaced.
Discontinuation of Study Drug
A subject will not be automatically withdrawn from the study if he or she has to discontinue the 
study drug before the end of the double-blind dosing phase.
Subjects who discontinue the study drug before the end of the double-blind dosing phase will be 
instructed to return to the study site, if possible, to conduct assessments, including venography 
assessments of the operated leg as described in Section 9.1.3, Double-Blind Dosing Phase. If a 
subject withdraws from the study before the end of the double-blind dosing phase, EOD and 
follow-up assessments should be obtained.
A subject's study drug must be discontinued for any of the following reasons:

The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it 
is in the best interest of the subject to discontinue study drug

The subject requests to discontinue the study drug permanently
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
Development of any condition that requires open-label treatment with an anticoagulant or 
other prohibited medication

Bleeding into a critical site, (eg, intracranial, intraspinal, intraocular, pericardial,
intra-articular, intramuscular with compartment syndrome, retroperitoneal)

Active uncontrolled hemorrhage

At the (exceptional) request of the sponsor
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow up

Withdrawal of consent
Withdrawal of consent should be a very unusual occurrence in a clinical study. Subjects 
who elect to stop the study drug are not automatically considered to have withdrawn 
consent. The investigator should make every effort to maintain a good relationship with 
subjects to avoid this occurrence. The recording of withdrawal of consent in the eCRF for 
this study will occur after a discussion between the investigator and the appropriate sponsor 
representative has taken place.
At the time of signing the ICF, a subject will agree to be contacted to obtain poststudy drug 
follow-up information should he or she decide to withdraw from the study. If a subject 
withdraws from the study before the end of the follow-up phase and is unwilling or unable to 
return for follow-up visits in person, he or she should be contacted and the study site should 
collect as much follow-up information as possible. This includes contacting the subject or the 
subject’s alternative means of contact (eg, subject’s children, spouse, significant other, caretaker, 
legal representative or health care professional), by telephone or mail to determine vital status 
and if an endpoint event has occurred, as agreed to by the subject during the initial informed 
consent process. If applicable, vital status may be obtained by reviewing the subject’s medical or 
public records, unless this process is not allowed by local regulations.
For subjects who withdraw consent and are not agreeable to any follow-up contact, it is 
recommended that the subject withdraw consent in writing, and the subject will be asked to 
supplement the withdrawal of consent with a signed written statement documenting refusal from 
all subsequent contact. If the subject refuses or is physically unavailable, the study site should 
document and sign the reason for the subject’s failure to withdraw consent in writing and 
maintain it with the subject’s source records.
When a subject withdraws consent before completing the study, it is not required for he/she to 
give a reason. If the reason for the withdrawal is known, it should be documented in the eCRF 
and in the source document.
If a subject is lost to follow up, every reasonable effort must be made by the study-site personnel 
to contact the subject and determine their status and the reason for discontinuation/withdrawal, 
including the possible use of locator agencies to determine vital status, as local law permits. The 
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measures taken to follow up must be documented. A subject will be considered lost to follow up 
only after all means of all subsequent contact have been exhausted.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in a statistical analysis plan (SAP), which will be 
prepared for Part 1 before the first subject is consented for Part 1. For Part 2, a draft SAP will be 
prepared before the first subject is consented into Part 1 and an updated Part 2 SAP based on the 
Part 1 data will be prepared before the first subject is consented in Part 2.
In Part 1, the intent is to escalate across the planned doses (0.3 to 0.6 to 1.2 mg/kg) of 
JNJ-64179375 based on the OC review of the totality of the data but with a focus on bleeding 
events. Specific analyses to be reviewed (eg, continual reassessment or escalation with overdose 
control methods) and dose-escalation decision guidelines will be included in the OC charter. 
After all subjects are expected to have completed the Day 10-14 visit for Part 1, an unblinded 
data review is planned and the selection of the dose range and doses for Part 2 will be based on 
the evaluation of the totality of the data but with a focus on the any bleeding and total VTE 
endpoints. Analyses to aid in dose selection will be prespecified in the OC charter and the Part 1 
SAP. No formal hypothesis testing is planned for Part 1 due to the limited sample size. Historical 
apixaban bleeding and VTE event rates may also be considered in making decisions. 
In Part 2, this study will use an adaptive design intended to optimize data collection for 
dose-response modeling. In Part 2, the primary goal is to assess the efficacy (total VTE endpoint) 
dose-response relationship of JNJ-64179375. A hybrid methodology that combines aspects of 
multiple testing with modeling techniques (MCP-Mod) will be used for evaluating dose-response 
trends and estimating the dose-response relationships for the efficacy and bleeding endpoints for 
JNJ-64179375.2,3,25 The sample size for Part 2 may be adjusted based on the observed bleeding 
and total VTE event rates in Part 1. Additional details are provided in Section 11.3, Efficacy and 
Bleeding Analyses.
If a sufficient number of JNJ-64179375 doses (ie, 4 or more) are studied in Part 2 then dose-
response modeling using the MCP-Mod approach will be the primary analysis strategy. If the 
number of JNJ-64179375 doses is not sufficient to support the MCP-Mod approach then linear 
dose-response modeling (if 3 doses are studied), or pairwise comparisons (if 2 doses are studied),
will be the primary analysis strategy. 
An unblinded data review is planned for Part 1 after all subjects are expected to have completed
the Day 10-14 visit to determine the dose range and doses of JNJ-64179375 for Part 2. Two 
planned, unblinded interim analyses and 1 unblinded administrative interim analysis are intended
for Part 2 of this study. Refer to Section 11.10, Interim Analyses for further details.
11.1.
Analysis Datasets
The 2 elements that define an analysis data set are: 
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
The analysis population, which specifies those subjects who will be included in an analysis

The observation period, which specifies the time window within which data will be included 
in an analysis
Efficacy Analyses
Two populations will be used in the efficacy analyses:

Modified Intent to Treat (ITT): all randomized subjects with an evaluable venography 
assessment or a confirmed symptomatic VTE event, or any death.

Efficacy Per Protocol: all randomized subjects with no major protocol deviations (to be 
defined in the SAP) and an evaluable venography assessment within 24 hours after the last 
dose of the oral study drug or with confirmed symptomatic VTE within 2 days of the last 
dose of oral study drug, or any death within 2 days of the last dose of oral study drug. 
Subjects without symptomatic VTE or death must also have received the single complete 
infusion of JNJ-64179375 or at least 18 doses of oral apixaban.
The 2 observation periods to be used in the efficacy analyses include the following:

Up to Day 10-14 visit (venography assessment)

Up to the Week 18 visit
The primary efficacy endpoint analysis (total VTE) will use the modified ITT population up to 
the Day 14 observation period. Additional details will be provided in the SAP.
Bleeding Event Analyses
Two populations will be used in the bleeding event analyses:

Safety: all randomized subjects who received at least 1 dose (partial or complete) of active 
study drug

Safety Per Protocol: all randomized subjects with no major protocol deviations who received 
the single complete infusion of JNJ-64179375 or at least 18 doses of oral apixaban or with a 
bleeding event centrally adjudicated by the CEC within 2 days of the last dose of oral study 
drug
The 3 observation periods to be used in the bleeding event analyses include the following:

Up to Day 10-14 visit (venography assessment)

