Clinical trial NCT03891524
Conditions: Arthroplasty, Replacement, Knee
Sponsor: Janssen Research & Development, LLC
Start date: 2019-06-17; Completion date: 2021-04-06
Enrollment: 1242 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the efficacy of JNJ-70033093 in preventing total venous thromboembolism (VTE) events (proximal and/or distal deep vein thrombosis \[DVT\] \[asymptomatic confirmed by venography assessment or objectively confirmed symptomatic\], nonfatal pulmonary embolism \[PE\], or any death) during the treatment period.

Detailed description:
JNJ-70033093 is an oral anticoagulant for prevention and treatment of thromboembolic events (for example, VTE) that binds and inhibits activated form of human coagulation Factor XI (FXIa) with high affinity and selectivity. The study will consist of 3 phases: up to 30-day screening phase before total knee replacement (TKR) surgery, 10 to14 day postoperative dosing phase, and 4-week follow-up phase. The hypothesis of this study is JNJ-70033093 reduces risk of total VTE during treatment period. The total duration of participation following randomization will be approximately 6 weeks. Efficacy evaluations include unilateral venography assessment of operated leg and assessments of symptomatic DVT, PE, or death. Safety evaluation includes adverse events, clinical laboratory tests, and physical examinations. The safety and efficacy will be monitored throughout the study.

Arms: arm 1: Participants will receive JNJ-70033093 25 milligram (mg) (1\*25 mg capsule) and 1 placebo capsule twice daily (BID), orally for 10 to 14 postoperative days. arm 2: Participants will receive JNJ-70033093 50 mg (2\*25 mg capsules) BID orally for 10 to 14 postoperative days. arm 3: Participants will receive JNJ-70033093 100 mg (1\*100 mg capsule) and 1 placebo capsule BID orally for 10 to 14 postoperative days. arm 4: Participants will receive JNJ-70033093 200 mg (2\*100 mg capsules) BID orally for 10 to 14 postoperative days. arm 5: Participants will receive JNJ-70033093 25 mg (1\*25 mg capsule) once daily and 1 placebo capsule in the morning and 2 placebo capsules in the evening, orally for 10 to 14 postoperative days. arm 6: Participants will receive JNJ-70033093 200 mg (2\*100 mg capsules in the morning) once daily and 2 placebo capsules in the evening, orally for 10 to 14 postoperative days. arm 7: Participants will receive JNJ-70033093 50 mg (2\*25 mg capsules in the morning) once daily and 2 placebo capsules in the evening, orally for 10 to 14 postoperative days. arm 8: Participants will receive enoxaparin 40 mg once daily subcutaneously for 10 to 14 postoperative days.
Interventions: intervention 1: JNJ-70033093 25 mg intervention 2: JNJ-70033093 50 mg intervention 3: JNJ-70033093 100 mg intervention 4: JNJ-70033093 200 mg intervention 5: Placebo intervention 6: Enoxaparin 40 mg
Intervention descriptions: intervention 1: Participants will receive JNJ-70033093 25 mg (1\*25 mg capsule) BID (in Group A) or once daily (in Group E), orally for 10 to 14 postoperative days. intervention 2: Participants will receive JNJ-70033093 50 mg (2\*25 mg capsules) BID orally for 10 to 14 postoperative days. intervention 3: Participants will receive JNJ-70033093 100 mg (1\*100 mg capsule) BID, orally for 10 to 14 postoperative days. intervention 4: Participants will receive JNJ-70033093 200 mg (2\*100 mg capsules) BID (in Group D) or once daily (in Group F), orally for 10 to 14 postoperative days. intervention 5: Participants will receive placebo matching to JNJ-70033093, orally. intervention 6: Participants will receive enoxaparin 40 mg once daily subcutaneously for 10 to 14 postoperative days.

Protocol documents:
Prot_002.pdf: 
1
Status: Approved, Date: 10 September 2019
Janssen Research & Development *
Clinical Protocol
Protocol Title
A Randomized, Open-Label, Study Drug-Dose Blind, Multicenter Study to Evaluate the 
Efficacy and Safety of JNJ-70033093 (BMS-986177), an Oral Factor XIa Inhibitor, Versus 
Subcutaneous Enoxaparin in Subjects Undergoing Elective Total Knee Replacement 
Surgery
Short Title
A Randomized Study to Evaluate the Safety and Efficacy of Oral JNJ-70033093 Versus 
Enoxaparin in Subjects Undergoing Elective Total Knee Replacement
AXIOMATIC-TKR - Antithrombotic treatment with factor XIa inhibition to Optimize
Management of Acute Thromboembolic events in TKR
Protocol 70033093THR2001; Phase 2
JNJ-70033093
*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, Inc; Janssen Pharmaceutica NV; 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.
JNJ-70033093 (BMS-986177) is being codeveloped under a collaboration agreement between Bristol-
Myers Squibb Company (BMS) and Janssen Pharmaceuticals, Inc. (Janssen).
US sites of this study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312).
EudraCT NUMBER: 2018-004237-32
Status:
Approved
Date:
10 September 2019
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-172187276, 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.
NCT03891524


JNJ-70033093
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Approved, Date: 10 September 2019
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 5
1.
PROTOCOL SUMMARY ................................................................................................................... 13
1.1.
Synopsis......................................................................................................................................... 13
1.2.
Schema .......................................................................................................................................... 19
1.3.
Schedule of Activities (SoA)........................................................................................................... 20
2.
INTRODUCTION................................................................................................................................ 24
2.1.
Study Rationale.............................................................................................................................. 24
2.2.
Background .................................................................................................................................... 24
2.2.1.
Enoxaparin Sodium .................................................................................................................... 31
2.3.
Benefit/Risk Assessment ............................................................................................................... 32
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 33
4.
STUDY DESIGN ................................................................................................................................ 35
4.1.
Overall Design................................................................................................................................ 35
4.2.
Scientific Rationale for Study Design............................................................................................. 36
4.2.1.
Study-Specific Ethical Design Considerations ...........................................................................39
4.3.
Justification for Dose...................................................................................................................... 41
4.4.
End of Study Definition................................................................................................................... 43
5.
STUDY POPULATION ...................................................................................................................... 43
5.1.
Inclusion Criteria ............................................................................................................................ 43
5.2.
Exclusion Criteria ........................................................................................................................... 45
5.3.
Lifestyle Considerations................................................................................................................. 47
5.4.
Screen Failures .............................................................................................................................. 47
6.
STUDY TREATMENT........................................................................................................................ 48
6.1.
Study Drugs Administered ............................................................................................................. 48
6.2.
Preparation/Handling/Storage/Accountability ................................................................................ 50
6.3.
Measures to Minimize Bias: Randomization and Blinding.............................................................51
6.4.
Study Drug Compliance ................................................................................................................. 52
6.5.
Concomitant Therapy..................................................................................................................... 52
6.6.
Dose Modification........................................................................................................................... 53
6.7.
Study Drug After the End of the Study........................................................................................... 53
7.
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ...............................................................................................54
7.1.
Discontinuation of Study Drug ....................................................................................................... 54
7.1.1.
Temporary Discontinuation......................................................................................................... 54
7.2.
Subject Discontinuation/Withdrawal From the Study.....................................................................54
7.2.1.
Withdrawal of Consent for the Use of Research Samples .........................................................55
7.3.
Lost to Follow Up ........................................................................................................................... 56
8.
STUDY ASSESSMENTS AND PROCEDURES ...............................................................................56
8.1.
Efficacy Assessments .................................................................................................................... 58
8.1.1.
Assessments for DVT................................................................................................................. 58
8.1.2.
Assessments for PE ................................................................................................................... 59
8.2.
Safety Assessments....................................................................................................................... 59
8.2.1.
Bleeding Events.......................................................................................................................... 60
8.2.1.1.
Classification of Bleeding Events ............................................................................................ 60


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8.2.1.2.
Approach to Subjects With a Bleeding Event.......................................................................... 60
8.2.2.
Physical Examination.................................................................................................................. 61
8.2.3.
Vital Signs................................................................................................................................... 62
8.2.4.
Clinical Safety Laboratory Assessments .................................................................................... 62
8.3.
Adverse Events and Serious Adverse Events ...............................................................................62
8.3.1.
Adverse Events of Interest.......................................................................................................... 62
8.3.1.1.
Bleeding Events - Adverse Events of Interest.........................................................................63
8.3.1.2.
Wound or Joint Complications................................................................................................. 63
8.3.1.3.
Liver Enzyme Elevations and Clinical Liver Events................................................................. 63
8.3.2.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 64
8.3.3.
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 65
8.3.4.
Follow Up of Adverse Events and Serious Adverse Events....................................................... 65
8.3.5.
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 65
8.3.6.
Pregnancy................................................................................................................................... 65
8.4.
Treatment of Overdose .................................................................................................................. 66
8.5.
Pharmacokinetics........................................................................................................................... 66
8.5.1.
Evaluations ................................................................................................................................. 66
8.5.2.
Analytical Procedures................................................................................................................. 67
8.5.3.
Pharmacokinetic Parameters and Evaluations...........................................................................67
8.6.
Pharmacodynamics........................................................................................................................ 67
8.7.
Biomarkers ..................................................................................................................................... 69
8.8.
Medical Resource Utilization and Health Economics .................................................................... 70
9.
STATISTICAL CONSIDERATIONS..................................................................................................70
9.1.
Sample Size Determination ........................................................................................................... 70
9.2.
Populations for Analyses................................................................................................................ 71
9.3.
Statistical Analyses ........................................................................................................................ 71
9.3.1.
Efficacy Analyses........................................................................................................................ 71
9.3.2.
Safety Analyses .......................................................................................................................... 72
9.3.3.
Other Analyses ........................................................................................................................... 73
9.4.
Periodic and Interim Analyses ....................................................................................................... 74
9.4.1.
Committees................................................................................................................................. 75
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 76
10.1.
Appendix 1: Abbreviations ............................................................................................................. 77
10.2.
Appendix 2: Clinical Laboratory Tests ........................................................................................... 79
10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 80
10.4.
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow Up, and Reporting............................................................................................................... 91
10.5.
Appendix 5: Contraceptive and Barrier Guidance and Collection of Pregnancy Information........ 96
10.6.
Appendix 6: Definition of Bleeding Events..................................................................................... 99
10.7.
Appendix 7: Protocol Amendment History ...................................................................................101
REFERENCES.......................................................................................................................................... 102
INVESTIGATOR AGREEMENT ............................................................................................................... 105
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:  Highlights of Pharmacokinetics and Product Metabolism Characteristics of JNJ-
70033093 .................................................................................................................................. 30
Table 2:
Assumed Total VTE Event Rates by Treatment Group in Sample Size Determination ........... 71
Table 3:
Analysis Populations................................................................................................................. 71


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FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 19
Figure 2:
Exposure-dependent Reductions in Thrombus Weights With JNJ-70033093 in Rabbits ........ 41
Figure 3:
Reduction in FXI Concentration Based on FXI ASO Compound Used in Phase 2 VTE 
Study......................................................................................................................................... 42
Figure 4:
Canonical Candidate Emax Dose-response Models Used in the MCP-Mod Analysis ............... 72


JNJ-70033093
Clinical Protocol 70033093THR2001 Amendment 1
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Approved, Date: 10 September 2019
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1
10-Sep-2019
Amendment JPN-1
24-July-2019
Original Protocol
11-Dec-2018
Amendment 1 (10 September 2019)
Overall Rationale for the Amendment:  The overall reasons for the amendment are to modify the study 
design with regards to the planned and optional doses and to remove the option for preoperative dosing.
Section Number
and Name
Description of Change
Brief Rationale
Title Page
The study name “AXIOMATIC-TKR -
Antithrombotic treatment with factor XIa 
inhibition to Optimize Management of Acute 
Thromboembolic events in TKR” was added 
to the title page.
The title page was revised to 
include the study name for better 
readability.
1.1. Synopsis Objectives
and Endpoints;
3. Objectives and Endpoints
Parenthesis placement was moved in the 
primary objective to include all deaths in the 
definition of total venous thromboembolism 
(VTE). 
Editorial error in the primary 
objective did not align with 
efficacy evaluations in the 
assessment of study outcomes.
1.1. Synopsis Objectives 
and Endpoints; 
1.1. Synopsis Hypothesis; 
3. Objectives and Endpoints
The hypothesis and the primary endpoint were 
revised to specify that the event rate will be 
analyzed by the “combined twice daily (BID)
dose group” instead of the “combined dose 
group”.
Also, the secondary endpoint was modified in 
regard to the bleeding criteria because there is 
no International Society on Thrombosis and 
Hemostasis (ISTH) assessment for clinically 
relevant nonmajor bleeding in the surgical 
setting. 
The language pertaining to the 
hypothesis, primary and 
secondary endpoints modified 
for enhanced clarity.
1.1. Synopsis Overall 
Design; 4.1. Overall 
Design; 8.2. Safety 
Assessments; 9. Statistical 
Considerations; 
10.3. Appendix 3, 
Regulatory, Ethical, and 
Study Oversight 
Considerations, Committees 
Structure/Operations 
Committee
Text specifying the frequency of reviews of 
unblinded data by the Operations Committee 
(OC) was changed from approximately every 
4 to 8 weeks to 3 to 8 weeks.
The frequency of reviews of 
unblinded data was modified as
agreed upon with the OC.
1.1. Synopsis, Overall 
Design; 1.2. Schema; 
4.1. Overall Design; 
9. Statistical 
Considerations; 
9.4. Periodic and Interim 
The number of subjects to be included at the 
first interim analysis was changed from 400 to 
approximately 300 subjects (approximately 50 
subjects in each of the JNJ-70033093 BID 
treatment groups).  
In addition, the text noting that the timing and 
The number of dose groups at 
the onset of the study was 
reduced by 2 groups, therefore,
the timing of the first interim 
analysis was changed. 
Because this is the first small-


JNJ-70033093
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Approved, Date: 10 September 2019
Section Number
and Name
Description of Change
Brief Rationale
Analyses
the cohorts will be defined in the OC charter 
was removed.
molecule that inhibits the 
activated form of human 
coagulation Factor XIa,
flexibility was needed in 
determining the timing of the 
interim analyses during OC 
review of the data.
1.1. Synopsis; 1.2. Schema; 
4.1. Overall Design; 
6.1. Study Drugs 
Administered
The option to administer preoperative doses of 
JNJ-70033093 was removed throughout the 
protocol.
Academic leadership advised 
that preoperative dosing would 
not be adopted by the orthopedic 
community in clinical practice, 
therefore testing was removed 
from the protocol.
1.1. Synopsis; 1.2. Schema; 
6.1. Study Drugs 
Administered; 
6.3. Measures to Minimize 
Bias: Randomization and 
Blinding; 9. Statistical 
Considerations
•    Once daily dose regimens of 
JNJ-70033093 were moved from the start of 
the study to possible doses after the interim 
analysis and the doses were changed from 
25 mg once daily and 200 mg once daily to 
50 mg once daily and 200 mg once daily.
•
Initial randomization changed from
1:1:1:1: 1:1:2 to 1:1:1:1:2
•
Initial number of dose groups changed 
from 7 to 5
•
Removed text noting the number of 
ongoing doses of JNJ-70033093 is expected to 
be no fewer than 4 doses.
The once daily doses were re-
evaluated, and the 50 mg once 
daily dose will be evaluated
because it more closely parallels 
the 25 mg BID dose and will 
allow for a more meaningful 
comparison between the once 
daily and BID doses.
1.1. Synopsis, Number of 
Subjects; 1.2. Schema; 
4.1. Overall Design; 
9. Statistical Considerations
Target and maximum number of subjects was 
changed from 1,200 and 1,500 to 900 and 
1,200, respectively. Text revised to specify 
that this is based on the possible addition of 
once daily doses and/or the evaluability rate.
It was also clarified that the number of 
subjects who were planned to be randomized 
into the dropped dosing regimen can be 
allocated to one of the other dosing groups.
The target number of subjects 
was changed based on the 
change in the study design.
1.1. Synopsis; 1.3. Schedule 
of Activities (SoA); 
4.1. Overall Design; 
4.2. Scientific Rationale for 
Study Design; 6.1. Study 
Drug Administered
•
Regarding the first dose of study drug, the 
specification for “the day after total knee 
replacement (TKR) surgery” was changed to 
“after the end of TKR surgery” and “next 
day” was removed.
•
“PO” was removed in front of days of the 
visit
•
10- to 14- postoperative days was changed 
to 10 to 14 days.
•
Postoperative Day 10-14 visit was 
changed to Day 10-14. 
•
Footnote “r” added to SoA to specify 
optional pharmacodynamic (PD) samples for 
subjects randomized to enoxaparin.
During initiation of the study it 
was determined that standard-of-
care in certain regions should 
initiate anticoagulation on the 
day of surgery, not the morning 
after surgery. 
Collection of the PD sample was 
made optional for enoxaparin 
subjects in order to make dosing 
on the evening of surgery more 
practical.
1.1. Synopsis; 1.2. Schema; 
6.1. Study Drug 
Administered/Drug 
Enrollment in Group E was discontinued. 
Subjects randomized to this group prior to 
Amendment 1 will continue treatment.
Once daily study drug-dose
groups revised to reflect changes 
in the study design and allow 


JNJ-70033093
Clinical Protocol 70033093THR2001 Amendment 1
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Section Number
and Name
Description of Change
Brief Rationale
Administration
Enrollment in Group F was suspended and 
made optional until the OC determines that 
enrollment is appropriate.
For Group G, the 50 mg once daily dose was 
added (2 capsules JNJ-70033093: 25 mg in 
the morning and 2 placebo capsules in the 
evening). Text noting that enrollment in 
Group G will become optional per 
Amendment 1 was also added.
Optional Group H removed. 
Text noting that no optional dose will exceed 
a 400-mg total daily dose was removed.
flexibility of optional dosing in 
Groups F and G until final
determination by the OC.
1.1. Synopsis, Study Drug 
Groups and Duration; 
1.3. Schedule of Activities 
(SoA), Footnote 1; 
4.1. Overall Design; 
6.1. Study Drug 
Administered; 
6.5. Concomitant Therapy
Text added specifying that the study drug 
“must be the first anticoagulant administered 
postoperatively”. 
Text was needed to clarify the 
timing of postoperative doses of 
other anticoagulants in relation 
to the study drug.
1.1. Synopsis, Safety 
Evaluations; 1.1. Synopsis, 
Statistical Methods; 
1.3. Schedule of Activities 
(SoA), Footnote t; 
4.1. Overall Design; 
8.2. Safety Assessments; 
8.3.1. Adverse Events of 
Interest; 8.3.1.3. Liver 
Enzyme Elevations and 
Clinical Liver Events; 9.3.2. 
Safety Analyses
Changed terminology of Adverse Events of 
Special Interest to “Adverse Events of 
Interest”.
Terminology changed because 
for this study expected events 
and study endpoints are 
considered adverse events of 
interest. 