Up to the Week 5 visit

Up to the Week 18 visit
The primary bleeding event analysis (any bleeding) will use the safety population up to the 
Day 10-14 visit observation period.
11.2.
Sample Size Determination
A total of 1,500 subjects are planned for this study, of which up to 300 subjects will be enrolled 
in Part 1 and the remainder for the entire study will be enrolled in Part 2. In Part 1, the sample 
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size is not based on hypothesis testing but rather on making a preliminary assessment of the 
bleeding risk for the doses of JNJ-64179375. The event rate of any bleeding up to 14 days for 
apixaban 2.5 mg twice daily is expected to be between 5% and 10%. Figure 2 shows the 
probability to flag a higher event rate compared to apixaban for any dose of JNJ-64179375 in 
Part 1, assuming that the true underlying bleeding event rate in the apixaban group is 5%, 7.5%, 
or 10%. The figure presents the numbers of subjects in the JNJ-64179375 and apixaban 
treatment groups in rows and columns, respectively. The assumed event rate in the 
JNJ-64179375 group is presented as the relative risk to apixaban in the horizontal axis; the 
statistical comparison is based on the difference between event rates.
When the true underlying event rate in the apixaban group is 7.5%, there is a 67% probability for
a dose of JNJ-64179375 to have the lower bound of the 1-sided 90% CI for between-treatment 
difference exclude 0 if the true relative risk (or risk ratio) is 3 (ie, the true underlying event rate 
in the JNJ-64179375 group is 22.5%), with 40 subjects in the JNJ-64179375 group (ie, any 
1 planned cohort of JNJ-64179375 subjects) and 30 subjects in the apixaban group (ie, pooled 
apixaban subjects from 3 planned cohorts). The probability will increase to 81% when the dose 
of JNJ-64179375 is repeated in another planned or optional cohort, where there will be 80 
subjects in the JNJ-64179375 treatment group and 40 subjects in the pooled apixaban group.
Figure 2:
Probability to Flag a Higher Event Rate in the JNJ-64179375 Group Than in the Apixaban 
Group at a 1-Sided, 10% -Level
JNJ-9375=JNJ-64179375
In Part 2, it is anticipated that 10% to 20% of subjects will either not have the venography 
assessment of the operated leg performed as scheduled or will not have an evaluable venography 
assessment for any DVT or proximal DVT. Assuming that 80% of venography assessments are 
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evaluable and the true underlying total VTE event rates are 15%, 10%, 8%, and 6% at potential 
doses of JNJ-64179375 of 0.3, 0.6, 0.9, and 1.2 mg/kg, respectively, with a total sample size of 
1,200 subjects, the study is expected to have over 90% power to declare proof-of-efficacy, which 
is defined as either a statistically significant dose-response trend or a total VTE event rate lower 
than 30% in the pooled doses of JNJ-64179375 at a 1-sided, 2.5% -level. The exact power will 
vary because of the nature of the adaptive study design.
For comparison with apixaban in Part 2, if the true underlying total VTE and any bleeding event 
rates are as specified in Table 7, a simulation study demonstrates that there will be approximately 
90% probability to identify a dose within the dose range of 0.3 to 1.2 mg/kg, of which both the 
model-predicted total VTE and any bleeding event rates met the prespecified noninferiority (NI) 
criterion (the upper bound of the 1-sided 90% CI for the odds ratio [JNJ-64179375 to apixaban]
is equal to or lower than 1.5 for total VTE and any bleeding events).
Table 7:
Assumed Efficacy and Safety Event Rates by Treatment Group in Sample Size Determination
for Part 2
JNJ-64179375
Apixaban
0.3 mg/kg
0.6 mg/kg
0.9 mg/kg
1.2 mg/kg
2.5 mg bid
Total VTE
(Efficacy)
15%
10%
8%
6%
15%
Any Bleeding
(Safety)
5%
6%
7%
8%
8%
bid=twice daily; VTE=venous thromboembolism
11.3.
Efficacy and Bleeding Analyses
A dose-response trend will be assessed with respect to the primary efficacy (total VTE) and 
safety (any bleeding) endpoints in Part 2. Depending on the number of doses studied, a set of up 
to 7 candidate models (doses are in logarithm scale) will be used to cover a suitable range of 
possible efficacy dose-response shapes (linear, Emax, exponential, sigEmax1, sigEmax2, 
sigEmax3, and sigEmax4) (see Figure 3). 
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Figure 3:
Candidate Models for Total VTE (Efficacy)
sigEmax 2
sigEmax 3
sigEmax 4
Linear
Emax
Exponential
sigEmax 1
0.3
0.6
0.9 1.2
1.80.3
0.6
0.91.2
1.80.3
0.6
0.91.2
1.8
0.3
0.6
0.91.2
1.8
5
10
15
20
25
5
10
15
20
25
Dose (mg/kg)
Event Rate (%)
VTE=venous thromboembolism
Similarly, a set of up to 6 candidate models will be used to cover a suitable range of safety dose-
response shapes (linear, Emax, exponential, sigEmax1, sigEmax2, and sigEmax3) (see Figure 4). 
The set of safety candidate models used will be similarly chosen as for the efficacy candidate 
models, which is dependent on the number of doses studied in Part 2.
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Figure 4:
Candidate Models for Any Bleeding (Safety)
sigEmax 1
sigEmax 2
sigEmax 3
Linear
Emax
Exponential
0.3
0.6
0.9 1.2
1.80.3
0.6
0.9 1.2
1.80.3
0.6
0.9 1.2
1.8
4
6
8
10
4
6
8
10
Dose (mg/kg)
Event Rate (%)
Each of the dose-response shapes in the candidate set will be tested using the corresponding 
contrast t-test statistic, employing a critical value derived for the maximum of the t-test statistics 
(based on the associated multivariate t-distribution) to ensure appropriate multiplicity correction 
that preserves the Type I error rate. A dose-response trend is established for an endpoint when 
the maximum of the t-test statistics for the corresponding endpoint exceeds the critical value.
Predicted event rates at a specific dose will be derived for each candidate model. The weighted 
average of these predicted event rates (weights are determined by the model goodness-of-fit), 
will then be used to estimate the target dose.4,16 The minimum dose that meets the NI efficacy 
criterion (defined as the upper bound of the 1-sided 90% CI for model-predicted 
JNJ-64179375/apixaban odds ratio less than 1.5) is considered as the minimum effective dose. 
The highest dose to be considered to proceed is the maximum dose that meets the NI safety
criterion
(defined as the upper bound of the 1-sided 90% CI for model-predicted 
JNJ-64179375/apixaban odds ratio less than 1.5). Any dose between the minimum effective dose 
and the highest dose to proceed is considered an eligible dose to be further studied in a 
subsequent study(ies). The final dose selection will be based on the consideration of the total 
benefit-risk balance. 
The determination of the NI criterion above is based on 2 considerations: 1) distribution of the 
point estimate for the odds ratio for the given sample size when the NI criterion is met; and 
2) the balance between the false-positive rate (incorrectly conclude an inferior dose to be 
comparable to apixaban) and the false-negative rate (incorrectly conclude an efficacious dose to 
be inferior to apixaban). With the given sample size and event rates as specified in Table 7, the 
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median corresponding odds ratio in 10,000 simulated studies is approximately 1.0 for total VTE 
and 0.94 for any bleeding. With the same assumptions, these NI criteria will yield approximately 
90% probability to correctly identify an eligible dose for subsequent study(ies).
The details of the adaptive decision guidelines for adding and/or dropping treatment groups or 
changing the randomization ratio in Part 2 will be specified in the IDMC charter and the
Part 2 SAP.
Prespecified clinical variables of interest for the efficacy subgroup analyses include region, age, 
sex, weight/body mass index, renal function, surgery duration, TXA use, tourniquet use, and 
mechanical VTE prophylaxis device use. The same variables will be used for safety subgroup 
analyses with the addition of aspirin/NSAID use.
11.4.
Pharmacokinetic Analyses
Plasma concentrations of JNJ-64179375 will be listed for all subjects by time of collection and 
dose level. For each dose, descriptive statistics, including mean, median, standard deviation
(SD), and coefficient of variation will be calculated for the plasma concentrations at each 
nominal sampling time. Plasma concentrations of JNJ-64179375 versus time profiles will be 
plotted for each subject based on actual sampling times, and mean concentration versus time 
profiles will be plotted for each dose level based on planned sampling times. 
Data will be listed for all subjects with available plasma concentrations per treatment group. 
Subjects will be excluded from the PK analysis if their data do not allow for accurate assessment 
of the PK (eg, incomplete administration of the study drug; missing information of dosing and 
sampling times; concentration data not sufficient for PK parameter calculation).
All plasma concentrations below the lowest quantifiable concentration or missing data will be 
labeled as such in the concentration database. Concentrations below the lower quantifiable 
concentration will be treated as zero in the summary statistics. All subjects and samples excluded 
from the analysis will be clearly documented in the study report.
In addition, a population PK model will be developed and the dependence of PK of 
JNJ-64179375 on population covariates (eg, demographics, laboratory variables) will be 
evaluated. This will be performed using nonlinear mixed-effects modeling with the software 
package NONMEM. The mean (and variance) values for specific PK parameters (eg, CL and 
Vz) will be estimated and the statistical significance of the relationships between the covariates 
and PK parameters will be evaluated. The results of this population PK (PK parameters 
signifying relationship between PK and various covariates) analysis will be reported separately, 
in a document other than the CSR.
11.5.
Immunogenicity Analyses
The incidence of antibodies to JNJ-64179375 will be summarized for all subjects who receive a 
dose of JNJ-64179375 and have at least 1 appropriate sample obtained after study drug 
administration for the detection of antibodies to JNJ-64179375.
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A listing of subjects who are positive for antibodies to JNJ-64179375 will be provided. The 
maximum titers of antibodies to JNJ-64179375 will be summarized for subjects who are positive 
for antibodies to JNJ-64179375.
Analyses of the impact of immunogenicity on PK, PD, PK/PD, efficacy, and safety endpoints
will be performed to further characterize the immune responses that are generated.
11.6.
Pharmacodynamic/Biomarker Analyses
The PD parameters are TT, ECT, PT, aPTT, and D-dimer. Descriptive statistics including mean, 
median, SD, minimum, and maximum will be provided for the PD parameters. The parameters of 
TT, PT, and aPTT may be statistically analyzed using mixed models. The mixed model for the 
change from baseline PD parameters will include dose and visit as fixed effects and subjects as 
random effects. The least-squares means for change from baseline and associated 95% CIs will 
be provided. Other PD parameters may be analyzed similarly.
11.7.
Pharmacokinetic/Pharmacodynamic Analyses
The PK/PD relationships will be investigated graphically and, if appropriate, may be further 
analyzed using suitable statistical methods.
Plasma PK exposures (Cmax, AUCinf, and/or time-matched concentration) from the population 
PK model versus PD variables (eg, TT and aPTT) and safety/efficacy endpoints will be 
graphically examined. This can be accomplished by plotting relevant PD measures versus 
PK exposure parameters (quantiles/deciles) for preliminary assessment and possible model 
identification. If the graphical representation of the relationship indicates possible correlation, 
then these data may be analyzed statistically using a suitable model. For example, a 
mixed-effects linear model may be used to identify the possible relationship between PK and PD. 
Other models using time-matched concentrations with PD may also be used for exploring the 
relationship further, as appropriate. Other PD variables (eg, ECT) may be analyzed in a similar 
fashion. The details of the analyses plan will be presented in a population PK modeling plan that 
is separate from the SAP.
Preliminary assessments of these relationships will be made available to the IDMC at both 
interim analyses to support their evaluations.
11.8.
Health Resource Utilization Analyses
Health resource utilization will be descriptively summarized by treatment group.
11.9.
Safety Analyses
All safety data will be fully listed. The reporting of the safety data of all subjects receiving at 
least 1 active dose of JNJ-64179375 or apixaban will include the incidence and type of adverse 
events, plus absolute values and changes in blood pressure (systolic and diastolic), HR, clinical 
laboratory data, and physical examinations from predose to the final postdose time point.
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Adverse Events
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded 
using the MedDRA. Treatment-emergent adverse events are adverse events with onset during the 
treatment phase or that are a consequence of a preexisting condition that has worsened since 
baseline. All reported adverse events will be included in the analysis. For each adverse event, the
percentage of subjects who experience at least 1 occurrence of the given event will be 
summarized by treatment group. In addition, comparisons between treatment groups will be 
provided if appropriate.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or a serious adverse event.
Based on the mechanism of action of JNJ-64179375 and given that it is a monoclonal antibody, 
adverse events of special
interest will include bleeding events, infusion reactions,
hypersensitivity reactions, and wound or joint complications as described in Section 9.7.2, 
Adverse Events of Special Interest. Subjects with adverse events of special interest may be 
counted or listed using MedDRA SMQs (eg, hemorrhage excluding laboratory terms SMQ). All 
suspected symptomatic efficacy (thrombotic) events will also be captured as adverse events of 
special interest.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Part 1 and Part 2 SAP) will be used in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline 
and for observed values and changes from baseline at each scheduled time point. Frequency 
tabulations of the changes from baseline will be presented in pre- versus posttreatment 
cross-tabulations (with classes for below, within, and above normal ranges). Frequency 
tabulations of the abnormalities will be made. A listing of subjects with any laboratory results 
outside the reference ranges will be provided. A listing of subjects with any markedly abnormal 
laboratory results will also be provided.
Vital Signs
Descriptive statistics of temperature, HR, and blood pressure (systolic and diastolic) (supine)
values and changes from baseline will be summarized at each scheduled time point. The 
percentage of subjects with values beyond clinically important limits will be summarized.
Physical Examination
Descriptive statistics of changes from baseline will be summarized at each scheduled time point.
Physical examination findings will be summarized at each scheduled time point. Descriptive 
statistics will be calculated at baseline and for observed values and changes from baseline at each 
scheduled time point. Frequency tabulations of the abnormalities will be made.
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11.10. Interim Analyses
Two planned, unblinded interim analyses will be conducted in Part 2 by the IDMC as part of the 
adaptive approach that will be used to guide decisions to drop and/or add doses of JNJ-64179375 
and adjust the randomization ratio based on available efficacy, safety, PK, and PD data. The 
objectives of the interim analyses are to:

Test futility

Test dose-response trends to determine if the dose range being studied is appropriate for 
both efficacy and safety

Determine if a dose(s) should be added and/or dropped to optimize data collection for 
dose-response modeling

Determine how to allocate the remaining subjects optimally (based on observed efficacy, 
safety, or balanced efficacy/safety results)
These 2 interim analyses will be performed after approximately 400 and 800 subjects are 
enrolled and are expected to have completed the Day 10-14 visit. Depending on interim analysis 
results, possible modification options to study conduct are stopping the study prematurely for 
futility, adding/dropping a dose of JNJ-64179375, and adjusting randomization ratio based on 
optimization of the dose-response model estimation.
Subject randomization will be balanced until the first interim analysis. Adaptation guidelines, 
including futility, adding/dropping a dose, modification of the randomization ratio, will be 
specified in the IDMC charter and the Part 2 SAP.
Administrative Interim Analysis
An unblinded administrative interim analysis is planned to be conducted by the sponsor after all
subjects are expected to have completed the Day 10-14 visit in Part 2 to facilitate additional 
study planning. Details of this interim analysis will be described in the Part 2 SAP. The conduct 
and integrity of the study will not be altered by the results of this interim analysis.
11.11. Committees
11.11.1.
Operations Committee
During Part 1 of the study, an OC consisting of members of the academic leadership of the study, 
including the SC and IDMC chairpersons, and clinical and biostatistics representatives from the 
sponsor (not directly involved in study monitoring) will review ongoing unblinded safety and 
efficacy data. The OC will be responsible for:

Reviewing ongoing safety and efficacy data by unblinded subject treatment assignments
approximately every 1 to 3 weeks

Determining the cohort sizes and number of cohorts for the up to approximately 300 unique 
subjects in Part 1

Making dose-escalation decisions in Part 1, including but not limited to deciding whether to 
proceed with optional cohorts and at what dose(s)
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
Reviewing the data for Part 1
The details of the OC function and composition, as well as dose-escalation decision guidelines 
will be described in the OC charter.
After all the subjects to be enrolled in Part 1 are expected to have completed the Day 10-14 visit, 
an unblinded review of available preliminary safety, tolerability, efficacy, PK, and PD data will 
be conducted to determine the dose range and number of dose groups (maximum of 4 for 
JNJ-64179375 and 1 for apixaban) for Part 2. This Part 1 data review will be conducted by the 
OC, SC, IDMC, and the sponsor.
11.11.2.
Independent Data Monitoring Committee
An unblinded IDMC will be established to monitor ongoing safety data in Part 2. The 
IDMC activities will include participation in the unblinded data review after all subjects in Part 1 
are expected to have completed the Day 10-14 visit to determine the dose range and doses of 
JNJ-64179375 for Part 2 and to conduct the 2 planned interim analyses, applying the adaptive 
design rules for the study as described in Section 11.10, Interim Analyses. The IDMC will 
consist of individuals who are not participating in the conduct of the study and will include at 
least one medical expert in the relevant therapeutic area and at least one statistician. Following 
the interim analyses, the IDMC will be responsible for providing their recommendations for 
study modifications to the SC and sponsor. The IDMC responsibilities, authorities, and 
procedures will be documented in a separate charter.
11.11.3.
Steering Committee
A SC with expertise in thrombosis, thromboprophylaxis, hematology, orthopedic surgery, and 
clinical studies will be commissioned to provide scientific leadership for both Parts 1 and 2 of 
the study. The SC will be responsible for providing advice to the sponsor in an effort to ensure 
the scientific validity and integrity of the study and for the publication of results. In Part 2, the 
SC will receive recommendations from the IDMC regarding suggested modifications to the study 
based on the review of the unblinded data by the IDMC. The sponsor, in collaboration with the 
SC, will ultimately decide whether to accept the recommendations and will oversee the 
implementation of any modifications, if applicable. Details regarding the composition, roles, and 
responsibilities of the SC will be documented in a separate charter.
11.11.4.
Clinical Events Committee
A CEC will be established to review, adjudicate, and classify endpoint events in Parts 1 and 2 of 
the study as they become available in a blinded, consistent, and unbiased manner according to 
the definitions provided in the CEC charter. Committee members will not have direct operational 
responsibilities for the conduct of the study, nor will they directly enroll subjects or be involved 
in study monitoring. Further details regarding the composition, roles, and responsibilities of the 
CEC will be documented in a separate charter.
The CEC will have responsibility for reviewing, adjudicating, and classifying the following
assessments and study endpoint events or events that appear suggestive of a study endpoint 
event:
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
Venography assessment of the operated leg

Suspected symptomatic DVT

Suspected symptomatic PE

Suspected bleeding events

Suspected MI

Suspected stroke 

Suspected peripheral arterial embolism

Death
The CEC will verify all components of the bleeding and efficacy endpoint events. The CEC will 
centrally adjudicate all clinical events based on the endpoint definitions. All necessary source 
documents will be sent to the CEC in a blinded fashion to enable adjudication and verification of 
events. The CEC-adjudicated and investigator-reported results on efficacy and safety outcomes 
will be provided for both of the interim analyses. The CEC-adjudicated events will be used in the 
final analysis.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established standard operating procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
Adverse events of special interest have been identified for this study and are described in 
Section 9.7.2, Adverse Events of Special Interest.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting adverse events or serious adverse events. 
Open-ended and nonleading verbal questioning of the subject is the preferred method to inquire 
about adverse event occurrence. For some studies, subjects are not always able to provide valid 
verbal responses to open-ended questions. In these circumstances, events will be solicited. In this 
study, subjects will be queried directly to solicit potential bleeding events using general 
questions about any bleeding and specific questions about common minor bleeding events that 
could be overlooked by the subject (eg, bruising, gingival bleeding, epistaxis).
Solicited Adverse Events
Solicited adverse events are predefined local and systemic events for which the subject is 
specifically questioned. In this study, bleeding events will be solicited.
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Unsolicited Adverse Events
Unsolicited adverse events are all adverse events for which the subject is specifically not 
questioned.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
A laboratory test abnormality that is considered by the investigator to be clinically relevant
(eg, causing the subject to discontinue the study drug, requiring treatment, or causing apparent 
clinical manifestations) should be reported as an adverse event.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and European Union Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
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*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must 
be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For JNJ-64179375, the expectedness of an 
adverse event will be determined by whether or not it is listed in the Investigator's Brochure.
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2, Attribution Definitions.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
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12.1.3.
Severity Criteria
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting or safety 
evaluation include, but are not limited to:

Overdose of a sponsor study drug. Overdose is defined as any occasion when the subject has 
taken or received (accidentally or intentionally or unspecified) any single dose OR a 
cumulative daily dose that is higher than the maximal target single dose OR a cumulative 
daily dose as defined in the study protocol. For apixaban, this is defined as more than 10 mg 
per day or more than 15 days of treatment. For JNJ-64179375, this is defined as more than 
the planned single-dose amount or more than 1 dose.