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Section Number
and Name
Description of Change
Brief Rationale
1.1. Synopsis Endpoints; 
1.1. Synopsis 
Pharmacokinetic 
Evaluations; 1.1. Synopsis 
Statistical Methods; 
3. Objectives and 
Endpoints; 
8.5.3. Pharmacokinetic 
Parameters and Evaluations; 
9.3.3. Other Analyses 
For the study endpoints as well as the 
pharmacokinetic evaluations, the word “level” 
was removed from the description of
JNJ-70033093 exposure.
Exposure level is not a typical 
description. Therefore, the term 
“exposure” alone is sufficient as 
the exposure level is not defined 
in the protocol. 
1.1. Synopsis, Overall 
Design; 4.1. Overall 
Design; 6.2. Preparation/ 
Handling/Storage/ 
Accountability; 6.4. Study 
Drug Compliance
Text added noting that selected sites may also 
use scanning technology to manage clinical 
study supplies and drug compliance activities. 
Subjects enrolled at selected sites may use an 
application on the subject’s own 
smartphone/tablet to confirm study drug 
administration (JNJ-70033093 capsules only) 
and receive notifications as per protocol 
scheduled events (eg, next clinical site visit) 
as well as additional study information.
Adding pilot program at selected 
sites to compare manual methods 
of compliance monitoring, 
subject retention, end-to-end 
subject engagement, and drug 
accountability with an automated 
method.
1.3. Schedule of Activities 
(SoA)
•
Timing for randomization was changed 
from Day of surgery -2 to postoperatively, 
following the primary unilateral elective TKR 
surgery.  In addition, the statement that all 
subjects must be randomized prior to surgery 
was removed.
•
Laboratory samples at the up to Day -30 
timepoint were removed. The Factor XI (FXI)
antigen required at this time point was also 
moved to 0 hour.
•
Specified 
that 
enoxaparin 
may 
be 
administered preoperatively 12 hours prior to 
the surgical procedure in accordance with 
local standard-of-care. Sites that routinely 
administer preoperative enoxaparin should 
continue their standard practice for all study 
subjects at that site. Per standard-of-care, 
study drug should not be used for the 
preoperative dose of enoxaparin for subjects 
in either treatment group.
As a result of the removal of 
JNJ-70033093 preoperative 
dosing, randomization will now 
be conducted postoperatively 
because the first dose of study 
drug will not be administered 
until 12 to 24 hours after wound 
closure. In addition, laboratory 
samples to be collected prior to 
surgery are no longer necessary 
since the 0-hour samples will be
collected prior to study drug for 
all subjects. Because 
randomization will now occur 
postoperatively, clarification 
added that 0-hour samples
cannot be drawn until after 
randomization because some are 
conditional samples based on the 
treatment group.
1.3. Schedule of Activities 
(SoA)
Text added to footnote d: Day 4 procedures 
may be conducted up to +2 days (ie, samples 
may be drawn on Days 5 or 6) and Day 7 
procedures may be conducted +2 days
(ie, Day 8 or 9).
Text added to allow flexibility 
with laboratory testing on 
weekend days.
1.3. Schedule of Activities 
(SoA), Footnote e; 
6.1. Study Drugs 
Administered
Text added to clarify that if using the +6-hour 
window to allow the 12-hour sample to be 
drawn the following morning, the evening 
dose of study drug on Day 1 or Day 4 should 
be administered, but there must be a minimum 
of 6 hours between doses on these days.
Twice daily dosing should 
commence at the initiation of 
treatment and should not be 
dictated by the pharmacokinetic 
(PK) sample schedule.
1.1. Synopsis; 1.3. Schedule 
of Activities (SoA), 
Footnote q; 6.1. Study Drug 
Administered
Text added to specify that on the day of the 
Day 10-14 visit, study drug dosing should 
occur first thing in the morning, and the PK 
sample should not be drawn until at least 
Text added for clarity on 
handling of PK samples and 
dosing.


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Clinical Protocol 70033093THR2001 Amendment 1
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Approved, Date: 10 September 2019
Section Number
and Name
Description of Change
Brief Rationale
1 hour after the dose is taken. Also added text 
noting that subjects who discontinue study 
drug early do not need to have PK sampling 
conducted at any subsequent visits.  
2.2. Background
Table 1 updated.
Changes reflect the most recent 
edition of the Investigator’s 
Brochure, Edition 5.
4.1. Overall Design  
Modified text to specify the OC may unblind 
any member of the Steering Committee and 
that any member unblinded will no longer be 
involved in the operational aspects of the trial.
Revised to allow the OC 
flexibility in consulting with the 
Steering Committee members 
when discussing data resulting in 
recommendations to revise the 
study design.
4.1. Overall Design  
Deleted sentence: Pharmacokinetic, PD, and 
biomarker samples will also be collected and 
assessed.
Corrected error, since PK/PD 
samples will not be collected at 
Week 6.
4.2. Scientific Rationale for 
Study Design, Choice of 
Comparator
Clarified text to add that 40-mg daily dose of 
enoxaparin will be used in this study as it is 
the dosage regimen used in “most” approved 
countries for the indication being studied.
Text modified because some 
countries use enoxaparin 30 mg 
or 20 mg BID for VTE 
prophylaxis post TKR surgery.
4.2. Scientific Rationale for 
Study Design, Choice of 
Biomarkers
Text changed from postoperatively “at 
approximately 12 to 24 hours” to “on Day 1 
(0 hour) prior to study drug administration”.
Text edited to reflect the correct 
time the cardiac troponins would 
be drawn postoperatively.
4.3. Justification for Dose
Additional justification provided for using a 
more conservative approach for the lowest 
proposed once daily dose based on 
maintaining pharmacological effect of aPTT 
prolongation at ≥1.5 times over the full dosing 
interval.
Additional language needed to 
justify the lowest proposed once 
daily dose.
5.1. Inclusion Criteria; 
5.3. Lifestyle 
Considerations
Half-life restrictions for birth control 
measures were increased by 2 days. The 
following criteria were updated accordingly:
•  #8 Requirement for birth control for females 
was increased from 32 to 34 days
•
#9 Requirement for egg donation for 
females was increased from 32 to 34 days
•
#10 Requirement for birth control for 
males was increased from 92 to 94 days
•
#11 Requirement for sperm donation for 
males was increased from 92 to 94 days
Updated to take a more 
conservative approach by 
utilizing the upper end of the 
JNJ-70033093 half-life for birth 
control measures. The half-life of 
JNJ-70033093 as 18 hours 
versus 11 hours was used and 
therefore, the 5 half-lives of the 
study drug increased to 4 days 
rather than the 2 days previously 
used.  
5.2. Exclusion Criteria
Second bullet from Exclusion Criterion 4 was 
removed.
Exclusion Criterion 5 corrected to state 
contrast-induced nephropathy instead of
neuropathy
Exclusion Criterion 8 modified to include 
sensitivities to heparin and pork products
Exclusion criteria revised for 
clarity.
5.3. Lifestyle 
Considerations
The following criterion was modified:
#3 Timepoint requirement for the restriction 
on donating blood was changed from “at least 
Lifestyle restriction revised for 
clarity.


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and Name
Description of Change
Brief Rationale
4 days after completion of the study” to “until 
after completion of the study”
5.4. Screen Failures
Text noting subjects eligible for rescreening 
only in cases when TKR surgery is 
rescheduled outside of the 30-day window 
was removed.
Text was deleted to allow 
subjects to be rescreened for 
reasons other than rescheduled 
surgery.
6.1. Study Drug 
Administered, Drug 
Administration
Language added to specify that if a dose of 
JNJ-70033093 is missed, the capsule should 
be taken as soon as possible; 2 doses can also 
be taken together in the evening if the 
morning dose is missed.  No more than 
2 doses should be taken in 1 day.
Instructions added to give 
direction for what to do for a 
missed dose of JNJ-70033093 
study drug.
6.2. Preparation/Handling/ 
Storage/Accountability
Temperature range for storage of study drug 
was removed and text was added noting the 
storage conditions would be specified in the 
product label.
Text removed for consistency 
with the product label.
6.5. Concomitant Therapy
Removed text specifying that “in those 
situations where the study drugs are 
administered preoperatively, intermittent 
pneumatic compression is still permitted until 
the time of the first postoperative dose of the 
study drug”.
Text removed, given that the 
option for preoperative dosing 
was removed.
7.2. Subject 
Discontinuation/Withdrawal 
From the Study
The last sentence in this section was revised to 
state that if a subject discontinues study drug 
and does not withdraw consent, then the 
subject should continue to have all remaining 
assessments completed.
Language modified because 
continuation of remaining study 
procedures should not be 
applicable to subjects who 
withdraw consent.
8. Study Assessments
Blood volume in the table for high-sensitive 
cardiac troponin T (hs-cTnT) sample is 4.0 
mL not 2.7 mL, and the total blood volume 
was changed from 155.7 to 134.9 mL. Total 
blood volume collected in the study noted in 
the table also was corrected (approximately 
135 mL, with 95 mL for PD/biomarkers).
Total blood volume for subjects randomized 
to enoxaparin was also added (115 mL) to the 
text because no PK samples are drawn.
Corrected discrepancy in the 
volume of laboratory samples 
between volume of blood to be 
collected for each subject and the 
actual volumes of the collection 
tubes that are supplied by the 
central laboratory.
8. Study Assessments; 
8.2.4. Clinical Safety 
Laboratory Assessments
The timepoint for collection of the 
hematology and chemistry laboratory tests 
and urine sample for urinalysis at screening 
was removed.
Text revised to align with the 
sequence of laboratory 
assessments specified by the 
central laboratory. In addition, 
timepoints of hematology and 
chemistry laboratory tests and 
urine sample were modified.
Screening laboratory testing was 
removed because preoperative 
dosing will not be implemented.
8.3.1.3.  Liver Enzyme 
Elevations and Clinical 
Liver Events
Modified language to clarify the criterion of 
alanine aminotransferase (ALT) and/or
aspartate aminotransferase (AST) ≥3 times (x) 
upper limit of normal (ULN), confirmed by 
repeat is not required to be reported as an 
adverse event of interest.
Expected reporting of liver 
enzyme elevations as adverse 
events of interest clarified.
Previous language was unclear, 
the liver enzyme elevations do 
not meet the criteria for 


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Section Number
and Name
Description of Change
Brief Rationale
mandatory adverse event of 
interest reporting.
8.3.6. Pregnancy
Text edited to note that if a subject becomes 
pregnant during the study, the subject must be 
discontinued from further study intervention.
Pregnancy is an exclusion 
criterion for the study, therefore 
study drug should be 
discontinued in the event of 
pregnancy.
8.4. Treatment of Overdose
Text edited to specify the threshold for 
reporting an overdose applied to both 
JNJ-70033093 and enoxaparin and overdose 
that is considered excessive and medically 
important by the investigator should be 
reported as a serious adverse event (medically 
important event).
Corrected language to include 
enoxaparin because the protocol 
text defined the threshold for 
reporting an overdose of 
JNJ-70033093 but not 
enoxaparin.
8.5. Pharmacokinetics
Pharmacokinetic specimen type changed from 
serum samples to plasma samples.
Correction that PK samples are 
plasma samples.
Typo, wording contains incorrect 
PK specimen type.
9.1. Sample Size 
Determination, Table 2
Assumed total VTE rate for 25 mg once daily
was deleted and the assumed rate of 24% was 
added for 50 mg once daily.
Table was updated to reflect the 
change in planned once daily
dosing because it is anticipated 
that 50 mg once daily, as the 
lowest once daily dose being 
tested, would perform at a level 
equivalent to enoxaparin.
9.2. Populations for 
Analyses
Week 6 visit was removed from the 
description of the modified intent-to-treat 
(mITT) population.  
The description for the mITT 
population revised because
subjects will have only 1 valid 
venography visit at Day 10-14.
9.3.1. Efficacy Analyses
The study objective was modified to add text 
noting the importance of showing a 
statistically significant <30% event rate in 
total VTE in the combined dose group.
The text noting that data from preoperative 
dose regimens will not be used in the 
modified MCP-Mod analysis and separate 
analysis was deleted.
The statistical rationale for the 
study objective was revised for 
clarity.
9.3.2. Safety Analyses
Edited text to specify that height and weight 
will be summarized.
Changes in physical examination 
are not specified in the electronic 
case report form (eCRF). Any 
changes in physical examination 
are evaluated and captured as 
adverse events as appropriate.  
Height and weight are recorded 
in the eCRF.
10.6. Appendix 6/ 
Definition of Bleeding 
Events
The description of clinically relevant 
nonmajor bleeding was revised to indicate a 
modified version of the criteria from the 
ADVANCE-2 study, in tandem with clinical 
judgement, will be used to classify clinically 
relevant nonmajor bleeding events.  
Modified to be in alignment with 
the standard practice used by the 
Clinical Events Committee
(CEC).


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Section Number
and Name
Description of Change
Brief Rationale
Also, the descriptions listed for each bleeding 
type are examples not criteria. 
The example of a hematoma was revised to 
remove “and a drop of hemoglobin is present 
with no external evidence of bleeding”.
The description of minimal bleeding was 
revised to specify it specifically must be 
considered a “clinically overt” bleeding event 
to be included in this category. 
Moved reference 27, 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, from the 
clinically relevant nonmajor category to the 
minimal bleeding definition.
Throughout the protocol
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted.


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
A Randomized, Open-Label, Study Drug-Dose Blind, Multicenter Study to Evaluate the Efficacy and 
Safety of JNJ-70033093 (BMS-986177), an Oral Factor XIa Inhibitor, Versus Subcutaneous Enoxaparin 
in Subjects Undergoing Elective Total Knee Replacement Surgery
JNJ-70033093 (Bristol-Meyers Squibb Company [BMS]-986177) is a small-molecule therapeutic agent 
that binds and inhibits the activated form of human coagulation Factor XIa (FXIa) with high affinity and 
selectivity. It is being codeveloped under a collaboration agreement between BMS and its global affiliates 
and Janssen Pharmaceutical Research and Development, LLC. JNJ-70033093 is being developed as an 
orally administered anticoagulant for the prevention and treatment of thromboembolic events (eg, venous 
thromboembolism [VTE]).
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
!
To determine the efficacy of JNJ-70033093 in 
preventing total VTE events (proximal and/or 
distal 
DVT
[asymptomatic 
confirmed 
by 
venography assessment or objectively confirmed 
symptomatic], nonfatal PE, or any death) during 
the treatment period.
!
Total VTE during the treatment period up to 
the time of venography as assessed by the 
CEC. Proof-of-efficacy is reached by either 
showing a positive dose-response or having
less than a 30% total VTE event rate in the 
combined twice daily (BID) dose group.
Secondary
!
To assess the dose-response of JNJ-70033093 
for the occurrence of the endpoint of any 
bleeding events during the treatment period.
!
The composite endpoint of any bleeding 
event on treatment. Any bleeding will be 
defined as the composite of major bleeding 
according to the ISTH criteria modified for 
the surgical setting, clinically relevant 
nonmajor bleeding events, or minimal 
bleeding events as assessed by the CEC.
!
To determine the efficacy of JNJ-70033093 in 
preventing total VTE events during the full 
study period.
!
Total VTE as assessed by the CEC through 
Week 6.
!
To assess the dose-response of JNJ-70033093 
for the rate of any bleeding throughout the full 
study period.
!
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 as assessed by the CEC 
through Week 6.


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Objectives
Endpoints
!
To assess the dose-response of JNJ-70033093 
for the prevention of major VTE (death, 
asymptomatic or symptomatic proximal DVT or 
PE) during the treatment period and throughout 
the full study period.
!
Major VTE as assessed by the CEC during 
the treatment period and through Week 6.
!
To assess the effect of individual doses of 
JNJ-70033093 compared with enoxaparin for 
both efficacy and safety endpoints.
!
Total VTE and any bleeding as assessed by 
the CEC during the treatment period and 
during the full study period (6 weeks).
!
To compare the effect of JNJ-70033093 with 
enoxaparin for the individual components of the 
total VTE endpoint.
!
All individual components of the primary 
efficacy endpoint as assessed by the CEC 
during the treatment period and during the 
full study period (6 weeks).
!
To assess the PK of JNJ-70033093 in men and 
women undergoing primary unilateral TKR 
surgery and the relation of these measures to 
efficacy and safety endpoints (eg, exposure-
response analyses).
!
Estimation of PK parameters and the effects 
of demographics and laboratory values 
(eg, body 
weight, 
age, 
gender, 
renal 
function) on the PK of JNJ-70033093.
!
Estimation of the relationship between 
JNJ-70033093 exposure with probability of 
total VTE during the treatment period up to 
the time of venography and the probability 
of the composite endpoint of major or 
clinically 
relevant 
nonmajor 
bleeding 
events, and the individual components of the 
composite endpoint of any bleeding event 
on treatment.
Exploratory
!
To evaluate PD to assess its relationships to PK
and the relation of these measures to efficacy 
and safety endpoints (eg, exposure-response 
analyses).
!
Changes in PD (aPTT, PT, FXI clotting 
activity, anti-FXa activity, and TGA).
!
Estimation of the relationship between 
JNJ-70033093 exposure with the changes in 
PD.
!
To evaluate exploratory biomarkers to assess 
their relationship to the probability of total VTE 
during the treatment period.
!
Estimation of the changes in biomarkers 
with the probability of total VTE during the 
treatment period up to the time of 
venography and the probability of the 
composite endpoint of major or clinically 
relevant nonmajor bleeding events, and the 
individual components of the composite 
endpoint of any bleeding event on treatment.