Suspected abuse/misuse of a sponsor study drug

Accidental or occupational exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or nonserious, will be 
reported from the time a signed and dated ICF is obtained until completion of the subject's last 
study-related procedure, which may include contact for follow up of safety. Serious adverse 
events, including those spontaneously reported to the investigator through the Week 18 visit, 
must be reported using the Serious Adverse Event Form. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame specified in 
the protocol.
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All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments.
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the eCRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
"upper respiratory infection"). Investigators must record in the eCRF their opinion concerning 
the relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate IEC/IRB that 
approved the protocol unless otherwise required and documented by the IEC/IRB. A SUSAR will 
be reported to regulatory authorities unblinded. Participating investigators and IEC/IRB will 
receive a blinded SUSAR summary, unless otherwise specified.
The subject must be provided with a "wallet (study) card" and instructed to carry this card with 
them for the duration of the study indicating the following:

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form and Safety Report Form of the eCRF, which must be completed and 
reviewed by a physician from the study site, and transmitted to the sponsor within 24 hours. The 
initial and follow-up reports of a serious adverse event should be transmitted electronically or by 
facsimile (fax).
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All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). Note: Hospitalizations that were planned before the signing of the ICF, and where 
the underlying condition for which the hospitalization was planned has not worsened, will 
not be considered serious adverse events. Any adverse event that results in a prolongation of 
the originally planned hospitalization is to be reported as a new serious adverse event.
The cause of death of a subject in a study through the Week 18, whether or not the event is 
expected or associated with the study drug, is considered a serious adverse event.
12.3.3.
Pregnancy
All initial reports of pregnancy in partners of male subjects must be reported to the sponsor by 
the study-site personnel within 24 hours of their knowledge of the event using the appropriate 
pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal 
death, stillbirth, congenital anomalies, ectopic pregnancy) are considered serious adverse events 
and must be reported using the Serious Adverse Event Form.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
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13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drugs
JNJ-64179375 or JNJ-64179375 Placebo
The JNJ-64179375 supplied for this study is a sterile, preservative-free liquid with a 
concentration of 50 mg/mL of monoclonal antibody in a solution composed of 10 mM sodium 
phosphate, 8.5% (w/v) sucrose, 0.04% (w/v) polysorbate 20, and 10 g/mL EDTA at a pH of 7.1.
JNJ-64179375 will be provided frozen in a glass vial with an approximately 3-mL fill volume.
JNJ-64179375 has a molecular mass of 149,139 Dalton for the G0F/G0F glycoform and 
isoelectric points, ranging from 6.1 to 6.4. The absorptivity constant for JNJ-64179375 at 280 nm 
was determined to be 1.37 (mg/mL)-1cm-1. It will be manufactured and provided under the 
responsibility of the sponsor.
Placebo infusions will be 0.9% normal saline.
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Apixaban or Matching Apixaban Placebo
Apixaban will be supplied for this study as over-encapsulated 2.5-mg tablets in a red-colored, 
hard, gelatin capsule. The over-encapsulated tablet will be backfilled with microcrystalline 
cellulose to prevent the tablet from rattling in the capsule shell.
Matching apixaban placebo capsules will consist of microcrystalline cellulose within a red-colored, 
hard, gelatin capsule.
14.2.
Packaging
JNJ-64179375 will be packaged in individual kits. Each kit will consist of 1 vial of 
JNJ-64179375 frozen liquid in a carton. JNJ-64179375 will not be dispensed in child-resistant 
packaging. It will be stored in a locked pharmacy and only dispensed after preparation for an 
IV infusion.
Apixaban or matching apixaban placebo will be packaged in bottles containing 30 capsules. The 
bottles will be child resistant.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
JNJ-64179375 must be stored at -40°C ± 10°C (-30°C to -50°C) or -70°C ± 20°C (-50°C to 
-90°C), and protected from light. Before use, the drug product should be diluted to the required 
dose strength using 0.9% normal saline. Diluted drug product for IV administration must be 
administered with in-line filtration.
Apixaban and matching apixaban placebo must be stored at controlled temperatures, as indicated 
on the product-specific labeling.
Refer to the pharmacy manual/IPPI for additional guidance on study drug preparation, handling, 
and storage.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. For the single IV dose of JNJ-64179375 the study drug 
vial(s) used to prepare the dose that will be administered to the subject must be documented in 
the IWRS. For oral apixaban or matching apixaban placebo, the dispensing of study drug to the 
subject, and the return of study drug from the subject (if applicable), must be documented in the 
IWRS. Subjects must be instructed to return all original containers, whether empty or containing 
study drug. All study drug will be stored and disposed of according to the sponsor's instructions. 
Study-site personnel must not combine contents of the study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
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environmental conditions. Unused study drug, and study drug returned by the subject, must be 
available for verification by the sponsor's study site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug, or used returned study drug for destruction, will be 
documented in the IWRS. When the study site is an authorized destruction unit and study drug 
supplies are destroyed on-site, this must also be documented in the IWRS.
Potentially hazardous materials such as used ampules, needles, syringes, vials containing 
hazardous liquids (this does not include the used vials of study drug), and used infusion supplies
should be disposed of immediately in a safe manner and therefore will not be retained for drug 
accountability purposes.
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Study drug may not be relabeled or reassigned for use by 
other subjects. The investigator agrees neither to dispense the study drug from, nor store it at, 
any site other than the study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator's Brochure for JNJ-64179375

Laboratory manuals

IWRS manual

Venography manual

eCRF manual

Sample ICF

IPPI

Guidelines for Reporting Bleeding Event Verbatim Terms 

Subject contact cards (wallet card)

Contact information page
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
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JNJ-64179375 is an investigational drug that is being developed for multiple thrombosis-mediated 
conditions. The nonclinical and clinical data obtained to date with JNJ-64179375 support 
administration of single doses in a well-controlled clinical research study. The present study is 
needed to support further clinical development of JNJ-64179375, and the study design is based on 
sound scientific rationale, as described in this protocol. Thorough scientific evaluation of any 
promising treatment before marketing authorization is an ethical requirement. In the continuing 
search for medications with improved efficacy and safety profiles, it is necessary to fully 
investigate and understand new products.
The primary ethical concern is that the safety and efficacy profile of JNJ-64179375 has not been 
well established as it has only been studied in a limited number of healthy male subjects. Subjects 
in this study who are at risk for VTE following TKR surgery are being asked to take a new 
treatment for the prevention of VTE. Based on the nonclinical and Phase 1 clinical study, a range 
of doses of JNJ-64179375 has been selected for further evaluation in Part 1 of this study. The 
starting dose of 0.3 mg/kg is expected to provide efficacy and be well tolerated. Subsequent dose 
escalation will be based on the evaluation of the observed efficacy and safety data on a regular 
basis (ie, every 1 to 3 weeks) by the OC, which will consist of individuals with both clinical and 
statistical expertise. Women will be exposed to JNJ-64179375 for the first time. The nonclinical 
studies did not show any difference between males and females for blood levels or tolerability of 
JNJ-64179375. Based on the Part 1 results, doses that are expected to provide efficacy and to be 
well tolerated will be selected for evaluation in Part 2. In Part 2, the IDMC will review VTE and 
bleeding events to closely monitor the safety of subjects participating in the study. Subjects in both 
parts will be monitored for 18 weeks after the single IV administration of JNJ-64179375.
The primary risk with any anticoagulant drug is the potential for bleeding events, and because 
JNJ-64179375 is a monoclonal antibody, infusion and hypersensitivity reactions could also be 
potentially observed. Based on the nonclinical evaluations of JNJ-64179375, the risk for these 
events is anticipated to be low (ie, all planned doses are below those shown to statistically 
significantly increase bleeding risk) and no cytokine release or allergic reactions have been 
observed in animals. In addition, subjects in the first-in-human SAD study did not experience any 
infusion or hypersensitivity reactions. A bleeding signal was detected at the 2.125- and 
2.5-mg/kg doses in healthy male subjects. This signal consisted primarily of increased local 
bruising at the venipuncture and infusion sites in subjects who received JNJ-64179375 compared 
with placebo. The starting dose of 0.3 mg/kg in Part 1 is approximately one-seventh of this dose 
and was well tolerated in the SAD study. The highest planned dose (1.2 mg/kg) in Part 1 of this 
study is approximately 50% of the 2.125-mg/kg dose and will only be studied if lower doses are 
tolerated. Subjects in this study will be carefully observed for both bleeding events and infusion or 
hypersensitivity reactions throughout the duration of the study and management strategies for each 
type of event are outlined in the protocol (see Section 9.7.2.1.2, Approach to Subjects With a 
Bleeding Event and Section 9.7.2.2, Infusion or Hypersensitivity Reactions, respectively).
Venography assessments will be used to evaluate for the presence of DVT. The x-ray used in the 
imaging exposes the body to a small dose of ionizing radiation. The risks of radiation exposure 
may be tied to the number of x-rays and x-ray treatments a person has had over their lifetime. 
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Given that all of the subjects in this study will be 50 years of age, the incremental risk of this 
radiation exposure is considered small. X-rays are the oldest and most frequently used form of 
medical imaging. Other risks associated with venography assessments include pain, infection, 
and/or bleeding at the site of venous access and the risks from contrast medium administration 
(ie, allergy, nephrotoxicity, and/or possible irritation of the venous system leading to the 
development of DVT). In previous studies, venography assessments have been well tolerated and 
do provide clinically useful information about the presence or absence of DVT following 
surgery.26
There are risks associated with venipuncture and multiple blood sample collection, including 
prolonged bleeding due to the anticoagulant effects of JNJ-64179375. The total blood volume to be 
collected for safety, PK, and PD laboratory tests is approximately 95.4 mL for subjects with dense 
PK sampling and approximately 80.4 mL for subjects with sparse PK sampling. This is well below 
the standard blood donation volume for healthy donors as set forth by the World Health 
Organization (standard donation of 450 mL every 79 days) and is therefore considered to be 
acceptable for subjects following TKR surgery.34
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)
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
Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct, unless required locally), the ICF, applicable 
recruiting materials, and subject compensation programs, and the sponsor has received a copy of 
this approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data, or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB
(at least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required.
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At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
16.2.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any study-
related activity. The ICF(s) that is/are used must be approved by both the sponsor and by the 
reviewing IEC/IRB and be in a language that the subject can read and understand. The informed 
consent should be in accordance with principles that originated in the Declaration of Helsinki, 
current ICH and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the subject will receive for their surgery or postoperative care. Subjects will be 
told that alternative treatments are available if they refuse to take part and that such refusal will 
not prejudice future treatment. Finally, they will be told that the investigator will maintain a 
subject identification register for the purposes of long-term follow up if needed and that their 
records may be accessed by health authorities and authorized sponsor personnel without 
violating the confidentiality of the subject, to the extent permitted by the applicable law(s) or 
regulations. By signing the ICF the subject is authorizing such access, which includes permission 
to obtain information about his or her survival status.
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the subject.
If the subject is unable to read or write, an impartial witness should be present for the entire 
informed consent process, (which includes reading and explaining all written information) and 
should personally date and sign the ICF after the oral consent of the subject is obtained.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
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put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original 
medical records (source data/documents) for study-related monitoring, audit, IEC/IRB review, 
and regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory PK, immunogenicity, and PD biomarker research is not conducted under standards 
appropriate for the return of data to subjects. In addition, the sponsor cannot make decisions as to 
the significance of any findings resulting from exploratory research. Therefore, exploratory 
research data will not be returned to subjects or investigators, unless required by law or local 
regulations. Privacy and confidentiality of data generated in the future on stored samples will be 
protected by the same standards applicable to all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand JNJ-64179375, to 
understand thrombosis, to understand differential drug responders, and to develop tests/assays 
related to JNJ-64179375, and VTE prophylaxis. The research may begin at any time during the 
study or the poststudy storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers.
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 16.1, Study-Specific Design 
Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
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amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IEC/IRB (where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required
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
Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
and date of birth (as allowed by local regulations). In cases where the subject is not randomized 
into the study, the date seen and date of birth (as allowed by local regulations) will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following:
subject identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all adverse events and follow up of adverse events; concomitant medication; 
drug receipt/dispensing/return records; study drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if 
applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study.
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as 
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the clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the sponsor. If the electronic source system is utilized, references made to 
the eCRF in the protocol include the electronic source system but information collected through 
the electronic source system may not be limited to that found in the eCRF. Data in this system 
may be considered source documentation.
17.5.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format.
All CRF entries, corrections, and alterations must be made by the investigator or authorized 
study-site personnel. The investigator must verify that all data entries in the CRF are accurate 
and correct.
The study data will be transcribed by study-site personnel from the source documents onto an 
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the 
sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documents. Data must be entered into
eCRF in English. The eCRF must be completed as soon as possible after a subject visit and the 
forms should be available for review at the next scheduled monitoring visit.
If necessary, queries will be generated in the electronic data capture (eDC) tool. If corrections to 
a CRF are needed after the initial entry into the eCRF, this can be done in either of the following
ways:

Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor, and direct 
transmission of IWRS data, adjudication data from the CEC, and laboratory data from a central 
laboratory into the sponsor's data base. Written instructions will be provided for collection, 
handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study.
The sponsor will review eCRF for accuracy and completeness during on-site monitoring visits 
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. In addition, data will be reviewed centrally as described in 
Section 17.8, Monitoring. After upload of the data into the study database selected data will be 
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verified for accuracy and consistency with the data sources (refer to Section 17.8, Monitoring for 
further details).
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will use a combination of monitoring techniques (central, remote, or on-site 
monitoring) to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study-site visit log that will be kept at the study site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare data entered into the CRF with the source documents
(eg, hospital/clinic/physician’s office medical records); a sample may be reviewed. The nature 
and location of all source documents will be identified to ensure that all sources of original data 
required to complete the CRF are known to the sponsor and study-site personnel and are 
accessible for verification by the sponsor study-site contact. If electronic records are maintained 
at the study site, the method of verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the recorded data are consistent with the original source data. Findings from this
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review will be discussed with the study-site personnel. The sponsor expects that, during 
monitoring visits, the relevant study-site personnel will be available, the source documents will 
be accessible, and a suitable environment will be provided for review of study-related 
documents. The monitor will meet with the investigator on a regular basis during the study to 
provide feedback on the study conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The study is considered completed with the last visit for the last subject participating in the 
study. The final data from the study site will be sent to the sponsor (or designee) after completion 
of the final subject assessment at that study site, in the time frame specified in the clinical trial 
agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Subject privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and 
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available for consultation during routinely scheduled study-site audit visits conducted by the 
sponsor or its designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding JNJ-64179375 or the 
sponsor's operations (eg, patent application, formulas, manufacturing processes, basic scientific 
data, prior clinical data, formulation information) supplied by the sponsor to the investigator and 
not previously published, and any data, including biomarker research data, generated as a result 
of this study, are considered confidential and remain the sole property of the sponsor. The 
investigator agrees to maintain this information in confidence and use this information only to 
accomplish this study, and will not use it for other purposes without the sponsor's prior written 
consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of JNJ-64179375 and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a CSR generated by the sponsor and will contain data 
from all study sites that participated in the study as per protocol. Recruitment performance or 
specific expertise related to the nature and the key assessment parameters of the study will be 
used to determine a coordinating investigator for the study. Results of PK, PD, and cost
effectiveness analyses performed will be reported in separate reports and will not require a 
revision of the CSR. Study subject identifiers will not be used in publication of results. Any work 
created in connection with performance of the study and contained in the data that can benefit 
from copyright protection (except any publication by the investigator as provided for below) 
shall be the property of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
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information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 18 months of the availability of the final data
(tables, listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law.
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REFERENCES
1.
Baglin TP, Langdown J, Frasson R, Huntington JA. Discovery and characterization of an antibody directed 
against exosite I of thrombin. J Thromb Haemost. 2016;14:137-142.
2.
Bornkamp B, Pinheiro J, Bretz F. Planning and analyzing dose finding experiments. 
http://www.cran.r-project.org/web/packages/dosefinding. Updated July 26, 2016. Accessed January 24, 2017.
3.
Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques in dose-response 
studies. Biometrics. 2005;61:738-748.
4.
Buckland ST, Burnham K, Augustin NH. Model selection: an integral part of inference. Biometrics. 
1997;53:603-618.
5.
Büller HR, Bethune C, Bhanot S, et al; FXI-ASO TKA Investigators. Factor XI antisense oligonucleotide for 
prevention of venous thrombosis. N Engl J Med. 2015;372(3):232-240.
6.
Cohen AT, Agnelli G, Anderson FA, et al. Venous thromboembolism (VTE) in Europe. The number of VTE 
events and associated morbidity and mortality. Thromb Haemost. 2007;98:756-764.
7.
Dahl OE, Borris LC, Bergqvist D, et al. International Surgical Thrombosis Forum. Major joint replacement. A 
model for antithrombotic drug development: from proof-of-concept to clinical use. Int Angiol. 2008;27(1):
60-67.
8.
Eliquis [Summary of Product Characteristics]. Uxbridge, Middlesex, United Kingdom: Bristol-Myers Squibb/
Pfizer EEIG; 2016. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002148/
human_med_001449.jsp&mid=WC0b01ac058001d124. Accessed February 9, 2017.
9.
Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the 
prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. 
J Thromb Haemost 5(11):2178-2185.
10.
Falck-Ytter Y, Francis CW, Johanson NA, et al; American College of Chest Physicians. Prevention of VTE in 
orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of 
Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2_suppl):
e278S-e325S.
11.
Francis CW, Davidson BL, Berkowitz SD, et al. Ximelagatran versus warfarin for the prevention of venous 
thromboembolism after total knee arthroplasty. A randomized, double-blind trial. Ann Intern Med. 
2002;137(8):648-655.
12.
Fuji T, Fujita S, Tachibana S, Kawai Y. A dose-ranging study evaluating the oral factor Xa inhibitor edoxaban 
for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty. J Thromb 
Haemost. 2010;8(11):2458-2468.
13.
Fuji T, Wang CJ, Fujita S, et al. Safety and efficacy of edoxaban, an oral factor Xa inhibitor, versus enoxaparin 
for thromboprophylaxis after total knee arthroplasty: the STARS E-3 trial. Thromb Res. 2014;134(6):
1198-1204.
14.
Geerts WH (2004), Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP 
Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:338S-400S.
15.
Ginsberg JS, Davidson BL, Comp PC, et al. Oral thrombin inhibitor dabigatran etexilate versus North 
American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. 
J Arthroplasty 24(1):1-9.
16.
Hjort NL, Claeskens G. Frequentist model average estimators. J Am Stat Assoc. 2003;98:879-899.
17.
Investigator’s Brochure: JNJ-64179375, Edition 1. Janssen Research & Development, LLC 
(29 September 2016).
18.
Investigator’s Brochure. Addendum 1.0 to Investigator’s Brochure, Edition 1.0. Janssen Research & 
Development, LLC (02 June 2017).
19.
JCS Joint Working Group. Guidelines for the diagnosis, treatment and prevention of pulmonary 
thromboembolism and deep vein thrombosis (JCS 2009). Circ J. 2011;75(5):1258-1281.
NCT03251482