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Objectives
Endpoints
!
Explore 
the 
presence 
and 
incidence 
of 
asymptomatic MINS as it relates to total knee 
arthroplasty.
!
The presence of an isolated elevated 
hs-cTnT 
measurement 
postoperatively 
without 
an 
alternative 
explanation 
(eg, sepsis, atrial fibrillation) in subjects 
with normal preoperative hs-cTnT. An 
incremental rise in hs-cTnT without an 
alternate explanation in individuals with 
elevated preoperative hs-cTnT.
anti-FXa=anti-Factor Xa; aPTT=activated partial thromboplastin time; BID=twice daily; CEC=Clinical 
Endpoint Committee; DVT=deep venous thrombosis; FXI=Factor XI; hs-cTnT=high-sensitive cardiac 
troponin T; ISTH=International Society on Thrombosis and Hemostasis; MINS=myocardial injury in 
noncardiac surgery; PD=pharmacodynamic; PE=pulmonary embolism; PK=pharmacokinetic; 
PT=prothrombin time; TGA=thrombin generation assay; TKR=total knee replacement; VTE=venous 
thromboembolism
Hypothesis
The primary hypothesis is that JNJ-70033093 reduces the risk of total venous thromboembolism (VTE)
during the treatment period. This can be achieved by either a statistically significant dose-response trend 
or an event rate for the combined twice daily (BID) doses of JNJ-70033093 that is statistically lower than 
30%. The event rate of 30% is a conservative estimate of the total VTE rate in subjects given placebo.
OVERALL DESIGN
This is an open-label, study drug-dose blind, active-controlled, multicenter, dose-ranging study of 
JNJ-70033093 in subjects undergoing primary unilateral elective total knee replacement (TKR) surgery. 
The study uses the prospective, randomized, open-label, blinded endpoint (PROBE) design. Men and 
women who are ∀50 years of age are eligible to participate if they are considered medically stable and 
appropriate for anticoagulant prophylaxis as determined by the investigator. 
The study will be conducted in 3 phases, which includes an up to 30-day screening phase before surgery, 
a 10- to 14-day postoperative dosing phase, and a 4-week #10 days 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 end of study is considered as the last visit for the last subject in the study.
Selected sites may also use scanning technology to manage clinical study supplies and drug compliance 
activities. Subjects enrolled at selected sites may use an application on the subject’s own 
smartphone/tablet to confirm study drug administration (JNJ-70033093 capsules only) and to receive 
notifications as per protocol scheduled events (eg, next clinical site visit) as well as additional study 
information.
An Operations Committee (OC), Steering Committee, and independent Clinical Events Committee (CEC) 
will be commissioned for this study. The OC will be unblinded, the Steering Committee will be blinded to 
the dose and frequency of JNJ-70033093, and the CEC will be blinded to both the study drug and the 
dose. The OC will be responsible for reviewing ongoing safety and efficacy data by unblinded subject 
treatment assignments approximately every 3 to 8 weeks on a periodic basis.
Unblinded periodic and interim analyses will be conducted by the OC for the purposes of safety oversight 
and as part of the adaptive approach. The first interim analysis will be triggered when approximately
300 subjects (approximately 50 subjects in each of the JNJ-70033093 BID treatment groups) have 
completed venography or have had a symptomatic VTE event. Both periodic and the interim analyses 
results will be used to guide the decision to drop a dose of JNJ-70033093 and/or readjust the 
randomization ratio. The number of subjects who were planned to be randomized into the dropped dosing 


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regimen can be allocated to one of the other dosing groups. The interim analysis will also serve as the 
formal venue to assess study status and possibly add once daily 50 or 200 mg dose of JNJ-70033093 
based on available efficacy and safety data. If pharmacokinetic/pharmacodynamic (PK/PD) analysis 
results are available at the time of the interim analysis, the results will be included in the review.
Additional interim analyses will be conducted, as needed, at the discretion of the OC.
NUMBER OF SUBJECTS
A target of 900 subjects will be randomly assigned to treatment in this study, with an option to increase 
the randomization target to approximately 1,200 subjects based on the possible addition of once daily
dose groups, and/or the evaluability rate. The number of subjects who were planned to be randomized into 
the dropped dosing regimen can be allocated to one of the other dosing groups.
STUDY DRUG GROUPS AND DURATION
Eligible subjects will be randomly assigned to treatment with either JNJ-70033093 or enoxaparin
postoperatively following unilateral elective TKR surgery. Subjects will know the treatment to which they 
were assigned but subjects randomly assigned to JNJ-70033093 will remain blinded to the dose and 
frequency (ie, BID versus once daily). 
First dosing of both study drugs will occur while the subject is still hospitalized, with administration 
beginning a minimum of 12 hours and a maximum of 24 hours after the end of TKR surgery, which is 
defined as the time of wound closure, and must be the first anticoagulant administered postoperatively.
Enoxaparin may be administered preoperatively 12 hours prior to the surgical procedure in accordance 
with local standard-of-care. Sites that routinely administer preoperative enoxaparin should continue their 
standard practice for all study subjects at that site. Per standard-of-care, study drug should not be used for 
the preoperative dose of enoxaparin for subjects in either treatment group.
Following discharge or transfer to an alternate facility, subjects will continue to take the assigned study 
drug for a total of 10 to 14 days. Unilateral venography assessment of the operated leg will be performed 
within 1 calendar day after the last dose of either JNJ-70033093 or enoxaparin is taken. Study visits 
should be conducted in the morning, when possible study drug dosing should not occur until after the 
pharmacokinetic (PK) sample has been drawn. On the day of the Day 10-14 visit, study drug dosing 
should occur first thing in the morning, and the PK sample should not be drawn until at least 1 hour after 
the dose is taken.
The total duration of participation following randomization will be approximately 6 weeks.
Each subject randomly assigned to JNJ-70033093 will take 4 capsules a day, 2 capsules in the morning 
and 2 capsules in the evening at approximately the same time each day, as follows:
Group A: JNJ-70033093 25 mg BID (1 capsule JNJ-70033093 25 mg and 1 placebo capsule, BID)
Group B: JNJ-70033093 50 mg BID (2 capsules JNJ-70033093 25 mg BID)
Group C: JNJ-70033093 100 mg BID (1 capsule JNJ-70033093 100 mg and 1 placebo capsule, BID)
Group D: JNJ-70033093 200 mg BID (2 capsules JNJ-70033093 100 mg BID)
Group E: JNJ-70033093 25 mg once daily (1 capsule JNJ-70033093 25 mg and 1 placebo capsule in the 
morning and 2 placebo capsules in the evening). Enrollment in this group discontinued per Amendment 1. 
Subjects randomized to this group prior to Amendment 1 will complete study procedures.
Group F: JNJ-70033093 200 mg once daily (2 capsules JNJ-70033093 100 mg in the morning and 
2 placebo capsules in the evening). Enrollment in Group F suspended per Amendment 1 and may become 


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optional depending on OC decision. Subjects randomized to this group prior to Amendment 1 will 
complete study procedures.
Group G: JNJ-70033093 50 mg once daily (2 capsules JNJ-70033093 25 mg in the morning and 2 
placebo capsules in the evening) Enrollment in Group G will become optional per Amendment 1.
Subjects randomly assigned to JNJ-70033093 who take the first dose of study drug on the evening of 
surgery should take the 2 capsules assigned to the Day 1 morning dose (left side of blister card). On 
subsequent days the first dose should always be the left 2 capsules and the evening dose should be the 
2 capsules on the right.
Subjects randomly assigned to enoxaparin (Group I) will take a subcutaneous (SC) dose of 
enoxaparin 40 mg once daily, supplied as a prefilled syringe.
EFFICACY EVALUATIONS
Efficacy evaluations will include unilateral venography assessment of the operated leg and assessments of 
symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), or death to assess the primary, 
secondary, and exploratory efficacy outcomes.
PHARMACOKINETIC EVALUATIONS
Plasma samples will be analyzed to determine concentrations of JNJ-70033093 using a validated, 
specific, and sensitive (eg, liquid chromatography-mass spectrometry/mass spectrometry) method by or 
under the supervision of the sponsor. Pharmacokinetic samples will be collected from all subjects 
randomly assigned to JNJ-70033093. 
In addition, residual plasma PK samples may be stored for future analysis of the metabolite profile, if 
needed. 
Based on the individual plasma concentration-time data, using the actual dose taken and the actual 
sampling times, PK parameters (eg, apparent clearance, apparent volume of distribution) and exposure for 
exposure-response analysis of JNJ-70033093 and associated variables will be derived using population 
PK modeling. 
PHARMACODYNAMIC AND BIOMARKER EVALUATIONS
Venous blood samples will be collected for pharmacodynamic (PD) evaluation of aPTT, PT, Factor XI 
(FXI) clotting activity, anti-Factor Xa (anti-FXa) activity, thrombin generation assay (TGA), and 
biomarker evaluation (D-dimer, high-sensitive cardiac troponin T [hs-cTnT], and FXI antigen). Factor XI 
clotting activity will be assessed in subjects randomly assigned to JNJ-70033093 and anti-FXa activity 
will be assessed in subjects randomly assigned to enoxaparin. Subjects who experience a suspected major 
and clinically relevant nonmajor bleeding event or symptomatic VTE should have PD samples collected 
as soon as practically possible after the event occurs.
Blood samples will also be collected and a plasma sample archived for future exploratory PD research 
related to the safety and/or efficacy of JNJ-70033093. 
SAFETY EVALUATIONS
The safety and tolerability of JNJ-70033093 will be evaluated throughout the study by the assessment of 
adverse events, including serious adverse events, adverse events of interest (ie, bleeding events, liver 
enzyme elevations and clinical liver events, and wound or joint complications), clinical laboratory tests 
(ie, hematology, clinical chemistry, urinalysis), and physical examination. Safety evaluations may be 
performed at unscheduled timepoints, if deemed by the investigator or appropriate designee as necessary 
to ensure the safety of the subject. All suspected symptomatic efficacy events (VTE) will also be captured 
as adverse events of interest.


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STATISTICAL METHODS
Assuming the evaluability rate (rate of subjects with a valid assessment of potential efficacy outcome and 
who take a least 1 dose of study drug) is 80%, if the true underlying total VTE event rates are as 
projected, the study is expected to have over 99% power to declare proof-of-efficacy at a 1-sided, 
5% ∃-level. Proof-of-efficacy is defined as either a statistically significant dose-response trend or primary 
endpoint event rate for the combined BID JNJ-70033093 groups that is statistically lower than 30%. The 
exact power will vary because of the nature of the adaptive study design. 
Comparison with enoxaparin will be based on the comparison between the highest dose of JNJ-70033093
with acceptable safety and enoxaparin. For example, if the highest dose of JNJ-70033093 with acceptable 
safety is 200 mg BID, the number of evaluable subjects at this dose and enoxaparin groups is expected to 
be 120 and 240 subjects respectively, the power to detect a statistically significantly lower total VTE 
event rate against enoxaparin, at 1-sided, 5% ∃-level, is over 90%.
The study objectives include proof-of-efficacy and estimation of dose-response relationship in total VTE. 
The dose-response trend and estimation of the dose-response relationship will be addressed by a unified 
(modified) multiple comparison procedures and modeling (MCP-Mod) approach, utilizing collective data 
from postoperative regimens. 
The intent-to-treat (ITT) population will include all randomized subjects who have signed an informed 
consent. The modified intent-to-treat (mITT) population will be a subset of the ITT population consisting 
of subjects with a valid assessment of potential efficacy outcome and who take at least 1 dose of the study 
drug. The primary analyses of efficacy endpoints will be based on CEC-adjudicated events from the 
mITT population. The primary efficacy endpoint and its components will be summarized by dose and 
treatment group.
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, or subject narratives will be provided, as appropriate, for those subjects who die, 
who discontinue the study drug due to an adverse event, or who experience a severe or a serious adverse 
event.
Adverse events of interest that will be counted or listed are bleeding events, wound or joint complications, 
and liver enzyme elevations and clinical liver events.
The safety population will be a subset of the ITT population consisting of subjects who take at least 
1 dose of the study drug. The analyses of bleeding adverse events will be based on the CEC-adjudicated 
events; all other nonefficacy or nonbleeding adverse events will be based on investigator-reported events 
in the safety population.
Estimation of the dose-response relationship in any bleeding will be addressed by a unified (modified) 
MCP-Mod approach as with efficacy. Any bleeding, major bleeding, clinically relevant nonmajor 
bleeding, composite of major or clinically relevant nonmajor bleeding, and minimal bleeding will be 
summarized by the dose and treatment group.
Laboratory data will be summarized by type of laboratory test.
Population PK analysis of plasma concentration-time data of JNJ-70033093 will be performed using 
nonlinear mixed-effects modeling. Data will be listed for all subjects with available plasma concentrations 
per treatment group.
For each treatment group, descriptive statistics, including arithmetic mean, standard deviation (SD),
coefficient of variation, median, minimum, and maximum will be calculated for all individual derived 


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PK parameters including exposure information of JNJ-70033093. Descriptive statistics will be used to 
summarize JNJ-70033093 plasma concentrations at each sampling time point. Exposure-response 
analyses will be conducted to explore the relationship of the plasma concentration of JNJ -70033093 with 
efficacy and safety endpoints. 
Descriptive statistics, including mean, median, SD, minimum, and maximum will be provided for the 
percent change from baseline of the PD (activated partial thromboplastin time [aPTT], prothrombin time
[PT], FXI clotting activity, anti-FXa activity, thrombin generation assay [TGA]) and biomarker (D-dimer, 
hs-cTnT) parameters by nominal time of collection and dose and regimen level. The parameters may be 
statistically analyzed using mixed models. FXI antigen levels will be summarized.
The relationship between observed plasma concentration of JNJ-70033093 and measured PD markers will 
be investigated graphically. If appropriate, PK/PD exposure and response relationships may be further 
analyzed quantitatively. 
The relationship between the plasma PK exposure of JNJ-70033093 derived from the population PK 
model will be correlated with the measured PD markers and safety/efficacy endpoints via graphical 
analysis.
1.2.
Schema
Figure 1:
Schematic Overview of the Study






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g
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 pharmacodynamic (PD) samples should be collected as soon as practically possible for 
any subject who experiences a suspected symptomatic thrombotic or bleeding event.
h
Must be signed before first study-related activity and before TKR surgery. At the time of informed consent, 2 alternative means of contact for each subject will be 
collected (eg, contact information of the subject’s children, spouse, significant other, caretaker, legal representative, health care professional).
i
The investigator will need to determine if the subject is medically appropriate for anticoagulant prophylaxis on the basis of physical examination, medical history, 
and clinical laboratory tests performed as part of screening for elective TKR surgery. Minimum criteria for the availability of documentation supporting the 
eligibility criteria are described in Source Documents in Section 10.3, Appendix 3, Regulatory, Ethical, and Study Oversight Considerations. 
j
Pregnancy testing to be done within 2 days of the first dose of study drug.
k
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, use of all mechanical venous thromboembolism [VTE] prophylaxis methods) will be collected in the electronic case report form (eCRF).
l
All subjects will receive the first postoperative dose (JNJ-70033093 or enoxaparin) while the subject is still hospitalized, with administration beginning 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, and must be the first anticoagulant administered 
postoperatively. Enoxaparin may be administered preoperatively 12 hours prior to the surgical procedure in accordance with local standard-of-care. Sites that 
routinely administer preoperative enoxaparin should continue their standard practice for all study subjects at that site. Per standard-of-care, study drug should not 
be used for the preoperative dose of enoxaparin for subjects in either treatment group. Subjects randomly assigned to JNJ-70033093 who take the first dose of 
study drug on the evening of surgery should take the 2 capsules assigned to the Day 1 morning dose (left side of blister card). On subsequent days the first dose 
should always be the left 2 capsules and the evening dose should be the 2 capsules on the right. Subjects will be given a supply of study drug at the time of 
discharge or transfer to an alternate facility, with instructions to take the study drug, at approximately the same time each day for 10 to 14 days.
m
Height and weight should be obtained at the screening visit, with weight only at the final visit. Wounds will be assessed at all visits as part of the adverse event 
assessment.
n
Subjects who complete dosing will return to the study-site for final EOD assessments (at the Day 10-14 visit), at which time unilateral venography of the operated 
leg will be performed within 1 calendar day after the last dose of either JNJ-70033093 or enoxaparin is taken. If dosing is prematurely discontinued, the 
venography 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. 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. In addition, if the subject
is objectively diagnosed with a PE meeting the specified definitions prior to Day 10-14, a subsequent venography assessment of the operated leg is not required.
o
Suspected symptomatic VTE (DVT, PE, death) will be reported by the investigator and reviewed by the Clinical Events Committee (CEC) to ascertain if a 
thrombotic event has occurred.
p
The baseline laboratory assessments, including PD and biomarkers, may be taken at any time on Day 1, after randomization and before the first dose of study drug.


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q
All sites will collect PK blood samples for subjects randomly assigned to JNJ-70033093 at all visits up to Day 10-14. The Day 1 and Day 4 samples will be drawn 
at approximately 2, 4, and 12 hours after the first oral dosing of that day. The Day 2 blood sample will be drawn before the first dose of study drug on Day 2 and 
may be done with the subject as an inpatient or outpatient. The Day 7 sample will be drawn approximately 12 hours after the previous dose. Study visits should be 
conducted in the morning, when possible. Study drug dosing should not occur until after the PK sample has been drawn. On the day of the Day 10-14 visit, study 
drug dosing should occur first thing in the morning, and the PK sample should not be drawn until at least 1 hour after the dose is taken. For subjects who 
discontinue study drug early PK sampling does not need to be conducted at any subsequent visits. 
r
Pharmacodynamic samples are optional for subjects randomized to enoxaparin.
s
Factor XI clotting activity will be assessed in subjects randomly assigned to JNJ-70033093 and anti-FXa activity will be assessed in subjects randomly assigned to 
enoxaparin. Archive samples will be collected from all subjects at these timepoints.
t
All adverse events 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, including all adverse events of interest (ie, bleeding events, liver enzyme elevations and clinical liver events, and wound or joint 
complications). All suspected symptomatic efficacy events (VTE) will also be captured as adverse events of interest.


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2.
INTRODUCTION
JNJ-70033093 (Bristol-Meyers Squibb Company [BMS]-986177) is a small-molecule 
therapeutic agent that binds and inhibits the activated form of human coagulation Factor XIa
(FXIa) with high affinity and selectivity. It is being codeveloped under a collaboration agreement 
between BMS and its global affiliates and Janssen Pharmaceutical Research and Development, 
LLC. JNJ-70033093 is being developed as an orally administered anticoagulant for the
prevention and treatment of thromboembolic events (eg, venous thromboembolism [VTE]).
JNJ-70033093 is expected to provide noninferior or superior efficacy with reduced bleeding risk 
versus active comparators. Evidence to support this target profile includes the following:
!
Congenital deficiency of Factor XI (FXI) appears to provide protection from both arterial 
and venous thrombotic events and is rarely associated with unprovoked major bleeding 
(ie, less bleeding than with other factor deficiencies like Factor X).18
!
Knockout mice with essentially no FXI develop normally, are resistant to both venous and 
arterial thrombosis, and do not have any spontaneous bleeding.37
!
A Phase 2 study in subjects undergoing total knee replacement (TKR) with preoperative 
dosing of a FXI antisense oligonucleotide (ASO) that resulted in >80% reduction in FXI 
levels demonstrated superior efficacy compared with enoxaparin 40 mg once daily (total 
VTE 4% [95% confidence interval {CI}: 1, 12] vs 30.0% [95% CI: 20, 43], p<0.001) with 
numerically less major or clinically relevant nonmajor bleeding events (3% [95% CI: <1, 9] 
vs 8% [95% CI: 3, 17], p=0.16).4
For the most comprehensive nonclinical and clinical information regarding JNJ-70033093, refer 
to the latest edition of the Investigator's Brochure (IB) for JNJ-70033093.
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.
2.1.
Study Rationale
This study will evaluate the efficacy and safety of JNJ-70033093 in a TKR population. Data 
from this study will be used, in part, to define the therapeutic window of this FXIa-inhibitor. 
Results from this study will be used to develop Phase 3 studies in subjects requiring 
anticoagulation, including a possible indication of VTE prevention in subjects undergoing 
orthopedic procedures.
2.2.
Background
Nonclinical Studies
JNJ-70033093 is a high affinity, direct, small-molecule inhibitor of human coagulation FXIa,
with an inhibition constant (Ki) of 0.11 nM. JNJ-70033093 has >5,000-fold selectivity for FXIa 
over other blood coagulation proteases and structurally related enzymes involved in digestion, 
fibrinolysis, and inflammation, except chymotrypsin and plasma kallikrein where the Ki values 
are 35 nM and 44 nM, respectively. Human deficiency of plasma prekallikrein is tolerated 


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without a known phenotype. The protein digestive function of chymotrypsin in the intestine is
partially redundant with trypsin. Based on these observations, it is not expected that inhibition of 
chymotrypsin or plasma kallikrein activity will be a safety concern. To date, nonclinical 
toxicological studies have not shown any issues attributable to inhibition of either of these 
enzymes. 
In 
standard 
plasma 
coagulation 
assays, 
JNJ-70033093 
produced 
concentration-dependent increases in activated partial thromboplastin time (aPTT), but not 
prothrombin time (PT), indicating a selective effect on the intrinsic pathway. In the in-vitro 
thrombin generation assay (TGA) using human platelet-rich plasma, JNJ-70033093 (0.1 – 10 
μM) increased the lag time and time to peak, while reducing peak thrombin and endogenous 
thrombin potential. In the thromboelastography assay using human whole blood, JNJ-70033093 
produced a concentration-dependent increase in the reaction time but did not affect the maximum 
amplitude. Consistent with its mode of action, JNJ-70033093 did not have any direct effect on 
platelet aggregation induced by adenosine diphosphate, collagen, or arachidonic acid in human 
platelet-rich plasma in-vitro. Evaluations of the antithrombotic and antihemostatic effects of 
intravenous (IV) JNJ-70033093 infusions were performed in anesthetized rabbits. JNJ-70033093 
caused dose-dependent inhibition of thrombosis formation in injured arteries. In this experiment, 
the JNJ-70033093 plasma concentrations required to reduce thrombus weight by 20% and 50% 
were 34.5 ng/mL (55 nM) and 235 ng/mL (375 nM), respectively. In the same model, 
JNJ-70033093 also restored blood flow to an artery partially occluded by a preexisting thrombus. 
In this experiment, the JNJ-70033093 plasma concentration required to reduce thrombus weight 
by 50% was 665 ng/mL (1,060 nM). JNJ-70033093 did not increase bleeding times in rabbits, 
even at doses that produced approximately 80% inhibition of thrombus formation. The 
combination of JNJ-70033093, at a dose that produces approximately 80% inhibition of 
thrombus formation, and aspirin, at a dose that increases bleeding time by approximately 2-fold, 
did not lead to increased bleeding in rabbits over aspirin treatment alone. Additional rabbit 
cuticle bleeding-time studies were conducted with JNJ-70033093 in combination with 
clopidogrel and aspirin. However, off-target effects due to thrombin inhibition (as observed by a 
1.8-fold increase in ex-vivo thrombin time coagulation assay) at these high drug exposures 
observed in rabbits confounded the interpretation of those studies.21
Safety Pharmacology
JNJ-70033093, at maximum-tested concentrations of 15.66 to 93.97 %g/mL (serum/protein free), 
did not exhibit substantial off-target activity against a panel of 42 targets that included G-protein 
coupled receptors, monoamine neurotransmitter transporters, ligand-gated and non-ligand-gated 
ion channels, nuclear hormone receptors, or selected enzymes (acetylcholinesterase, monoamine 
oxidase, and phosphodiesterase). In in-vitro studies, JNJ-70033093 inhibited cardiac human 
ether-a-go-go gene/rapidly activating delayed rectifier potassium current (hERG/IKr) potassium 
channel currents, with a concentration at which 50% inhibition was observed (IC50) of 4.2 %g/mL 
(6.7 %M; 33 times [x] and 14x the projected free/unbound maximum plasma concentration [Cmax]
in humans at 200 mg once daily and twice daily [BID], respectively). At 6.26 %g/mL (10 %M), 
JNJ-70033093 had minimal effects on cardiac sodium channel currents (22.9% to 25.3% 
inhibition at 1 and 4 Hz, respectively) and calcium channel currents (13.9% inhibition).21


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In an exploratory study in anesthetized rabbits, JNJ-70033093 was associated with decreased 
blood pressure (up to -14.1% pretest) and increased heart rate (up to +20.9% pretest) at plasma 
concentrations ∀5.7 %g/mL, with prolonged QT interval corrected for heart rate using 
Fridericia’s formula (by ~6.5 ms) also noted at 19.61 %g/mL (13x and 5.5x the projected Cmax at 
200 mg once daily and BID, respectively. In a non-Good Laboratory Practice telemetry study in 
rats, there were minimal increases in blood pressure (&5%) at Cmax ∀5.0 %g/mL and heart rate 
(&6%) at Cmax of 16.14 %g/mL. These rabbit and rat findings were considered nonadverse due to 
their small magnitude. Importantly, in conscious monkeys, no JNJ-70033093-related 
hemodynamic or electrocardiogram changes were identified at any dose tested in 2 telemetry 
studies (Cmax &5.46 %g/mL) or 3 repeat-dose toxicity studies after approximately 2 weeks 
(Cmax &21.2 %g/mL, electrocardiogram not assessed), 6 weeks (Cmax &7.24 %g/mL), and 9 months 
(Cmax &6.56 %g/mL) of dosing. The exposure at the no observed adverse effect level (NOAEL) in 
the 9-month monkey study was 4.3x and 1.8x the projected Cmax in humans at 200 mg once daily
and BID, respectively. Taken together, the in-vitro and in vivo data indicate low potential of 
JNJ-70033093 for cardiovascular effects in humans.21
Toxicology
The nonclinical safety profile of JNJ-70033093 has been evaluated in a comprehensive battery of 
in-vitro studies and in vivo toxicity studies mainly in rats and monkeys. JNJ-70033093 has a 
high affinity for human FXIa (Ki = 0.11 nM) and cynomolgus monkey FXIa (Ki = 0.15 nM), but 
has a very weak affinity for rat FXIa (Ki = 490 nM). As such, the rat was chosen for evaluation 
of potential off-target toxicity, and the monkey was chosen as a non-rodent species to assess both 
on-target as well as off-target toxicity. 
The scope of the toxicology evaluations, as summarized below, supports continued testing of 
JNJ-70033093 in humans. Unless otherwise specified, exposure multiples at NOAELs and 
pertinent findings in toxicology studies are expressed relative to the projected exposures at 
200 mg once daily (Cmax of 1.512 %g/mL and area under the concentration versus time curve 
from 0 to 24 hours of the last measurable concentration [AUC0-24h] of 14.634 %g•h/mL) and 
200 mg BID (Cmax of 3.579 %g/mL and AUC0-24h of 60.514 %g•h/mL), the highest once daily and 
BID doses proposed for the Phase 2 study.
The protein binding for of JNJ-70033093 is comparable in rat, monkey, and human sera 
(97.1%, 89.1%, and 91.5%, respectively). As such, the exposure multiples have not been 
corrected for free fraction and are expressed as ratios of total exposure unless otherwise 
specified.
JNJ-70033093 was nongenotoxic in-vitro (Ames and cytogenetics assays, tested at maximum 
concentrations required by the International Council for Harmonisation [ICH] guidelines) and in 
vivo (micronucleus assessment; conducted as part of a 6-week toxicity study) in rats at doses up 
to 200 mg/kg/day (AUC0-24h of 319 %g·h/mL; 22x and 5.3x the projected exposure in humans at 
200 mg once daily and BID, respectively). Likewise, BMT 210370, an aniline metabolite of 
JNJ-70033093, was negative in the exploratory assays for mutagenicity and clastogenicity.21


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In definitive embryo-fetal development studies,21 JNJ-70033093 was neither embryo-fetal lethal 
or teratogenic. The exposures at the developmental NOAEL were 11x and 2.7x in rats 
(166 %g·h/mL) and 4.7x and 1.1x in rabbits (68.4 %g·h/mL) relative to the projected human area 
under the plasma concentration-time curve (AUC) at 200 mg once daily and BID, respectively.
JNJ-70033093 was well tolerated by rats at all doses tested for 2 and 6 weeks (10, 50, and 
200 mg/kg/day) and for 6 months (10, 30, and 50 mg/kg/day).21 Relative to Day 1 values, 
AUC exposures to JNJ-70033093 were decreased following repeated dosing. This finding was 
rat specific, noted in both sexes (with greater effects in males), and most evident in the 6-month 
study (with Week-26 AUCs 0.3x in males and 0.5x to 0.6x in females, relative to Day-1 values). 
Other noteworthy findings in rats were limited to increased serum alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), and/or glutamate dehydrogenase at ∀50 mg/kg/day in 
the subchronic studies and at ∀10 mg/kg/day in the 6-month study. These findings were 
considered nonadverse due to their minimal to mild magnitude, transient and/or non-progressive 
nature with continued dosing, lack of concurrent increases in serum bilirubin suggestive of 
altered liver function, full reversibility upon dosing cessation, and absence of microscopic 
evidence of liver injury. The NOAEL in the 6-month study was 50 mg/kg/day and the associated 
AUC values at Week 26 (26.1 %g•h/mL in males and 96.3 %g•h/mL in females) were &6.6x and 
&1.6x the projected exposures in humans at 200 mg once daily and BID, respectively.
JNJ-70033093 was clinically well tolerated by monkeys at all doses tested for 2 weeks (10, 50, 
and 150 mg/kg/day), 6 weeks (5, 15, and 50 mg/kg/day), and 9 months (10, 30, and 
50 mg/kg/day).21 There was no substantial accumulation or loss of exposures after repeated 
dosing. Consistent with the intended pharmacology of JNJ-70033093, exposure-dependent 
prolongations of aPTT were noted at ∀10 mg/kg/day across all studies. At 50 mg/kg/day in the 
2-week and 9-month studies, there were also accompanying increases in PT in some monkeys. 
Overall, the increased aPTT and PT were considered nonadverse as they were not associated 
with clinical or microscopic signs of bleeding and were fully reversible after cessation of dosing. 
Additional JNJ-70033093-related changes in monkeys were limited to decreases in red blood cell 
parameters and serum albumin at ∀50 mg/kg/day in the 2-week study and were considered
adverse only in 1 female at 50 mg/kg/day with very high JNJ-70033093 exposure (AUC of 
540 %g•h/mL). As such, the high dose in the subsequent 6-week and 9-month studies was capped 
at 50 mg/kg/day. Based on the absence of adverse findings at any dose tested, the high dose of 
50 mg/kg/day was considered the NOAEL for the 9-month study and the associated AUC 
(76.2 %g•h/mL at Week 39) was 5.2x and 1.3x the projected exposure in humans at 200 mg once 
daily and BID, respectively. 
Collectively, the results of nonclinical toxicology studies demonstrated an acceptable safety 
profile and support the use of JNJ-70033093 in humans at doses up to 200 mg BID.
Pharmacokinetic Profile
The pharmacokinetic (PK) characteristics of JNJ-70033093 were evaluated in rats, rabbits, dogs, 
and monkeys after IV and oral dosing.21 The absolute oral bioavailability of JNJ-70033093 was 
18% and 32% in rats and monkeys, respectively. JNJ-70033093 was a substrate of human efflux 


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transporters including P-glycoprotein (P-gp). After IV administration, the terminal elimination 
half-life was short (1.4, 2.5, 4.0, and 2.7 hours in rats, rabbits, dogs, and monkeys, respectively) 
and the total plasma clearance was low in all the species (9% to 23% of the reported liver blood 
flow). JNJ-70033093 distributed extravascularly in animals. Serum protein binding was 91.5% in 
human, and 89.1% to 97.1% in animals. Uptake studies with human hepatocytes suggested that 
active transport processes are at least partially involved in the hepatic uptake of JNJ-70033093. 
Further studies with rifamycin SV (an organic anion-transporting polypeptide [OATP] inhibitor) 
suggested that OATPs are not involved in the hepatic uptake of JNJ-70033093 (confirmed in a 
clinical drug-drug interaction (DDI) study [CV010014]).21.
In-vitro, JNJ-70033093 was the predominant drug-related compound (representing 94% to 99% 
of total drug-related ultraviolet [UV] peak area) in incubations with liver microsomes or 
hepatocytes. No unique metabolite was observed in human hepatocyte or microsome incubates. 
In rats, intact monkeys, and monkeys from a cholecystocentesis study, following a single oral 
dose of 200-, 150-, and 30-mg/kg, respectively, JNJ-70033093 was the predominant drug-related 
compound detected in plasma (approximately 99%, 87.2%, and 90.8% of total drug-related UV 
peak area at Cmax, respectively). In rats and monkeys, several metabolites were detected 
including an aniline containing metabolite, Met 17 (BMT 210370), which represented 6% to 
36% of the AUC of JNJ-70033093 in monkey, but was present at very low levels in rat plasma 
(metabolite was nongenotoxic as described later). In monkeys from the cholecystocentesis study, 
numerous metabolites were detected in bile including BMT 210370. No glutathione conjugate 
was detected in-vitro or in vivo. In bile duct-cannulated rats and monkeys, orally administered 
[14C] JNJ-70033093 was cleared primarily through biliary elimination.21 In dogs and monkeys, 
following IV doses of 0.5 mg/kg, urinary excretion was found to be a minor route of elimination.
Cytochrome P450 (CYP) 3A4/5 was identified as the primary enzyme responsible for the 
oxidative metabolism of JNJ-70033093. The potential DDIs with CYP3A inhibitors were 
confirmed in a clinical DDI study. JNJ-70033093 exhibited little or no reversible and 
time-dependent inhibition of the CYPs. JNJ-70033093 did not inhibit uridine diphosphate 
glucuronosyltransferase (UGT) 1A1 enzyme (IC50 ∀20 %M or 12.5 %g/mL). Relative to the 
Cmax values of JNJ-70033093 in humans (6.09 %M or 3.8 %g/mL after 200-mg BID doses), 
JNJ-70033093 showed low potential to induce the CYP1A2, CYP2B6, or CYP3A4 messenger 
ribonucleic acid levels in primary human hepatocytes (absence of CYP3A induction confirmed 
in a clinical DDI study).
JNJ-70033093 was a substrate of P-gp, but not of organic anion transporter (OATPs). 
JNJ-70033093 inhibited breast cancer resistance protein (IC50=19.6 %M or 12.3 %g/mL), 
OATP1B1 (IC50=4.8 %M
or 3.0 %g/mL), OATP1B3 (IC50=9.7 %M
or 6.1 %g/mL), 
sodium-taurocholate cotransporting polypeptide (NTCP, IC50=19.6 %M or 12.3 %g/mL), bile salt 
export pump (IC50=7.1 %M or 4.4 %g/mL), multidrug and toxin extrusion (MATE) protein 1 
(IC50=9.0 %M or 5.6 %g/mL), and MATE2K (IC50=28.7 %M or 18.0 %g/mL) transporters. No or 
low inhibition (IC50 >50 %M or 31.3 %g/mL) of P-gp, multiple drug-resistance protein (MRP) 2, 
OAT3, organic cation transporter (OCT) 1, and OCT2 was observed. 


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Overall, from a perpetrator standpoint and based on the IC50 values and observed Cmax values of 
6.09 %M (3.8 %g/mL) in humans (at the highest BID dose of 200 mg proposed for Phase 2), 
JNJ-70033093 is not anticipated to cause clinically relevant DDIs with substrates of CYPs, 
UGT1A1, P-gp, NTCP, MRP2, MATE2K, OAT1, OAT3, OCT1, or OCT2 (IC50=19.6 %M to 
>50 %M). However, there is a potential for DDIs with substrates of OATP1B1, OATP1B3, 
MATE1, or bile salt export pump at anticipated clinical doses and associated concentrations. In 
addition, a low potential for gastrointestinal interaction exists with substrates of P-gp and breast 
cancer resistance protein. From a victim standpoint, there is a potential for DDIs with inhibitors 
of CYP3A4/5 and P-gp, but not with inhibitors of OATPs.
Clinical Studies
JNJ-70033093 has been and is currently being investigated in a number of studies in humans, 
including:
!
Single- and multiple-ascending dose study
!
Drug-drug interaction study with itraconazole, diltiazem, rifampin, and aspirin
!
Clinical pharmacology studies of special populations, including subjects with end-stage 
renal disease (ESRD) undergoing hemodialysis, renal impairment, and hepatic impairment
!
Open-label safety and tolerability study in ESRD
!
Relative bioavailability
!
Japanese PK study
!
Secondary stroke prevention study
To date, no dose-limiting safety findings have been observed in these studies.
Human Pharmacokinetics
The first-in-human study with JNJ-70033093 investigated single oral doses between 4 and 
500 mg and multiple oral doses between 5 and 500 mg taken over a 14-day period. In the 
single-dose portion of the study, approximately dose proportional increases were observed 
between 20 and 200 mg once daily. Coadministration of a high-fat diet resulted in an 
approximately 1.4-fold increase in exposure at doses of 200 mg while 500 mg of JNJ-70033093
was associated with approximately 2-fold increases in exposure (AUC). Table 1 summarizes the 
clinical pharmacology of JNJ-70033093.


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Table 1:  Highlights of Clinical Pharmacology after Oral Administration of Single and Multiple Doses of JNJ-
70033093 (BMS-986177) to Healthy Participants and Subjects with Renal or Hepatic 
Impairment
Properties
Clinical Results
Tmax
2-4 hrs. Rapid absorption and quick onset PD effect
T1/2
~11 hrs (terminal T1/2); Suitable for BID or once daily dosing
Accumulation index
Accumulation ratio 1.14 – 1.75 for dose range 20-500 mg once daily, 3.99 for 
200 mg BID in MAD
Exposure
Average Cmax: 15.4 – 7,595 ng/mL; Average AUC: 172-95,110 ng x hr/mL
Proportionality
Greater than dose proportional from 4-20 mg and approximately dose proportional 
between 20-200 mg in SAD; Greater than dose proportional from 5-20 mg and dose 
proportional from 20-200 mg, and greater than dose proportional from 200-500 mg 
in MAD 
High-fat meal increases Cmax by 53% and AUC by 39% at 200 mg, respectively and 
increases Cmax by 80% and AUC by 110% at 500 mg, respectively
Metabolites
No significant metabolites
CYP3A4 inhibitors or 
inducer DDI
Itraconazole: 150% increase in AUC; 28% increase in Cmax
Diltiazem: 38% increase in AUC; 9% increase in Cmax
Rifampin: 85% decrease in AUC; 78% decrease in Cmax
Aspirin DDI
Aspirin does not impact PK of JNJ-70033093; Cmax and AUC of acetylsalicylic acid 
increased by 41% and 24%, compared to dosing of aspirin alone after 5 days
Japanese 
Pharmacokinetics were comparable between Japanese participants and participants 
in CV010001 (mainly Caucasian)
Renal impairmenta
Cmax was similar for all renal function groups; AUC increased by 41% and 54% in 
participants with eGFR values of 30 and 15 mL/min/1.73 m2, respectively, 
compared with a participant with normal renal function with an eGFR of 
90 mL/min/1.73m2 based on linear regression
Hepatic Impairment (normal 
hepatic impairment vs mild 
or moderate hepatic 
impairment)
Primarily metabolized in the liver
- Similar Cmax and AUC (0-INF) between normal, mild and moderate hepatic 
impairment groups
Compared to normal participants
- Mild hepatic impairment (Child Pugh A category): 18% ↑ in Cmax and AUC(0-
INF)
- Moderate hepatic impairment (Child Pugh category B): 14% ↑ in Cmax and no 
change in AUC(0-INF)
When accounting for changes in protein binding, the differences in normal 
participants compared to: 
- Mild hepatic impairment (Child Pugh A category): 30% ↑ in Cmax and 29% ↑ in 
AUC(0-INF)
- Moderate hepatic impairment (Child Pugh category B): 41% ↑ in Cmax and 24% 
↑ in AUC(0-INF)
Relative bioavailability
Capsule formulation has similar PK profile to the SDD suspension used in Phase 1 
studies 
AUC=area under the plasma concentration-time curve; AUC(0-INF)=area under the plasma concentration-time 
curve (from zero to infinity); BID=twice daily; Cmax=maximum observed concentration; CYP=cytochrome P450; 
DDI=drug-drug interaction; eGFR=estimated glomerular filtration rate; hr(s)=hour(s); MAD=multiple-ascending 
dose; PD=pharmacodynamics; PK=pharmacokinetic; SAD=single ascending dose; SDD: spray-dried dispersion; 
T1/2=half-life; Tmax=time to maximum concentration
a
Preliminary results
Efficacy/Safety Studies
A recently completed multicenter, crossover, randomized, Phase 2a, proof-of-concept study in 
subjects undergoing hemodialysis for ESRD demonstrated that single doses of JNJ-70033093 up 
to 300 mg were safe and well tolerated and there were no reports of serious bleeding or other 
serious adverse events. An exploratory assessment of efficacy showed that the extent of clot 