JNJ-64179375      
Clinical Protocol 64179375THR2001 Amendment 1
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Approved, Date: 11 September 2017
20.
Kearon C. Noninvasive diagnosis of deep venous thrombosis. McMaster Diagnostic Imaging Practice 
Guidelines Initiative. Ann Intern Med. 1998;128:663-677.
21.
Lassen MR, Davidson BL, Gallus A, Pineo G, Ansell J, Deitchman D. The efficacy and safety of apixaban, an 
oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb 
Haemost. 2007;5:2368-2375.
22.
Lassen MR, Fisher W, Mouret P, et al; SAVE Investigators. Semuloparin for prevention of venous 
thromboembolism after major orthopedic surgery: results from three randomized clinical trials, SAVE-HIP1, 
SAVE-HIP2 and SAVE-KNEE. J Thromb Haemost. 2012;10(5):822-832.
23.
Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for 
thromboprophylaxis after knee replacement. N Engl J Med. 2009;361(6):594-604.
24.
Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for thromboprophylaxis after knee 
replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010;375:807-815.
25.
Pinheiro JC, Bornkamp B, Glimm E, Bretz F. Model-based dose findings under model uncertainty using 
general parametric models. Statistics Med. 2014;33:1646-1661.
26.
Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg. 1972;4:134-144.
27.
Schellong SM, Beyer J, Kakkar AK, et al. Ultrasound screening for asymptomatic deep vein thrombosis after 
major orthopaedic surgery: the VENUS study. J Thromb Haemost. 2007;5(7):1431-1437.
28.
Schulman S, Angeras U, Bergqvist D, Eriksson B, Lassen MR, Fisher W. Subcommittee on Control of 
Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis 
and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products 
in surgical patients. J Thromb Haemost. 2010;8(1):202-204.
29.
Segers AE, Prins MH, Lensing AW, Buller HR. Is contrast venography a valid surrogate outcome measure in 
venous thromboembolism prevention studies? J Thromb Haemost. 2005;3:1099-1102.
30.
Turpie AG, Lassen MR, Davidson BL, et al; RECORD4 Investigators. Rivaroxaban versus enoxaparin for 
thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 
2009;373(9676):1673-1680.
31.
Verhamme P, Tangelder M, Verhaeghe R, et al; TB-402 Study Group. Single intravenous administration of 
TB-402 for the prophylaxis of venous thromboembolism after total knee replacement: a dose-escalating, 
randomized, controlled trial. J Thromb Haemost. 2011;9(4):664-671.
32.
Warwick D. Prevention of venous thromboembolism in total knee and hip replacement. Circ. 2012;125:
2151-2155.
33.
Winters JL. Plasma exchange: concepts, mechanisms, and an overview of the American Society for Apheresis 
guidelines. Hematol Am Soc Hematol Education Program. 2012;2012:7-12.
34.
World Health Organization. Blood donor selection guidelines on assessing donor suitability for blood donation. 
Geneva: World Health Organization; 2012. http://www.ncbi.nlm.nih.gov/books/NBK138212/. 
Accessed 22 Sep 2016.
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Attachment 1: Sample Bleeding Risk History
Family History:
1.
Family history of bleeding disorder (at least one parent, grandparent, sibling 
or child)
Yes ⃝
No ⃝
If yes, what was the diagnosis? ______________________________________
Personal Lifetime History:
2.
Any blood vessel aneurysms (eg, intracranial) or arteriovenous 
malformations? 
Yes ⃝
No ⃝
If yes, specify diagnosis and date : ___________________________________
3.
Any history of any anemia?
Yes ⃝
No ⃝
If yes, specify diagnosis and date: ___________________________________
4.
Any history of any gastrointestinal ulcer disease?
Yes ⃝
No ⃝
If yes, specify diagnosis and date : __________________________________
5.
Any history of any gastrointestinal polyps?
Yes ⃝
No ⃝
If yes, specify diagnosis and date : __________________________________
6.
Any invasive procedures (eg, surgery, biopsy, dental extraction)? 
Yes ⃝
No ⃝
If yes, number _____ type of procedure ___________________ 
Any abnormal bleeding with any of the procedures?
Yes ⃝
No ⃝
If yes, describe and include date. ____________________________________
7.
Any intracranial bleeding 
Yes ⃝
No ⃝
If yes specify site:   ⃝ Subdural ⃝ SAH ⃝ Parenchymal Date: ___________
8.
Any blood in urine
Yes ⃝
No ⃝
If yes specify:   ⃝ Hematuria (Visible)   ⃝ Microscopic only   Date: ________
9.
Any muscle or joint bleeding
Yes ⃝
No ⃝
If yes specify:  ⃝ Muscle ⃝ Joint    Date: ______________
10.
Any lung bleeding
Yes ⃝
No ⃝
If yes specify:  ⃝ Blood in sputum  ⃝ Other, specify____________   
Date: __________
11.
Any upper gastrointestinal tract bleeding 
Yes ⃝
No ⃝
If yes specify:   ⃝ Hematemesis ⃝ Coﬀee-ground emesis ⃝ Melena  
Date: ______
12.
FEMALES ONLY: Childbirth?
If yes, specify if any bleeding complications?
Yes ⃝
No ⃝
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Personal History in the past 6 months:
Personal history of bleeding events in the past 6 months not involving invasive procedures 
(review below categories):
Gastrointestinal 
Bleeding-lower 
No ⃝
Yes ⃝ →
# episodes in last 6 months: ⃝ 1 ⃝ 2-5 ⃝ 6-12 ⃝ >12
Duration of average episode: ⃝ <1 min ⃝ 1-5 min⃝ >5 min
Type: ⃝ Hemorrhoids
⃝ Other, specify ________________________
Onset: ⃝ Spontaneous ⃝ AFer bowel movement
Nosebleeds
No ⃝
Yes ⃝ →
# episodes in last 6 months: ⃝ 1 ⃝ 2-5 ⃝ 6-12 ⃝ >12
Duration of average episode: ⃝ <1 min ⃝ 1-5 min⃝ >5 min
Onset: ⃝ spontaneous ⃝ secondary trauma (eg, blowing nose)
Resolution: ⃝ Usually resolved spontaneously
⃝ Required medical aJenKon
Bruising
No ⃝
Yes ⃝ →
# episodes in last 6 months: ⃝ 1 ⃝ 2-5 ⃝ 6-12 ⃝ >12
Onset: ⃝ With minimal or no trauma ⃝ With trauma
Average size: ⃝ <1 cm ⃝ 1-5 cm ⃝ >5 cm
Oral cavity bleeding
No ⃝
Yes ⃝ →
# episodes in last 6 months: ⃝ 1 ⃝ 2-5 ⃝ 6-12 ⃝ >12
Type: ⃝Gums, spontaneous
⃝ Gums, aFer brushing or ﬂossing
⃝ Other, specify ______________
Bleeding from minor 
wounds
No ⃝
Yes ⃝ →
# episodes in last 6 months: ⃝ 1 ⃝ 2-5 ⃝ 6-12 ⃝ >12
Duration of average episode: ⃝ <1 min ⃝ 1-5 min⃝ >5 min
Resolution: ⃝ Usually resolved spontaneously
⃝ Required medical aJenKon
FEMALES ONLY:
Dysfunctional 
uterine bleeding
No ⃝
Yes ⃝ →
# episodes in last 6 months: ⃝ 1 ⃝ 2-5 ⃝ 6-12 ⃝ >12
Duration of average episode: ⃝ <1 day ⃝ 1-5 days ⃝ >5 days
Resolution: ⃝ Usually resolved spontaneously
⃝ Required medical aJenKon
Any Other Bleeding Site(s) not mentioned under lifetime or past 6 month history 
sections:
Yes ⃝
No ⃝
If yes  →   specify site and date 
Note: The final questions will be part of the eCRF. Responses to these questions will be obtained 
by the investigator through an interview with the subject. These responses should be reviewed 
and any condition for which the use of apixaban is not recommended should be considered by 
the investigator when determining eligibility for the study.
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Attachment 2: Definitions of Bleeding Events
1.
Major Bleeding in Surgical Setting28
1.
Fatal bleeding, and/or
2.
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
3.
Extrasurgical site bleeding causing a fall in hemoglobin level of 20 g L)-1 (1.24 mmol L-1) or 
more, or leading to transfusion of 2 or more units of whole blood or red cells, with temporal 
association within 24 to 48 hours to the bleeding, and/or
4.
Surgical site bleeding that requires a second intervention open, arthroscopic, endovascular,
or a hemarthrosis of sufficient size as to interfere with rehabilitation by delaying 
mobilization or delayed wound healing, resulting in prolonged hospitalization or a deep 
wound infection, and/or 
5.
Surgical site bleeding that is unexpected and prolonged and/or sufficiently large to cause 
hemodynamic instability, as assessed by the surgeon. There should be an associate fall in 
hemoglobin level of at least 20 g L-1) (1.24 mmol L-1), 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.
2.
Clinically Relevant Nonmajor Bleeding23,24
Clinically relevant nonmajor bleeding is defined as any bleeding event that is:

Acute clinically overt bleeding

Does not satisfy additional criteria required for the bleeding event to be defined as a major 
bleeding event and meets at least 1 of the following criteria:
o
Epistaxis (nose bleed):

Subject seeks medical attention from a physician

Subject visits an emergency room

Bleeding requires an intervention (eg, nasal pack)

Single bleeding episode persists for 5 minutes or more
o
Gastrointestinal bleed:

Vomit containing frank blood or coffee-ground material, which tests positive for 
blood

Endoscopically confirmed bleeding

Frank blood per rectum or melenic stools
o
Hematuria

Overt, spontaneous bleeding

Bleeding (bloody urine) persists for 24 hours or more after instrumentation
o
Bruising/ecchymosis:

Any bruise that is assessed as “unusual” (eg, greater than expected following surgery)
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o
Hemoptysis:

Expectoration of blood or blood-stained sputum
o
Hematoma:

Overt blood collection with the surgical wound

Presence of a hematoma is demonstrated radiographically (eg, ultrasound, CT, 
magnetic resonance imaging) and a drop of hemoglobin is present with no external 
evidence of bleeding
Note: Any bleeding event not meeting major or clinically relevant nonmajor criteria will be recorded as 
minimal bleeding.
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INVESTIGATOR AGREEMENT
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