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formation in the hemodialysis circuit for JNJ-70033093 was similar to the active comparators 
(unfractionated heparin and enoxaparin), suggesting that JNJ-70033093 has clinically 
meaningful antithrombotic activity at the doses tested (See IB, Edition 5).21
A recently completed DDI study showed that JNJ-70033093 200 mg BID, taken by healthy 
subjects over a 7-day period with aspirin, was safe and well tolerated, and the bleeding time did 
not increase significantly. Subjects enrolled into this study were allowed to take, if clinically 
indicated, low-dose aspirin (<100 mg once daily).21
Detailed information on Phase 1 and 2a studies in JNJ-70033093 is provided in the IB.21
2.2.1.
Enoxaparin Sodium
The following information, taken from the European Union Summary of Product Characteristics
(SmPC), is intended to provide a brief, representative overview of enoxaparin.
Enoxaparin sodium is a low molecular-weight heparin (LMWH), with a mean molecular-weight 
of approximately 4,500 daltons. In the in-vitro purified system, enoxaparin has a high anti-Factor 
Xa (anti-FXa) activity (approximately 100 IU/mg) and low anti-Factor IIa or antithrombin 
activity (approximately 28 IU/mg). These anticoagulant activities are mediated through 
antithrombin III, resulting in antithrombotic activities in humans. At the recommended doses, 
enoxaparin sodium does not influence bleeding time and global blood coagulation tests 
significantly, nor does it affect platelet aggregation or binding of fibrinogen to platelets.
Enoxaparin sodium is indicated in the European Union for the:
!
Prophylaxis of thromboembolic disorders of venous origin, in particular those which may be 
associated with orthopedic or general surgery
!
Prophylaxis of VTE in medical patients bedridden due to acute illnesses, including cardiac 
insufficiency, respiratory failure, or severe infections
!
Treatment of venous thromboembolic disease presenting with deep vein thrombosis (DVT), 
pulmonary embolism (PE), or both
!
Treatment of unstable angina and non-Q-wave myocardial infarction (MI), administered 
concurrently with aspirin
!
Treatment of acute ST-segment elevation MI, including patients to be managed medically or 
with SC coronary intervention
!
Prevention of thrombus formation in the extracorporeal circulation during hemodialysis
In patients with a higher risk of thromboembolism, such as orthopedic surgery, the recommended 
dosage of enoxaparin sodium given by SC injection is 40 mg (4,000 IU) once daily, with the 
initial dose administered preferably at least 12 hours preoperatively.
Enoxaparin treatment is prescribed as standard-of-care for an average period of 10 to 14 days or 
until the risk of thromboembolism has diminished. A longer treatment duration may be 
appropriate in some patients following hip replacement, and enoxaparin sodium may be 


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continued for as long as there is a risk of VTE and until the patient is ambulatory. Continued 
therapy with 40 mg once daily for 3 weeks following initial therapy has been proven to be 
beneficial in patients post-hip replacement.
For further information regarding enoxaparin refer to the SmPC or United States Prescribing 
Information. Although the 40-mg once daily dose of enoxaparin is not approved for TKR in the 
United States, it has been recently used as a comparator in a number of direct oral anticoagulant 
(DOAC) studies (eg, ADVANCE-228 and RECORD-324).
2.3.
Benefit/Risk Assessment
An estimated 920,000 patients in Japan and Europe experience VTE annually, which includes 
DVT and PE6,22 and in the United States it is estimated that 900,000 patients experience a VTE 
annually, with 60,000 being fatal5. 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.42 This has 
led to recommendations in the guidelines that all patients undergoing TKR surgery should 
receive pharmacologic and/or mechanical VTE prophylaxis.12,22 Low molecular-weight heparin
and several DOACs, including apixaban, rivaroxaban, dabigatran, and edoxaban have been used 
in the prevention of VTE in patients undergoing TKR surgery. However, limitations of these 
drugs include the possibility of an increased risk of bleeding at their recommended dosages. The 
concern of orthopedic surgeons about bleeding is a major obstacle to the use of anticoagulation 
in the perioperative period, even when clinical study data show that the absolute risk of bleeding 
is lower than the risk of VTE.29
As an inhibitor to the intrinsic coagulation pathway, JNJ-70033093 directly blocks the 
amplification process associated with the activation of the intrinsic pathway and the inherent risk 
of thrombosis associated with activation of this physiologic process. This can occur directly by 
contact activation of FXI or by thrombin-mediated feedback activation that would occur when 
the extrinsic pathway is activated. The extrinsic and common coagulation pathways are left 
intact, allowing for
hemostasis to proceed. Therefore, in comparison with current 
standard-of-care, the use of JNJ-70033093, an inhibitor of a factor component of the intrinsic 
pathway, may have equal or greater efficacy 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 Patients who undergo elective total knee arthroplasty are 
at a high risk for the development of VTE with a 40% to 60% chance of developing 
asymptomatic DVT without any form of prophylaxis. It is estimated that 10% to 20% of distal 
DVT will extend into the proximal veins that carries with it a high risk of embolization and PE. 
In this setting, upwards of one-third of PEs will be fatal.19 Therefore, TKR is an appropriate 
setting for testing new and potentially safer means of anticoagulation.
The available preclinical and clinical evidence suggest that direct inhibition of FXIa by 
JNJ-70033093 has the potential to reduce the risk of thromboembolic events with a lower risk of 


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major bleeding than currently available DOACs. While bleeding was not observed to any 
significant degree at the high doses of JNJ-70033093, either in healthy subjects or in those with 
ESRD undergoing hemodialysis, there is a potential risk of bleeding with any antithrombotic 
agent. Therefore, subjects will be closely monitored for bleeding, with oversight of the study by 
the Operations Committee (OC). 
More detailed information about the known and expected benefits and risks of JNJ-70033093
may be found in the IB.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
!
To determine the efficacy of JNJ-70033093 
in preventing total VTE events (proximal 
and/or distal DVT [asymptomatic confirmed 
by venography assessment or objectively 
confirmed symptomatic], nonfatal PE, or any 
death) during the treatment period.
!
Total VTE during the treatment period up to 
the time of venography as assessed by the 
CEC. Proof-of-efficacy is reached by either 
showing a positive dose-response or having
less than a 30% total VTE event rate in the 
combined BID dose group.
Secondary
!
To assess the dose-response of JNJ-70033093 
for the occurrence of the endpoint of any 
bleeding events during the treatment period.
!
The composite endpoint of any bleeding event
on treatment. Any bleeding will be defined as 
the composite of major bleeding according to 
the ISTH criteria modified for the surgical 
setting, clinically relevant nonmajor bleeding 
events, or minimal bleeding events as assessed
by the CEC.
!
To determine the efficacy of JNJ-70033093 
in preventing total VTE events during the full 
study period.
!
Total VTE as assessed by the CEC through 
Week 6.
!
To assess the dose-response of JNJ-70033093 
for the rate of any bleeding throughout the 
full study period.
!
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 as assessed 
by the CEC through Week 6.
!
To assess the dose-response of JNJ-70033093 
for the prevention of major VTE (death, 
asymptomatic or symptomatic proximal DVT 
or PE) during the treatment period and 
throughout the full study period.
!
Major VTE as assessed by the CEC during the 
treatment period and through Week 6.
!
To assess the effect of individual doses of 
JNJ-70033093 compared with enoxaparin for 
both efficacy and safety endpoints.
!
Total VTE and any bleeding as assessed by the 
CEC during the treatment period and during the 
full study period (6 weeks).
!
To compare the effect of JNJ-70033093 with 
enoxaparin for the individual components of 
the total VTE endpoint.
!
All individual components of the primary 
efficacy endpoint as assessed by the CEC 
during the treatment period and during the full 


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Objectives
Endpoints
study period (6 weeks).
!
To assess the PK of JNJ-70033093 in men 
and women undergoing primary unilateral 
TKR surgery and the relation of these 
measures to efficacy and safety endpoints 
(eg, exposure-response analyses).
!
Estimation of PK parameters and the effects of 
demographics and laboratory values (eg, body 
weight, age, gender, renal function) on the PK 
of JNJ-70033093.
!
Estimation 
of 
the 
relationship 
between 
JNJ-70033093 exposure with probability of 
total VTE during the treatment period up to the 
time of venography and the probability of the 
composite endpoint of major or clinically 
relevant nonmajor bleeding events, and the 
individual components of the composite 
endpoint of any bleeding event on treatment.
Exploratory
!
To evaluate PD to assess its relationships to 
PK and the relation of these measures to 
efficacy 
and 
safety 
endpoints 
(eg, exposure-response analyses).
!
Changes in PD (aPTT, PT, FXI clotting 
activity, anti-FXa activity, and TGA).
!
Estimation 
of 
the 
relationship 
between 
JNJ-70033093 exposure with the changes in 
PD.
!
To evaluate exploratory biomarkers to assess 
their relationship to the probability of total 
VTE during the treatment period.
!
Estimation of the changes in biomarkers with 
the probability of total VTE during the 
treatment period up to the time of venography 
and the probability of the composite endpoint 
of major or clinically relevant nonmajor 
bleeding events, and the individual components 
of the composite endpoint of any bleeding 
event on treatment.
!
Explore the presence and incidence of 
asymptomatic MINS as it relates to total knee 
arthroplasty.
!
The presence of an isolated elevated hs-cTnT 
measurement 
postoperatively 
without 
an 
alternative 
explanation 
(eg, sepsis, 
atrial 
fibrillation) 
in 
subjects 
with 
normal 
preoperative hs-cTnT. An incremental rise in 
hs-cTnT without an alternate explanation in 
individuals 
with 
elevated 
preoperative 
hs-cTnT.
anti-FXa=anti-Factor Xa; aPTT=activated partial thromboplastin time; CEC=Clinical Endpoint 
Committee; DVT=deep venous thrombosis; FXI=Factor XI; hs-cTnT=high-sensitive cardiac troponin T; 
ISTH=International Society on Thrombosis and Hemostasis; MINS=myocardial injury in noncardiac 
surgery; PD=pharmacodynamic; PE=pulmonary embolism; PK=pharmacokinetic; PT=prothrombin time; 
TGA=thrombin generation assay; TKR=total knee replacement; VTE=venous thromboembolism
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESIS
The primary hypothesis is that JNJ-70033093 reduces the risk of total VTE during the treatment 
period. This can be achieved by either a statistically significant dose-response trend or an event 


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rate for the combined BID doses of JNJ-70033093 that is statistically lower than 30%. The event 
rate of 30% is a conservative estimate of the total VTE rate in subjects given placebo.
4.
STUDY DESIGN
4.1.
Overall Design
This is an open-label, study drug-dose blind, active-controlled, multicenter, dose-ranging study
of JNJ-70033093 in subjects undergoing primary unilateral elective TKR surgery. The study uses 
the prospective, randomized, open-label, blinded endpoint (PROBE) design. Men and women 
who are ∀50 years of age are eligible to participate if they are considered medically stable and 
appropriate for anticoagulant prophylaxis as determined by the investigator and on the basis of 
clinical laboratory tests performed as part of screening for elective TKR surgery. A target of 
900 subjects will be randomly assigned to treatment in this study, with an option to increase the 
randomization target to approximately 1,200 subjects based on the possible addition of once 
daily dose groups, and/or evaluability rate.
Subjects meeting all of the enrollment criteria will be eligible to enter the study. The study will 
be conducted in 3 phases, which includes an up to 30-day screening phase before surgery, a 
10- to 14-day postoperative dosing phase, and a 4-week #10 days 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 participation following randomization 
will be approximately 6 weeks.
Screening for eligible subjects will be performed within and including 30 days before 
administration of the first dose of postoperative study drug. Eligible subjects will be randomly 
assigned to treatment with either JNJ-70033093 or enoxaparin postoperatively following 
unilateral elective TKR surgery. Subjects will know the treatment to which they were assigned 
but subjects randomly assigned to JNJ-70033093 will remain blinded to the dose and frequency 
(ie, BID versus once daily).
First dosing of both study drugs will occur while the subject is still hospitalized, with 
administration beginning a minimum of 12 hours and a maximum of 24 hours after the end of 
TKR surgery, which is defined as the time of wound closure, and must be the first anticoagulant 
administered postoperatively.
Enoxaparin may be administered preoperatively 12 hours prior to the surgical procedure in 
accordance with local standard-of-care. Sites that routinely administer preoperative enoxaparin 
should continue their standard practice for all study subjects at that site. Per standard-of-care, 
study drug should not be used for the preoperative dose of enoxaparin for subjects in either 
treatment group.
Following discharge or transfer to an alternate facility, subjects will continue to take the assigned 
study drug for a total of 10 to 14 days as described in Section 6.1, Study Drugs Administered. 
Unilateral venography assessment of the operated leg will be performed within 1 calendar day
after the last dose of either JNJ-70033093 or enoxaparin is taken. 


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Subjects will return to the study-site 6 weeks after the TKR surgery for study-related evaluations 
and procedures as described in the Schedule of Activities. Safety evaluations will include the 
monitoring of all adverse events, including nonserious adverse events, serious adverse events, 
adverse events of interest (ie, bleeding events, liver enzyme elevations and clinical liver events, 
wound or joint complications), clinical laboratory tests (ie, hematology, clinical chemistry, 
urinalysis), and physical examinations.
Selected sites may also use scanning technology to manage clinical study supplies and drug 
compliance activities. Subject’s enrolled at selected sites may use an application on the subject’s 
own smartphone/tablet to confirm study drug administration (JNJ-70033093 capsules only) and 
receive notifications as per protocol scheduled events (eg, next clinical site visit) as well as 
additional study information.
An OC, Steering Committee, and independent Clinical Events Committee (CEC) will be 
commissioned for this study. The OC will be unblinded and the Steering Committee will be 
blinded to the dose and frequency of JNJ-70033093, unless the OC finds it necessary to consult 
with and unblind select members of the Steering Committee. If any members of the Steering 
Committee are unblinded, they will no longer be involved in the operational conduct of the 
study. The CEC will be blinded to both the study drug and the dose. The OC will be responsible 
for reviewing ongoing safety and efficacy data by unblinded subject treatment assignments 
approximately every 3 to 8 weeks on a periodic basis. Refer to Committees Structure in Section 
10.3, Appendix 3, Regulatory, Ethical, and Study Oversight Considerations for details.
Unblinded periodic and interim analyses will be conducted by the OC for the purposes of safety 
oversight and as part of the adaptive approach. The first interim analysis will be triggered when 
approximately 300 subjects (approximately 50 subjects in each of the JNJ-70033093 BID 
treatment groups) have completed venography or have had a symptomatic VTE event. Both 
periodic and the interim analyses results will be used to guide the decision to drop a dose of 
JNJ-70033093 and/or readjust the randomization ratio.  The number of subjects who were 
planned to be randomized into the dropped dosing regimen can be allocated to one of the other 
dosing groups. The interim analysis will also serve as the formal venue to assess study status and 
possibly add once daily dosing of JNJ-70033093 based on available efficacy and safety data. If 
PK/PD analysis results are available at the time of the interim analysis, the results will be 
included in the review.
Additional interim analyses will be conducted, as needed, at the discretion of the OC. 
A diagram of the study design is provided in Section 1.2, Schema.
4.2.
Scientific Rationale for Study Design
Blinding, Control, Study Phase/Periods, Intervention Groups
Randomization will be used to minimize bias in the assignment of subjects to study drug and 
dose groups, to increase the likelihood that known and unknown subject attributes 
(eg, demographic and baseline characteristics) are evenly balanced across study drug groups, and 


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to enhance the validity of statistical comparisons across study drug groups. Subjects will be 
unblinded as to the study drug assignment (JNJ-70033093 or enoxaparin); however, they will 
remain blinded to the dose and frequency and the adjudication of clinical endpoint events will be 
conducted in a blinded fashion by an independent CEC to reduce potential bias during the 
evaluation of clinical endpoints.
Study Population
Total knee replacement is most commonly performed in older men and women to correct 
arthritic disease of the joint. Given that the risks of VTE and bleeding increase with age, the 
study has been appropriately designed to include both men and women who are at least 50 years 
of age. 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.12,22 Over the past 20 years, Phase 2 studies of 
injectable anticoagulants (LMWH, fondaparinux) and newer oral anticoagulants (apixaban, 
rivaroxaban, dabigatran, and edoxaban) were conducted in this population using venography to 
detect asymptomatic DVT.11,17,20,27,28,39
Choice of Comparator
This study will use LMWH as the comparator for consistency with all of these health-authority 
approved oral medications that were evaluated in large, similarly designed Phase 3 studies for 
the prevention of VTE in TKR surgery and also because it continues to be used widely for 
prophylaxis. Given that VTE and bleeding event rates vary across studies, the active control will 
also provide an internal reference for comparison with JNJ-70033093 in this study.
As one of the most widely used anticoagulants in joint arthroplasty, enoxaparin has been used as 
a comparator for the currently approved DOACs.41 Consistent with this approach, enoxaparin 
was chosen as the comparator in this study. Enoxaparin is approved worldwide for this indication
and has demonstrated favorable efficacy and safety (ie, bleeding) results. Refer to Section 2.2.1, 
Enoxaparin sodium for additional details.
The 40-mg daily dose of enoxaparin will be used in this study as it is the dosage regimen used in
most approved countries for the indication being studied. Enoxaparin will be administered once 
daily for 10 to 14 days, with an option to begin the first dose at least 12 hours before surgery, 
which is preferred by some surgeons, or 12 to 24 hours after the end of TKR surgery, defined as 
the time of wound closure.
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 symptomatic 
venous thromboembolism 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 a usual period of anticoagulation following TKR surgery as well as other forms of 
anticoagulation (eg, DOACs).


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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%).23 However, ultrasound has repeatedly 
been shown to have very low sensitivity compared with venography for detecting asymptomatic 
DVT in the postoperative setting.23,34 In a meta-analysis of 15 studies, the sensitivity of 
ultrasound compared with venography for detecting asymptomatic DVT was 47%.23 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% 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.34
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 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.4,14,26,40 Venography produces plausible and reliable results in clinical 
studies7,19,36 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.
Bilateral venography has been used in most but not all previous Phase 3 studies.15,17 Venography 
of the operated leg will be performed in this study. Unilateral venography of the operated leg 
detects over 90% of DVTs after TKR surgery16 and exposes subjects to less risk (radiation, 
contrast dye, venipuncture) and less discomfort.
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.25 Published guidelines that describe how to define major 
bleeding events after major orthopedic surgery will be followed.35 For nonmajor bleeding events, 
standardized definitions, as utilized in the Phase 3 TKR studies of apixaban, will be 


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followed.27,28 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 Measures
Pharmacokinetic blood samples will be collected and analyzed for subjects who are randomly 
assigned to treatment with JNJ-70033093 to further understand the PK characteristics and 
variability and assess the exposure-response of JNJ-70033093 in the TKR patient population.
Choice of PD Measures
Samples will be collected to evaluate the PD effect on the target of JNJ-70033093 or help to 
explain interindividual variability in clinical outcomes or may help to identify population 
subgroups that respond differently to an intervention. The goal is to evaluate the PD of 
JNJ-70033093 and aid in evaluating the intervention-clinical response relationship.
Choice of Biomarkers
Myocardial injury after noncardiac surgery is the most frequent vascular complication to occur 
perioperatively with an estimated frequency of approximately 8%. Affecting about 8 million 
adults worldwide, patients experiencing myocardial injury in noncardiac surgery (MINS) are at 
increased risk of death or cardiovascular complication. It is estimated that 85% of MINS occurs 
within 48 hours of surgery.8 Unlike the traditional definition of MI, MINS does not require 
symptoms or evidence of ischemia (eg, ST changes). In the VISIONS study, only 16% of 
subjects experiencing MINS had symptoms of an ischemic feature.2 In an observational study 
involving a tertiary care center, Rubin and colleagues estimated that the incidence of MINS in 
orthopedic procedures is approximately 19%.33
In this study, subjects will have cardiac troponins drawn postoperatively on Day 1 (0 hour) prior 
to study drug administration and Day 10-14; data derived from these analyses will be used to 
estimate the presence of MINS.
Factor XI antigen will also be used as a biomarker for potential bleeding and as an efficacy 
signal. Recent studies suggest that high levels of FXI are associated with increased risk for 
venous thrombosis and stroke, whereas reduced FXI levels are associated with protection from 
VTE. In addition to activation by Factor XIIa, FXI can also be activated by thrombin in a 
positive feedback reaction, further propagating thrombus growth. Measurement of FXI antigen in 
plasma at baseline, using a validated immunoassay, may help to improve understanding of 
thrombotic conditions and help identify subjects susceptible to cardiovascular events.13,31,44
4.2.1.
Study-Specific Ethical 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-70033093 is an investigational drug that is being developed for multiple thrombosis-mediated 
conditions. The nonclinical and clinical data obtained to date with JNJ-70033093 support 
administration of multiple doses in a well-controlled clinical research study. The present study is 
needed to support further clinical development of JNJ-70033093, 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-70033093 has not been 
fully established as it has only been studied in a limited number of 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 studies, a range of doses of 
JNJ-70033093 has been selected for further evaluation in this study. Preclinical studies looking at 
clot formation demonstrated that doses equivalent to 25 mg BID reduced clot formation by 50%.
The primary risk with any anticoagulant drug is the potential for bleeding events. Based on the 
nonclinical evaluations of JNJ-70033093, the risk for these events is anticipated to be low (ie, all 
planned doses are below those shown to have a statistically significant increase in bleeding risk). 
No bleeding signal was detected at the 200-mg BID dose in healthy male subjects. Subjects in this 
study will be carefully observed for bleeding events throughout the duration of the study and 
management strategies for each type of event are outlined in the protocol (see Section 8.2.1.2,
Approach to Subjects With a Bleeding Event).
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. 
Given that all 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.32,38
There may be risks associated with venipuncture and multiple blood sample collection, including 
prolonged bleeding due to the anticoagulant effects of JNJ-70033093. The total blood volume to be 
collected for safety, PK, PD, and biomarker laboratory tests is considered to be an acceptable 
amount of blood to be collected over this time period from the population in this study based upon 
the standard of the World Health Organization (WHO) for standard blood donation volume for 
healthy donors (standard donation of 350 [body weight >45 kg] to 450 [body weight >50 kg] mL 
every 12 weeks [males] to 16 weeks [females]).43


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4.3.
Justification for Dose
Identification of effective doses of JNJ-70033093 was based on inhibition of thrombus formation 
in a rabbit model of electrically induced carotid artery thrombus (ECAT) in rabbits. The rabbit 
ECAT model has been calibrated against clinical results in VTE prevention based on apixaban. 
In this model, targeting the concentration that led to 50% reduction in thrombus weight was 
correlated with the steady-state trough concentration of the clinical dose of apixaban. In the 
rabbit ECAT model, JNJ-70033093 caused a dose-dependent decrease in both clot weight 
(Figure 2) and preservation of blood flow without a significant increase in bleeding time. The 
equivalent to half the maximal effective concentration (EC50) plasma concentrations in the rabbit 
ECAT model was 235 ng/mL (375 nM). Making corrections for the difference in potency in 
human versus rabbit FXIa (where JNJ-70033093 is more potent than rabbit FXIa) and the 
differences in plasma protein binding between human versus rabbit (where protein binding is 
lower in human versus rabbit plasma) yields a human target of 34.5 ng/mL (55 nM) as the trough 
target concentration.21
Figure 2:
Exposure-dependent Reductions in Thrombus Weights With JNJ-70033093 in Rabbits
A Phase 2 study for VTE prophylaxis post TKR provides the only published data on the clinical 
safety and efficacy of reducing FXI activity. Subjects were treated for 36 days prior to surgery 
with an ASO to reduce the level of FXI. The study showed a dose-dependent reduction in the 
risk of VTE events compared with enoxaparin. Doses that did not reduce FXI levels to 20% or 
less of normal did not reduce the risk of VTE events compared with enoxaparin.4 About a 
1.5-fold prolongation in aPTT was observed at the dose that reduced FXI levels to 20% or less of 
normal. Figure 3 shows the dose-dependent decrease in FXI levels and clot weight observed in 


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the rabbit ECAT model with ASO-induced inhibition of FXI.21 Based on the dose-dependent 
reduction of FXI concentrations observed in the ASO VTE prevention study (ISIS 416158), a 
trough concentration of approximately 150 ng/mL of JNJ-70033093 was necessary to achieve an 
antithrombotic effect equal to the 80% reduction in FXI level in the rabbit ECAT model.
Figure 3:
Reduction in FXI Concentration Based on FXI ASO Compound Used in Phase 2 VTE Study
ASO=antisense oligonucleotide; C=concentration; FXI=Factor XI; FXI ASO=Factor XI antisense 
oligonucleotide; VTE=venous thromboembolism
Based on data obtained from healthy subjects, population PK modeling indicates that doses 
likely to achieve the trough concentration targets based on apixaban and ASO for a 
VTE prevention study are between 100 to 200 mg once daily and 25 to 50 mg BID. A 50-mg 
once daily dose prolongs the aPTT 1.5-fold for about 24 hours in healthy volunteers and the 
plasma concentrations achieved are above those required for antithrombotic efficacy (EC50) in 
the rabbit ECAT model of thrombosis for a sustained period time. The data indicating coverage 
of the target concentrations in the rabbit ECAT model for both apixaban and the FXI inhibitor 
ASO, supports the potential for JNJ-70033093 to provide similar or greater efficacy in patients. 
Finally, a lower risk of bleeding is anticipated with inhibition of FXIa than with inhibition of 
Factor Xa (FXa), based on the mechanistic rationale for targeting the intrinsic pathway via 
inhibition of FXIa.


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4.4.
End of Study Definition
A subject will be considered to have completed the study if he or she has completed assessments 
at Week 6 or has died prior to Week 6.
Subjects who prematurely discontinue the study drug for any reason before completion of the 
postoperative dosing phase can be considered to have completed the study if they have 
completed follow-up at Week 6.
The end of the study is considered the last visit for the last subject in the study. The final data 
from the study-site will be sent to the sponsor (or designee) after completion of the final subject 
visit at that study-site, in the time frame specified in the Clinical Trial Agreement.
5.
STUDY POPULATION
Screening for eligible subjects will be performed within and including 30 days before 
administration of the first dose of postoperative study drug. Refer to Section 5.4, Screen Failures 
for conditions under which the repeat of any screening procedures are allowed.
The inclusion and exclusion criteria for enrolling subjects in this study are described below. If 
there is a question about these criteria, the investigator must consult with the appropriate sponsor 
representative and resolve any issues before enrolling a subject in the study. Waivers are not 
allowed. 
For a discussion of the statistical considerations of subject selection, refer to Section 9.1, Sample 
Size Determination.
5.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
Male or female.
2.
50 years of age, or older.
3.
Medically stable and appropriate for anticoagulant prophylaxis as determined by the 
investigator on the basis of physical examination, medical history, and vital signs 
performed as part of screening for elective TKR surgery. 
4.
Medically stable and appropriate for 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. If the results of 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 and initialed by the investigator.


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5.
Has plans to undergo an elective primary unilateral TKR surgery.
6.
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.
Contraceptive (birth control) use by men or women should be consistent with local regulations 
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should 
be consistent with local regulations regarding the use of contraceptive methods for subjects in 
clinical studies.
7.
A woman of childbearing potential (WOCBP) must have a negative urine or highly 
sensitive serum (∋-human chorionic gonadotropin [∋-hCG]) up to 2 days before the 
administration of the study drug.
8.
Criterion modified per Amendment 1
8.1. A woman must be (as defined in Section 10.5, Appendix 5, Contraceptive and 
Barrier Guidance and Collection of Pregnancy Information).
a.
Not of childbearing potential
b.
Of childbearing potential and
o
Practicing a highly effective method of contraception (failure rate of 
<1% per year when used consistently and correctly) and agrees to remain 
on a highly effective method for the duration of study drug with 
JNJ-70033093 plus 5 half-lives of study drug plus 30 days (duration of 
ovulatory cycle) for a total of 34 days after the completion of treatment.
Examples of highly effective methods of contraception are located in 
Section 10.5, Appendix 5, Contraceptive and Barrier Guidance and 
Collection of Pregnancy Information.
o
Pregnancy testing (serum or urine) prior to the first dose of study drug.
9.
Criterion modified per Amendment 1
9.1. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study and for a period of 34 days after the last dose.
10.
Criterion modified per Amendment 1
10.1. A male subject must wear a condom when engaging in any activity with a 
WOCBP during the study and for the duration of treatment with JNJ-70033093 plus 
5 half-lives of the study drug plus 90 day (duration of sperm turnover) for a total of 
94 days after the completion of treatment. Male subjects should also be advised of the 
benefit for a female partner to use a highly effective method of contraception as a 


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condom may break or leak. This criterion does not apply to male subjects randomly 
assigned to enoxaparin.
11.
Criterion modified per Amendment 1
11.1. A male subject must agree not to donate sperm for the purpose of reproduction 
during the study and for the duration of treatment with JNJ-70033093 plus 5 half-lives 
of the study drug plus 90 days (duration of sperm turnover) for a total of 94 days after 
the completion of treatment. This criterion does not apply to male subjects randomly 
assigned to enoxaparin.
12.
Willing and able to adhere to the lifestyle restrictions (Section 5.3, Lifestyle 
Considerations) specified in this protocol.
5.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:
1.
History of any condition for which the use of LMWH is not recommended in the 
opinion of the investigator (eg, previous allergic reaction, creatinine clearance 
<30 mL/minute).
2.
History of severe hepatic impairment.
3.
Planned bilateral revision or unicompartmental procedure.
4.
Criterion modified per Amendment 1
4.1. Planned postoperative epidural analgesia with an epidural catheter.
!
If an epidural catheter was used, it must be removed at least 5 hours prior to 
postoperative study drug administration.
NOTE: if a subject had an epidural or spinal anesthesia procedure with bleeding or 
significant trauma at the time of surgery, they should not be randomized.
5.
Criterion modified per Amendment 1
5.1. 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).
6.
Known previous PE or DVT in either lower extremity.
7.
Known allergies, hypersensitivity, or intolerance to JNJ-70033093 or its excipients 
(refer to IB).


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8.
Criterion modified per Amendment 1
8.1. Contraindications to the use of or known allergies, hypersensitivities, or 
intolerance to enoxaparin per local prescribing information (eg, heparin and pork 
products).
9.
Any condition requiring chronic antithrombotic therapy (eg, atrial fibrillation, 
mechanical heart valve, recent coronary intervention), except for aspirin &100 mg per 
day.
10.
Use of strong CYP3A4/P-gp inhibitors or strong CYP3A4/P-gp inducers in the 7 days 
prior to randomization or the need for ongoing treatment with concomitant oral or 
IV therapy with strong CYP3A4/P-gp inhibitors or strong CYP3A4/P-gp inducers 
during the treatment period.
11.
Taken any disallowed therapies as noted in Section 6.5, Concomitant Therapy before 
the planned first dose of study drug.
12.
Planned use of intermittent pneumatic compression after the first postoperative dose 
of the study drug.
13.
Received an investigational study drug (including investigational vaccines) 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.
14.
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.
15.
Has surgery planned (except the TKR study) during the time the subject is expected to 
participate in the study for which anticoagulant therapy would be interrupted.
16.
Previously randomized subject in this study or participated in previous studies with 
JNJ-70033093.
17.
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.
18.
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, healthcare professional), as necessary, until the end of the study, 
should he or she discontinue prematurely.


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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 randomization such that he or she no
longer meets all eligibility criteria, then the subject should be excluded from participation in the 
study. Section 5.4, Screen Failures, describes options for rescreening. The required source 
documentation to support meeting the enrollment criteria are noted in Section 10.3, Appendix 3, 
Regulatory, Ethical, and Study Oversight Considerations. Randomized subjects must also meet 
these criteria prior to the first dose of the study drug.
5.3.
Lifestyle Considerations
Potential subjects must be willing and able to adhere to the following lifestyle restrictions during 
the course of the study to be eligible for participation:
1.
Refer to Section 6.5, 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 
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
3.
Criterion modified per Amendment 1
3.1. Avoid donating blood until after completion (ie, final follow-up visit) of the 
study.
4.
Criterion modified per Amendment 1
4.1. A WOCBP must agree to use one of the contraceptive methods allowed during 
the study for a minimum of 34 days after receiving the last dose of study drug as 
described in Section 10.5 of Appendix 5, Contraceptive and Barrier Guidance and 
Collection of Pregnancy Information. All men who are randomly assigned to JNJ-
70033093 and are sexually active with a WOCBP must agree to use a condom and 
must also not donate sperm for a minimum 94 days after receiving the last dose of 
study drug.
5.4.
Screen Failures
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 will identify subjects by subject identification number and age at initial informed consent. 


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In cases where the subject is not randomized into the study, the date seen and age at initial 
informed consent will be used.
Rescreening
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Subjects may only be rescreened on 1 occasion.
6.
STUDY TREATMENT
6.1.
Study Drugs Administered
Drug Administration
JNJ-70033093 will be provided as capsules for oral administration. Subjects will be instructed to 
take their assigned dose of the study drug orally each day. The study drug is to be taken with 
approximately 240 mL (8 ounces) of water. The capsules should be swallowed intact and 
subjects should not attempt to dissolve them in water. Each dose should be taken at 
approximately the same time each day. If a dose is missed, the capsules should be taken as soon 
as possible; 2 doses can also be taken together in the evening if the morning dose is missed. If 
an evening dose is missed it should not be taken with the next morning dose; no more than 2 
doses (4 capsules) should be taken in 1 day.
Eligible subjects will be randomly assigned to treatment with either JNJ-70033093 or enoxaparin 
postoperatively following unilateral elective TKR surgery. Subjects will know the treatment to 
which they were assigned but subjects randomly assigned to JNJ-70033093 will remain blinded 
to the dose and frequency (ie, BID versus once daily).
First dosing of both study drugs will occur while the subject is still hospitalized, with 
administration beginning a minimum of 12 hours and a maximum of 24 hours after the end of 
TKR surgery, which is defined as the time of wound closure, and must be the first anticoagulant 
administered postoperatively.
Enoxaparin may be administered preoperatively 12 hours prior to the surgical procedure in 
accordance with local standard-of-care. Sites that routinely administer preoperative enoxaparin 
should continue their standard practice for all study subjects at that site. Per standard-of-care, 
study drug should not be used for the preoperative dose of enoxaparin for subjects in either 
treatment group.
Study visits should be conducted in the morning, when possible and study drug dosing on the 
day of a study visit should not occur until after the PK sample has been drawn. On the day of the 
Day 10-14 visit, study drug dosing should occur first thing in the morning, and the PK sample 
should not be drawn until at least 1 hour after the dose is taken.
At the time of the interim analysis, the OC may implement a once daily dosing regimen(s) of 50 
and/or 200 mg of JNJ-70033093. Postoperative administration of the study drug will occur after 
the TKR surgery, while the subject is still hospitalized and with a minimum of 12 hours and a 


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maximum of 24 hours after the end of TKR surgery, defined as the time of wound closure, and 
must be the first anticoagulant administered postoperatively. On Day 1 and Day 4, the 12-hour 
PK samples should be drawn before administering the next scheduled dose of study drug. If 
using the +6-hour window to allow the 12-hour sample to be drawn the following morning, the 
evening dose of study drug on Day 1 or Day 4 should be administered, but there must be a 
minimum of 6 hours between doses on these days.
Study drug administration must be captured in the source documents and the electronic case 
report form (eCRF). Study-site personnel will instruct subjects on how to store study drugs for 
at-home use as indicated for this protocol.
Dosing
This study has an adaptive design, with the intent to optimize data collection for the 
dose-response evaluation using multiple comparison procedures and modeling (MCP-Mod).
Initially, eligible subjects will be randomly assigned in a 1:1:1:1:2 ratio to 1 of 5 parallel 
treatment groups, including 4 dose regimens of JNJ-70033093 or enoxaparin 40 mg once daily
given subcutaneously for 10 to 14 days.
The number of dose regimens, the option to implement once daily dosing regimens, and the 
randomization ratio will depend on the unblinded analysis results and the review by the OC.
JNJ-70033093
Each subject randomly assigned to JNJ-70033093 will take 4 capsules a day, 2 capsules in the 
morning and 2 capsules in the evening at approximately the same time each day, as follows:
!
Group A: JNJ-70033093 25 mg BID (1 capsule JNJ-70033093 25 mg and 1 placebo capsule, 
BID)
!
Group B: JNJ-70033093 50 mg BID (2 capsules JNJ-70033093 25 mg BID)
!
Group C: JNJ-70033093 100 mg BID (1 capsule JNJ-70033093 100 mg and 1 placebo 
capsule, BID)
!
Group D: JNJ-70033093 200 mg BID (2 capsules JNJ-70033093 100 mg BID)
!
Group E: JNJ-70033093 25 mg once daily (1 capsule JNJ-70033093 25 mg and 1 placebo 
capsule in the morning and 2 placebo capsules in the evening). Enrollment in this group 
discontinued per Amendment 1. Subjects randomized to this group prior to Amendment 1
will complete study drug treatment and study procedures
!
Group F: JNJ-70033093 200 mg once daily (2 capsules JNJ-70033093 100 mg in the 
morning and 2 placebo capsules in the evening). Enrollment in Group F suspended per 
Amendment 1 and will become optional depending on the OC decision. Subjects 
randomized to this group prior to Amendment 1 will complete the study drug treatment and 
study procedures
!
Group G: JNJ-70033093 50 mg once daily (2 capsules JNJ-70033093 25 mg in the morning 
and 2 placebo capsules in the evening). Enrollment in Group G will become optional 
depending on the OC decision per Amendment 1


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Subjects randomly assigned to JNJ-70033093 who take the first dose of study drug on the 
evening of surgery should take the 2 capsules assigned to the Day 1 morning dose (left side of 
blister card). On subsequent days, the first dose should always be the left 2 capsules and the 
evening dose should be the 2 capsules on the right.
JNJ-70033093 will be manufactured and provided under the responsibility of the sponsor. Refer 
to the IB for a list of excipients.
Enoxaparin
Subjects randomly assigned to enoxaparin (Group I) will receive a SC dose of enoxaparin 40 mg 
once daily, supplied as a prefilled syringe.
6.2.
Preparation/Handling/Storage/Accountability
All oral study drug must be stored at controlled temperatures ranging as specified on the product 
label. Enoxaparin will be stored in accordance with the approved product labeling which is also 
specified on the product label.
Refer to the pharmacy manual/study-site investigational product and procedures manual for 
additional guidance on study intervention preparation, handling, and storage.
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject, and the 
return of study drug from the subject (if applicable), must be documented on the drug 
accountability form. 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.
Selected sites may use scanning technology to manage clinical study supplies (JNJ-70033093 
and enoxaparin) and drug compliance activities (JNJ-70033093 only).
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 
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 on the drug return form. When the study-site is an authorized destruction unit and 
study drug supplies are destroyed on-site, this must also be documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner in a disposal container. 
The disposal container will be retained for verification purposes.
Study drug should be dispensed under the supervision of the investigator or an appropriate 
delegate and 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. Returned study drug must 


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not be dispensed again, even to the same subject. Whenever a subject brings his or her study drug 
to the study-site for pill count, this is not considered a return of supplies. 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.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Dynamic central randomization will be implemented in conducting this study. Initially, subjects
will be assigned to 1 of 5 study drug groups based on an algorithm implemented in the 
interactive web response system (IWRS) before the study. Following the interim analysis, the 
IWRS will be updated for randomization accordingly. Subjects will be stratified by region using 
dynamic central randomization to minimize the imbalance in the distribution of the number of 
subjects across study drug groups. Based on the algorithm, the IWRS will assign a unique study 
drug code, which will dictate the study drug assignment and matching study drug kit for the 
subject.
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 dosing blind 
for an individual subject.
Subjects will be unblinded as to their treatment assignment but those subjects randomly assigned 
to JNJ-70033093 will be blinded to the dose and regimen (ie, BID versus once daily). Under 
normal circumstances, the JNJ-70033093 dosing regimen 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 
dose 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. 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 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 randomized to JNJ-70033093 who have had their treatment dose assignment unblinded 
may continue on study drug unless the subject meets a study drug discontinuation criterion as 
described in Section 7.1, Discontinuation of Study Drug. Investigators should not disclose the 
treatment dose assignment to the subject whenever possible, even in a special situation where the 


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treatment dose assignment has been unblinded to the investigator. Subjects who have had their 
treatment dose 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, if the randomization codes and, if required, the translation 
of randomization codes into treatment and control groups will be disclosed to those authorized
individuals of the OC for the periodic data reviews and interim analyses, it will only be for those 
subjects included in the analysis. Refer to Section 10.3, Appendix 3: Regulatory, Ethical, and 
Study Oversight Considerations for additional details.
Data that may potentially unblind the JNJ-70033093 dose assignment (ie, study drug plasma
concentrations, PD 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 
investigators, the 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 PD markers (eg, aPTT) 
locally unless considered necessary for subject clinical care. If performed locally, the results of 
these laboratory assessments should not be used to determine 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.
6.4.
Study Drug Compliance
Drug supplies will be inventoried and accounted for throughout the study. The IWRS will track 
the study drug dispensed. In addition, the sites will enter the study drug returned by subjects into 
the IWRS.
Subjects randomly assigned to JNJ-70033093 will be required to return all blister cards at the 
Day 10-14 visit. For enoxaparin, subjects will be required to return unused study drug at the 
Day 10-14 visit, at which time study drug accountability will be performed. Start and stop dates 
and any interruptions will be recorded in the eCRF.
Subjects enrolled at selected sites may use an application on the subject’s own smartphone/tablet 
to confirm study drug administration (JNJ-70033093 capsules only).
6.5.
Concomitant Therapy
Only selected therapies taken before the first dose of study drug (eg, tranexamic acid, antiplatelet 
therapies, and nonsteroidal anti-inflammatory drugs [NSAIDs]) administered up to 7 days before 
first dose of study drug must be recorded.
Concomitant therapies, except those medications given as part of the surgical procedure, must be 
recorded throughout the study beginning with start of the first dose of study drug to the final 
visit.


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All pharmacologic therapies (prescription or over-the-counter medications, including products to 
manage bleeding, vaccines, vitamins, and herbal supplements) concomitant with and different 
from the study drug must be recorded in the eCRF. All concomitant non-pharmacologic therapies 
such as intermittent pneumatic compression devices, foot-pump devices, continuous passive 
motion devices, compression stockings, electrical stimulation, and acupuncture 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 indication. Modification of an 
effective preexisting therapy should not be made for the explicit purpose of entering a subject 
into the study.
Study drug must be the first anticoagulant administered after surgery. The following 
medications/therapies should not be given concomitantly with the study drug:
!
Additional anticoagulant(s) (eg, vitamin K antagonists, Factor IIa or FXa inhibitors). The 
study drug will be discontinued in subjects who develop any condition that requires 
long-term anticoagulation (eg, DVT, atrial fibrillation)
!
Antiplatelet therapies (eg, platelet adenosine diphosphate P2Y12 receptor antagonist 
[clopidogrel, ticagrelor, prasugrel]), except for aspirin &100 mg/day
!
Strong CYP3A4/P-gp inhibitors or strong CYP3A4/P-gp inducers in the 7 days before 
randomization or concomitant use with the study drug (concomitant use with study drug 
applies only to subjects taking JNJ-70033093)
!
Intermittent pneumatic compression after the first postoperative dose of study drug 
(all mechanical VTE prevention methods such as foot pumps, graduated compression 
stockings, and continuous passive motion devices are permitted)
Nonsteroidal anti-inflammatory drugs 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. If the investigator deems anticoagulation to be indicated after the last dose of study 
drug, anticoagulation therapy may begin after the venography per standard-of-care.
6.6.
Dose Modification
The assigned dose of JNJ-70033093, matching placebo, and enoxaparin will not be modified
during the course of the study. Subjects will receive the full dose of study drug on Day 1 and will 
remain on their assigned dosages throughout the treatment phase (ie, until Day 10-14 or early 
discontinuation of the study drug).
6.7.
Study Drug After the End of the Study
Subjects will be instructed that study drug will not be made available to them after they have 
completed/discontinued study drug and that they should return to their primary physician to 
determine standard-of-care.


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7.
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT
DISCONTINUATION/WITHDRAWAL
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 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 by email. 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 the study drug or withdraws may not be 
assigned to another subject. Subjects who withdraw will not be replaced.
7.1.
Discontinuation of Study Drug
A subject’s study drug must be discontinued if:
!
The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it 
is in the best interest of the subject to discontinue the study drug
!
Bleeding into a critical site (eg, intracranial, intraspinal, intraocular, pericardial, 
intra-articular in a nonoperative joint, intramuscular with compartment syndrome, 
retroperitoneal)
!
Drug-induced liver injury meeting the criteria for discontinuation (see Section 8.3.1.3, Liver 
Enzyme Elevations and Clinical Liver Events)
!
Development of any condition that requires open-label treatment with an anticoagulant or 
other prohibited medication
!
The subject requests to discontinue the study drug permanently
!
The subject becomes pregnant during the study 
!
At the (exceptional) request of the sponsor
If a subject discontinues study drug for any reason before the end of the postoperative dosing 
phase, the assessments should be continued as scheduled.
7.1.1.
Temporary Discontinuation
The study drug may be interrupted if a subject develops bleeding or elevated liver enzymes as 
described in Sections 8.2.1.2, Approach to Subjects With a Bleeding Event and 8.3.1.3, Liver
Enzyme Elevations and Clinical Liver Events, respectively.
7.2.
Subject Discontinuation/Withdrawal From the Study
A subject will not be automatically withdrawn from the study if he or she has to discontinue 
study drug before the end of the study drug regimen. 
A subject will be withdrawn from the study for any of the following reasons:


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!
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. Withdrawal of consent will be recorded in the eCRF for 
this study 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 follow-up 
information should he or she decided 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 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 email 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.
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. If the subject chooses to withdraw from the study 
completely and does not allow further contact by the investigator, then the investigator or 
designee will consult sources available in the public domain to check the health status of the 
subject as permitted by local law.
When a subject withdraws consent before completing the study, it is not required for he/she to 
give a reason. If the reason for withdrawal is known, it should be documented in the eCRF and in 
the source document. Study drug assigned to the withdrawn subject may not be assigned to 
another subject. Additional subjects will not be entered. If a subject discontinues study drug and
does not withdraw consent from the study before the end, Day 10-14 assessments should be 
obtained, including the venography of the operated leg (unless a PE or symptomatic proximal 
DVT has been diagnosed), and the remaining visits through the Week 6 assessments should be 
completed.
7.2.1.
Withdrawal of Consent for the Use of Research Samples
Withdrawal of Consent for the Use of Samples in Future Research
The subject may withdraw consent for use of samples for future research (refer to Long-Term 
Retention of Samples for Additional Future Research in Section 10.3, Appendix 3, Regulatory, 


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Ethical, and Study Oversight Considerations). In such a case, samples will be destroyed after 
they are no longer needed for the clinical study. Details of the sample retention for research are 
presented in the main ICF.
7.3.
Lost to Follow-Up
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 laws and 
regulations permit. The measures taken to follow-up must be documented in the subject’s source 
documents. A subject will be considered lost to follow-up only after all means of subsequent 
contact have been exhausted. Refer to Section 7.2, Subject Discontinuation/Withdrawal From the 
Study.
8.
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities summarizes the frequency and timing of efficacy, PK, PD, 
biomarkers, and safety measurements applicable to this study.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures 
be performed in the sequence specified in the central laboratory manual. Blood collections for 
PK, PD, and biomarker assessments should be kept as close to the specified time as possible. 
Other measurements may be done earlier than specified timepoints, if needed. Actual dates and 
times of assessments will be recorded in the source documentation and eCRF.
The total blood volume collected in the study by treatment group is as follows: for the 
JNJ-70033093 group - approximately 135 mL (20 mL for safety, 20 mL for PK, and 95 mL for 
PD/biomarkers) and for the enoxaparin group – approximately 115 mL (20 mL for safety, and up 
to 95 mL for PD/biomarkers).
Additional blood samples may be collected, if necessary, for additional safety, PK, PD, or 
biomarker assessments based on emerging data, but the maximum amount of blood drawn from 
each subject in 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.


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Volume of Blood to be Collected From Each Subject
Type of Sample
Volume per 
Sample (mL)
No. of Samples 
per Subject
Approximate
Total Volume 
of Blood (mL)a
Safety (including screening and post-intervention
assessments)
- Hematology
2.0
4
8
- Serum chemistry
2.5
4
10
Serum ∋-hCG pregnancy testsb
2.5
1
2.5
PK samples
2.0
10
20
PD and biomarker samples
-
aPTT and PT
4.5
7
31.5
-
TGA
4.5
7
31.5
-
FXI clotting activity or anti-FXa activity
1.8
3
5.4
-
hs-cTnT
4.0
2
8.0
-
FXI antigen
1.8
1
1.8
-
Archive sample
2.7
3
8.1
-
D-dimer
2.7
3
8.1
Approximate Totalc
134.9
anti-FXa=anti-Factor Xa; aPTT=activated partial thromboplastin time; ∋-hCG=beta-human chorionic gonadotropin; 
FXI=Factor XI; hs-cTnT=high-sensitive cardiac troponin T; No.=number; PD=pharmacodynamics(s); 
PK=pharmacokinetic(s); PT=prothrombin time; TGA=thrombin generation assay
a.
Calculated as the number of samples multiplied by amount of blood per sample.
b.
If a serum ∋-hCG pregnancy test is required, it will be performed by the study-site’s local laboratory.
c.
Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples and are not 
included in the total volumes.
Note: An indwelling IV cannula may be used for blood sample collection.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF and/or laboratory 
requisition form. It is important to record the exact date and time for PK sample collection even 
if the time deviates from the scheduled time of collection. If blood samples are collected via an 
indwelling cannula, an appropriate amount (eg, 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 (or equivalent) and charged with a volume 
equal to the dead space volume of the lock.
Refer to the Schedule of Activities for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manuals 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.


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Study-Specific Materials
The investigator will be provided with the following supplies:
!
IB
!
Pharmacy manual/study-site investigational product and procedures manual
!
Laboratory manuals for clinical, PK, PD, and biomarker laboratory specimens
!
IWRS Manual
!
Electronic data capture (eDC) Manual
!
Sample ICF
!
Venography manual
!
Guidelines for reporting bleeding event verbatim terms
!
Subject contact cards (wallet card)
!
Contact information page
8.1.
Efficacy Assessments
Efficacy evaluations will include unilateral venography assessment of the operated leg and 
assessments of symptomatic DVT, PE, or death to assess the primary, secondary, and 
exploratory efficacy outcomes.
8.1.1.
Assessments for DVT
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 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.
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.


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8.1.2.
Assessments for PE
For all subjects with symptoms of PE, spiral computed tomography, pulmonary angiography, or 
perfusion/ventilation lung scanning 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:
!
Positive spiral computed tomography scan of the chest revealing a segmental or more 
proximal thrombus
!
Positive 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 objectively diagnosed with a PE meeting the specified definitions prior to 
Day 10-14, a subsequent venography assessment of the operated leg is not required.
8.2.
Safety Assessments
The safety and tolerability of JNJ-70033093 will be evaluated throughout the study according to 
the timepoints provided in the Schedule of Activities by the assessment of adverse events, 
including nonserious adverse events, serious adverse events, adverse events of interest 
(ie, bleeding events, liver enzyme elevations and clinical liver events, and wound or joint 
complications), clinical laboratory tests (ie, hematology, clinical chemistry, urinalysis), and 
physical examinations. All bleeding events will be classified according to the definitions of 
bleeding events in Section 10.6, Appendix 6, Definition of Bleeding Events. Safety evaluations 
may also be performed at unscheduled timepoints, if deemed by the investigator or appropriate 
designee as necessary to ensure the safety of the subject. All suspected symptomatic efficacy 
events (VTE) will also be captured as adverse events of interest.
The OC will be responsible for reviewing ongoing safety and efficacy data by unblinded subject
treatment assignments approximately every 3 to 8 weeks on a periodic basis. They will also 
review the interim analysis data and make dose decisions, including but not limited to deciding 
whether to proceed with the optional dose regimen and at what dose(s). Details regarding the OC
are provided in Committees Structure in Section 10.3, Appendix 3, Regulatory, Ethical, and 
Study Oversight Considerations.
Adverse events will be reported and followed by the investigator as specified in Section 8.3, 
Adverse Events and Serious Adverse Events and Section 10.4, Appendix 4, Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-Up, and Reporting.
Any clinically relevant changes occurring during the study must be recorded on the adverse 
event section of the eCRF.


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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 condition is reached. 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Schedule of Activities.
8.2.1.
Bleeding Events
8.2.1.1.
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 Schedule of Activities.
The investigator’s classification of bleeding events according to the protocol classification will 
be collected in the eCRF (Section 10.6, Appendix 6, Definition of Bleeding Events). Additional 
information, including but not limited to the list below, will be collected for subjects with 
bleeding events and captured in the source documents and entered into the eCRF:
!
Location of the bleeding and duration
!
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
!
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.
8.2.1.2.
Approach to Subjects With a Bleeding Event
If a subject has a bleeding event requiring intervention during the study, the following measures 
should be considered:
!
Discontinue the study drug (refer to Section 7.1, Discontinuation of Study Drug)
!
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


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Currently, there is no reversal agent for JNJ-70033093; however, the anticoagulant effect of 
JNJ-70033093 dissipates in 48 to 72 hours. At therapeutic doses, the anticoagulant effects of 
JNJ-70033093 will not be reflected by international normalized ratio (INR) values but may be 
reflected by prolongation of aPTT. In-vitro spiking of human plasma with JNJ-70033093 
resulted in concentration-dependent increases in aPTT, which is consistent with its mechanism of 
action. Pre-incubation with activated 4-factor prothrombin concentrate complex (FEIBA) and 
Factor VIIa (Novo-Seven(), 2 commercially available nonspecific reversal agents, were able to 
prevent JNJ-70033093-induced prolongations in aPTT. These data demonstrate that FEIBA 
(and Factor VIIa by bypassing FXIa inhibition), can promote clotting and provide hemostasis.9
Furthermore, FEIBA was able to reverse bleeding induced by a FXIa-inhibitor compound in a 
rat-tail transection model of bleeding in anesthetized rats.10 Also, in FXI-deficient patients, 
recombinant Factor VIIa has been used successfully to prevent surgical bleeding without 
complication.
Therefore, if bleeding cannot be controlled by these measures, administration of FEIBA or 
Factor VIIa according to the dosages and dosing schedules that are recommended in their 
respective package inserts could be considered (Note: consultation with a coagulation expert is 
recommended before use).
Protamine sulfate partially reverses the anticoagulant activity of enoxaparin. For subjects 
receiving enoxaparin, if bleeding cannot be controlled by the above measures protamine can be 
considered at the dosages recommended in the SmPC.
8.2.2.
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 8.2.1.1, 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 the final visit. 
The physical examination will be conducted at the time points indicated in the Schedule of 
Activities. An assessment of the wound will be made at all visits as part of the adverse event 
assessment. 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.


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8.2.3.
Vital Signs
Vital signs measurements are not being collected in this study.
8.2.4.
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology and a urine sample for urinalysis will be 
collected as noted in Section 10.2, Appendix 2, Clinical Laboratory Tests. 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 
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. Hematology and chemistry 
laboratory tests and a urine sample for urinalysis will be obtained before dosing (0 hour) and will 
be performed by the central laboratory. Refer to Section 10.2, Appendix 2, Clinical Laboratory 
Tests for the list of tests to be performed by the central laboratory.
8.3.
Adverse Events and Serious Adverse Events
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 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.
There are no anticipated events in this study. Since this is one of the first studies to evaluate 
JNJ-70033093 in subjects, all adverse events and serious adverse events are important in 
understanding the safety of the study drug and will be collected for the duration of the study.
For further details on adverse events and serious adverse events (Definitions and Classifications; 
Attribution Definitions; Severity Criteria; Special Reporting Situations; Procedures) as well as 
product quality complaints, refer to Section 10.4, Appendix 4, Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-Up, and Reporting.
8.3.1.
Adverse Events of Interest
Investigators will be asked to provide more detailed information in the source documents and the 
applicable eCRF forms for adverse events of interest that are considered to be one of the 
following:
!
Bleeding events
!
Wound or joint complications


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Liver enzyme elevation and clinical liver events
Note: As previously noted in Section 8.2, Safety Assessments, all suspected symptomatic 
efficacy events (VTE) will also be captured as adverse events of interest. Asymptomatic 
DVT found on the planned Day 10-14 venography assessment does not need to be reported 
as an adverse event unless it meets the criteria for a serious adverse event (eg, prolonged 
hospitalization). Information from these asymptomatic events will be reported on the 
venography assessment eCRF.
8.3.1.1.
Bleeding Events - Adverse Events of Interest
Refer to Section 8.2.1, Bleeding Events, for further details on the classification of bleeding 
events as well as the approach to use with subjects who present with a bleeding event. 
8.3.1.2.
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 Schedule of Activities. 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 
interest. Any medical or surgical treatments for wound or joint complications will be recorded as 
well.
8.3.1.3.
Liver Enzyme Elevations and Clinical Liver Events
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur before the reporting of a potential drug-induced liver injury. Subjects meeting the 
following criteria for liver-related laboratory abnormalities for all cases must be reported as 
adverse events of interest and have study drug discontinued immediately:
!
ALT and/or AST ∀5x the upper limit of normal (ULN) for ∀7 consecutive days, confirmed 
by repeat
!
ALT and/or AST ∀10x ULN, confirmed by repeat*
!
Potential drug-induced liver injury (as defined below)
The following is not required to be reported as an adverse event of interest but treatment with the 
study drug should be interrupted if:
!
ALT and/or AST ∀3x ULN, confirmed by repeat*
*NOTE: If the ALT and/or AST elevation occurs within 1 calendar day of surgery and the repeat 
to confirm the elevation is lower than the initial elevation, with the repeat testing performed at 
least 24 hours after the first sample, the investigator should exercise clinical judgement to 
determine if the study drug should be immediately discontinued or interrupted. The value should 
be checked every 48 to 72 hours and if it continues to decrease the study drug can be continued.


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Subjects with abnormal liver function tests should be followed until the ALT/AST returns to 
<2x ULN or to baseline prior to considering the restart of treatment with the study drug, but no 
later than the scheduled Day 10-14 visit.
A potential drug-induced liver injury is defined as:
!
ALT or AST elevation ∀3x ULN
AND
!
Total bilirubin ∀2x ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase)
AND
!
No other immediately apparent possible causes of transaminase elevation and 
hyperbilirubinemia, including but not limited to: viral hepatitis, preexisting chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatoxic
!
In addition to discontinuing study drug and reporting all potential drug-induced liver injury 
as adverse events of interest.
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential drug-induced liver injury event. All occurrences of 
potential drug-induced liver injury events, meeting the defined criteria, must be reported as 
serious adverse events.
8.3.2.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
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 within 30 days after the last 
dose of study drug, 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.
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, which must be completed and signed 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 made by facsimile (fax).


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8.3.3.
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. 
Solicited Adverse Events
Solicited adverse events are predefined local and systemic events for which the subject is 
specifically questioned. 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).
Unsolicited Adverse Events
Unsolicited adverse events are all adverse events for which the subject is not specifically 
questioned.
8.3.4.
Follow-Up of Adverse Events and Serious Adverse Events
Adverse events, including pregnancy, will be followed by the investigator as specified in 
Section 10.4, Appendix 4, Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting.
8.3.5.
Regulatory Reporting Requirements for Serious Adverse Events
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 as per regulatory requirements 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 determination of the expectedness in the SUSARs will use the IB for JNJ-70033093 and the 
SmPC for enoxaparin.
8.3.6.
Pregnancy
All initial reports of pregnancy in all female subjects or partners of male subjects randomly 
assigned to JNJ-70033093 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. If a subject becomes pregnant during the study, the subject 
must be discontinued from further study intervention.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.


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8.4.
Treatment of Overdose
For this study, the accidental or intentional administration of any dose of JNJ-70033093 or 
enoxaparin that is considered both excessive and medically important by the investigator will be 
considered an overdose and should be reported as a serious adverse event (medically important 
event). The sponsor does not recommend specific intervention for an overdose (consult the 
approved product information for enoxaparin). There is no known antidote for overdose with 
JNJ-70033093 and no studies have been performed to assess methods of reversing JNJ-70033093
absorption effects; however, in theory, activated charcoal may reduce the absorption of JNJ-
70033093 if given early after administration of JNJ-70033093.
In the event of an overdose with JNJ-70033093, the investigator or treating physician should:
!
Contact the Medical Monitor listed in the Protocol Contact Page immediately.
!
Closely monitor the subject for adverse event/serious adverse event and laboratory 
abnormalities until JNJ-70033093 can no longer be detected systemically (at least 2 days).
!
Monitoring aPTT may be of help in determining the extent of anticoagulation.
!
Obtain plasma samples for PK and PD (aPTT and PT) analysis as soon as possible from the 
date of the last dose of study drug if requested by the Medical Monitor (determined on a 
case-by-case basis).
!
Document the quantity of the excess dose (number of capsules), the nature 
(accidental, intentional) as well as the duration of the overdosing in the eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the subject.
8.5.
Pharmacokinetics
Plasma samples will be used to evaluate the PK of JNJ-70033093. Plasma collected for PK may 
additionally be used to evaluate safety or efficacy aspects that address concerns arising during or 
after the study period. Genetic analyses will not be performed on these plasma samples. Subject 
confidentiality will be maintained.
8.5.1.
Evaluations
Venous blood samples of approximately 2 mL will be collected and divided into 2 aliquots for 
measurement of plasma concentrations of JNJ-70033093. All samples should be timed from the 
first postoperative dose taken. The dosing date and time of each dose of JNJ-70033093 on the 
preceding day will also be recorded in the eCRF. Subjects who experience a suspected bleeding 
event or symptomatic thrombotic event should have PK samples collected as soon as practically 
possible after the event occurs.
Samples collected for analyses of JNJ-70033093 plasma concentration may additionally be used 
to evaluate safety or efficacy aspects that address concerns arising during or after the study 
period for the evaluation of relevant biomarkers. Additional information about the collection, 
handling, and shipment of biological samples can be found in the PK Laboratory Manual.


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8.5.2.
Analytical Procedures
Pharmacokinetics
Plasma samples will be analyzed to determine concentrations of JNJ-70033093 using a validated, 
specific, and sensitive (eg, liquid chromatography-mass spectrometry/mass spectrometry)
method by or under the supervision of the sponsor. Pharmacokinetic samples will be collected 
from all subjects randomly assigned to JNJ-70033093. Detailed instruction for the PK blood 
collection, labeling, processing, storage, and shipping will be provided to the study-site in the 
procedures manual.
In addition, residual plasma PK samples may be stored for future analysis of the metabolite 
profile, if needed. If these analyses are conducted, they will be reported separately from the CSR.
The Schedule of Activities lists the sampling schedule to be followed for the assessment of PK. 
In addition to the times listed in the table, a sample for measurement of JNJ-70033093 plasma 
concentration should be collected as close to practically possible for any subject who experiences 
a suspected symptomatic thrombotic or bleeding event, or if requested by the Medical Monitor 
(determined on a case-by-case basis) in the event of an overdose.
8.5.3.
Pharmacokinetic Parameters and Evaluations
Parameters
Based on the individual plasma concentration-time data, using the actual dose taken and the 
actual sampling times, PK parameters (eg, apparent clearance, apparent volume of distribution) 
and exposure for exposure-response analysis of JNJ-70033093 and associated variables 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. The analysis of these parameters will 
be outlined in the population PK modeling plan and reported separately from the CSR.
Pharmacokinetic/Pharmacodynamic Evaluations
The relationship between the observed plasma concentration of JNJ-70033093 and measured 
PD markers will be investigated graphically. If appropriate, PK/PD exposure and 
response-relationships may be further analyzed quantitatively.
The relationships between the plasma PK exposure of JNJ-70033093 derived from the 
population PK model will be correlated with the measured PD markers and safety/efficacy 
endpoints via graphical analysis. When necessary, these data may be analyzed statistically using 
a suitable model. The details of the analyses plan will be presented in a population PK modeling 
plan that is separated from the Statistical Analysis Plan (SAP). The results will be reported 
separately from the CSR.
8.6.
Pharmacodynamics
Venous blood samples will be collected for PD evaluation of aPTT, PT, FXI clotting activity, 
anti-FXa activity, and TGA at the timepoints specified in the Schedule of Activities. Factor XI 


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clotting activity will be assessed in subjects randomly assigned to JNJ-70033093 and anti-FXa 
activity will be assessed in subjects randomly assigned to enoxaparin. Subjects who experience a 
suspected bleeding event or symptomatic thrombotic event should have PD samples collected as 
soon as practically possible after the event occurs. Additional information about the collection, 
handling and shipment of biological samples can be found in the PD laboratory manual.
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, DOACs, and direct thrombin inhibitors, including hirudin, 
argatroban, and dabigatran have an effect on the assay. Blood will be collected for measurement 
of changes in aPTT clotting time.
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 fibrinogen and 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, 
INRs are used to monitor warfarin therapy. It should be noted that currently, 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.
Factor XI Clotting Activity
Factor XI clotting activity is determined utilizing an aPTT-based 1-stage clotting time assay. 
Serial dilutions of normal pooled plasma are mixed with FXI-depleted plasma and the clotting 
times are measured according to standard aPTT protocol, to establish a reference range. Subject
test plasma is treated in the same way and compared with the reference plasma. The assay will be 
performed at a specialty laboratory.


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Anti-Factor Xa Activity
The plasma anti-FXa assay is used to monitor factor unfractionated heparin and LMWH. The 
plasma anti-FXa assay provides an accurate assessment of LMWH activity. Factor Xa is added 
to plasma containing a FXa-specific substrate and substrate hydrolysis is measured. A standard 
curve is generated by measuring the FXa chromogenic activity in control plasma samples that 
contain known concentrations of LMWHs. Chromogenic activity in patient plasma is then 
compared to the standard curve to determine the LMWH level.
Thrombin Generation Assay
The TGA is a global coagulation assay that evaluates the thrombogenic capacity of a plasma
sample and has been proposed that it may better reflect prothrombotic or hemorrhagic states than 
conventional clotting assays. In the traditional TGA, coagulation of citrated plasma is initiated 
through the extrinsic pathway by adding tissue factor, phospholipids, and calcium. For this study,
a kaolin slurry will be used instead to initiate coagulation through the contact activation pathway. 
Using this approach, a Factor XI-specific TGA can also be performed by diluting test plasma 
into FXI-deficient plasma and measuring kaolin-induced thrombin generation, similar to the 
approach used for FXI-specific clotting. Thrombin generation is continuously monitored through 
the product released by cleavage of a thrombin-specific fluorogenic substrate. The generated
thrombogram is used to determine several relevant parameters, including endogenous thrombin 
potential, defined as the net amount of thrombin that test plasmas can generate based on the 
relative strength of the pro- and anticoagulant reactions.
Archive Sample for Exploratory Research
Blood samples will be collected at the time points specified in the Schedule of Activities and a 
plasma sample archived for future exploratory PD research related to the safety and/or efficacy 
of JNJ-70033093. Refer to the PD laboratory manual for detailed instructions for sample 
collection, processing and shipment of archive samples for exploratory research.
8.7.
Biomarkers
Venous blood samples will be collected for measurement of D-dimer, high-sensitive cardiac 
troponin T (hs-cTnT), and FXI antigen assessment at the timepoints specified in the Schedule of 
Activities.
D-dimer
The various states of coagulation activation that occur in vivo lead to the production of thrombin 
and then, cross-linked fibrin. What follows is a reactive fibrinolysis, during which plasmin 
breaks down fibrin. D-dimer is the ultimate degradation product of cross-linked fibrin. The 
presence of D-dimer in plasma is an indirect marker of a coagulation activation followed by a 
reactive thrombolysis. Increased levels D-dimer 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 levels.


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High-sensitive Cardiac Troponin T
The troponin complex, consisting of troponin C, T, and I subunits, regulates the contraction of 
striated muscles. Damage to cardiac muscle tissue causes release of troponins into the 
bloodstream and circulating troponin levels correlate to the degree of muscle damage; 
accordingly, cardiac troponins are considered primary biomarkers for diagnosis of acute MI and 
risk assessment in acute coronary syndrome. Immunoassays are performed to detect cardiac 
troponin T in plasma samples prepared from venous blood collection. 
Factor XI Antigen
Measurement of FXI antigen in plasma at baseline, using a validated immunoassay, may help to 
improve understanding of thrombotic conditions and help identify subjects susceptible to 
cardiovascular events.  
8.8.
Medical Resource Utilization and Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study.
9.
STATISTICAL CONSIDERATIONS
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 the SAP.
This study will use an adaptive design intended to optimize data collection for dose-response 
modeling. It is estimated that approximately 900 subjects will be randomly assigned to treatment 
in this study, with an option to increase to approximately 1,200 subjects based on the possible 
addition of once daily dose groups, and/or evaluability rate. Initially, subjects will be randomly 
assigned to BID doses of JNJ-70033093 25, 50, 100, and 200 mg and enoxaparin 40 mg once 
daily in a 1:1:1:1:2 randomization ratio. Unblinded periodic and interim analyses will be 
conducted by the OC for the purposes of safety oversight and as part of the adaptive approach.
Periodic reviews will be conducted every 3 to 8 weeks and the first interim analysis, will occur 
when approximately 300 subjects will have completed the venography or have had a 
symptomatic VTE event. The dose regimens and randomization ratio may be adjusted post-
analyses, depending on the analysis results and safety review. These adjustments include 
dropping ineffective dose regimens or dose regimens with safety concerns (especially bleeding) 
as well as adding dose regimens (ie, once daily dose regimen). The randomization ratio may be 
modified to optimize data collection for dose-response estimation.
9.1.
Sample Size Determination
Assuming the evaluability rate (rate of subjects with a valid assessment of potential efficacy 
outcome and who take at least 1 dose of study drug) is 80%, if the true underlying total VTE 
event rates are as shown in Table 2, the study is expected to have over 99% power to declare 
proof-of-efficacy at a 1-sided, 5% ∃-level. Proof-of-efficacy is defined as either a statistically 
significant dose-response trend or primary endpoint event rate for the combined BID JNJ-


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70033093 groups that is statistically lower than 30%. The exact power will vary because of the 
nature of the adaptive study design. 
Comparison with enoxaparin will be based on the comparison between the highest postoperative 
dose with acceptable safety and enoxaparin. For example, if the highest dose for acceptable 
safety is 200 mg BID, the number of evaluable subjects at this dose and enoxaparin groups is 
expected to be 120 and 240 subjects respectively, the power to detect a statistically significantly 
lower total VTE event rate against enoxaparin, at 1-sided, 5% ∃-level, is over 90%.
Table 2:
Assumed Total VTE Event Rates by Treatment Group in Sample Size Determination
JNJ-70033093
Enoxaparin
25 mg
50 mg
100 mg
200 mg
40 mg once 
daily
BID
18%
14.5%
12.5%
11.0%
Once daily
24%
14%
23.8%
BID=twice daily VTE=venous thromboembolism
9.2.
Populations for Analyses
For purposes of analysis, the following populations are defined in Table 3:
Table 3:
Analysis Populations
Population
Description
ITT
(as termed Full Analysis Set in the ICH E9 guideline): This population consists of all 
randomized subjects who have a signed informed consent.
mITT
This population is a subset of the ITT population, consisting of subjects who take at least 1 dose 
of the study drug and have a valid assessment of potential efficacy outcome at the Day 10-14 
visit.
Safety
This population is a subset of the ITT population, consisting of subjects who receive at least 
1 dose of the study drug.
ICH=International Conference on Harmonisation; ITT=intent-to-treat; mITT=modified intent-to-treat
The valid assessment of potential efficacy outcome is defined as subjects meeting 1 of the 
following.
!
Had an evaluable venography at the Day 10-14 visit
!
Had symptomatic DVT or PE at the Day 10-14 visit and the Week 6 visit
!
Died before the Day 10-14 visit and before the Week 6 visit
9.3.
Statistical Analyses
9.3.1.
Efficacy Analyses
The study objectives include proof-of-efficacy and estimation of dose-response relationship in 
total VTE. 
The dose-response trend and estimation of dose-response relationship will be
addressed by a unified (modified) MCP-Mod approach,1,3,30 utilizing collective data from 
postoperative regimens. Proof-of-efficacy will be established by either a statistically significant 
dose-response trend, or by a statistically lower total VTE event rate in combined BID data


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compared with 30%. The rate of 30% is a conservative estimate of the total VTE rate in subjects
given placebo. The trend test consists of contrast tests defined by prespecified candidate models
(4 Emax dose-response modules with varying degrees of ED50, Figure 4), which provide estimates 
of dose-response (taking BID and once daily into consideration). 
Figure 4:
Canonical Candidate Emax Dose-response Models Used in the MCP-Mod Analysis
The efficacy of the drug is established when the maximum of the t-test statistics for the 
dose-response trend exceeds the critical value. Predicted event rates at a specific dose will be 
derived for the candidate model. 
The details of the adaptive decision guidelines will be specified in the OC charter and the SAP.
The primary analyses of efficacy endpoints will be based on CEC-adjudicated events from the 
mITT population. Subjects who do not receive any study drug will be excluded from the primary 
analysis. However, they will be included in sensitivity analyses as defined in the SAP. The 
primary efficacy endpoint and its components will be summarized by dose and treatment group.
Prespecified clinical variables of interest for the efficacy subgroup analyses include region, age, 
sex, body mass index, renal function, surgery duration, and tourniquet use.
9.3.2.
Safety Analyses
Adverse Events
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Study drug-emergent 
adverse events are adverse events with onset during the postoperative dosing 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.


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Summaries, listings, or subject narratives may be provided, as appropriate, for those subjects
who die, who discontinue the study drug due to an adverse event, or who experience a severe or 
a serious adverse event.
Adverse events of interest that will be counted or listed are bleeding events, wound or joint 
complications, and liver enzyme elevations and clinical liver events. 
The safety population will be a subset of the ITT population consisting of subjects who take at 
least 1 dose of the study drug. The analyses of bleeding adverse events will be based on the 
CEC-adjudicated events; all other nonefficacy or nonbleeding adverse events will be based on 
investigator-reported events in the safety population.
Estimation of the dose-response relationship in any bleeding will be addressed by a unified 
(modified) MCP-Mod approach as with efficacy. Any bleeding, major bleeding, clinically 
relevant nonmajor bleeding, composite of major or clinically relevant nonmajor bleeding, and 
minimal bleeding will be summarized by the dose and treatment group. The same variables 
specified for the efficacy subgroup analyses will be used for the safety subgroup analysis with 
the addition of aspirin/nonsteroidal anti-inflammatory drugs.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the SAP) will be used in the summary of laboratory data. 
Descriptive statistics will be calculated for each laboratory analyte at baseline and at each 
scheduled time point. 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.
Physical Examination
Height and weight will be summarized.
9.3.3.
Other Analyses
Pharmacokinetic Analyses
Population PK analysis of plasma concentration-time data of JNJ-70033093 will be performed 
using nonlinear mixed-effects modeling. Data may be combined with those of other selected 
studies to support a relevant structural model. Available baseline subject characteristics 
(ie, demographics, laboratory variables, genotypes, race) will be tested as potential covariates 
affecting PK parameters. Details will be given in a population PK analysis plan and the results of 
the population PK analysis will be presented in a separate report.
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 intervention; missing information of dosing 
and sampling times; concentration data not sufficient for PK parameter calculation).


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All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration database. All subjects and samples excluded from the analysis will be 
clearly documented in the study report.
For each treatment group, descriptive statistics, including arithmetic mean, standard deviation 
(SD), coefficient of variation, median, minimum, and maximum will be calculated for all 
individual derived PK parameters including exposure information of JNJ-70033093.
All plasma concentrations below the lowest quantifiable concentration or missing data will be 
labeled as such in the concentration data presentations or SAS dataset. 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 CSR.
Descriptive statistics will be used to summarize JNJ-70033093 plasma concentrations at each 
sampling time point.
Exposure-response analyses will be conducted to explore the relationship of the plasma 
concentration of JNJ-70033093 with efficacy and safety endpoints. The details of the analyses 
plan will be presented in a population PK modeling plan that is separate from the SAP. The 
results will be reported separately from the CSR.
Pharmacodynamic and Biomarker Analyses
Descriptive statistics, including mean, median, SD, minimum, and maximum will be provided 
for the percent change from baseline of the PD (aPTT, PT, FXI clotting activity, anti-FXa 
activity, TGA) and biomarker (D-dimer, hs-cTnT) parameters by nominal time of collection and 
dose and regimen level. The parameters may be statistically analyzed using mixed models. FXI 
antigen levels will be summarized.
Pharmacokinetic/Pharmacodynamic Analyses
The relationship between observed plasma concentration of JNJ-70033093 and measured 
PD markers will be investigated graphically. If appropriate, PK/PD exposure and response 
relationships may be further analyzed quantitatively. 
The relationship between the plasma PK exposure of JNJ-70033093 derived from the population 
PK model will be correlated with the measured PD markers and safety/efficacy endpoints via 
graphical analysis. When necessary, these data may be analyzed statistically using a suitable 
model. The details of the analyses plan will be presented in a population PK modeling plan that 
is separate from the SAP. The results will be reported separately from CSR.
9.4.
Periodic and Interim Analyses
Unblinded periodic and interim analyses will be conducted by the OC for the purposes of safety 
oversight and as part of the adaptive approach. The interim analysis will be triggered when 
approximately 300 subjects (approximately 50 subjects in each of the JNJ-70033093 BID 
treatment groups) will have completed the venography or have had a symptomatic VTE event.
Both periodic and interim analyses results will be used to guide the decision to drop doses of 


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JNJ-70033093 and/or adjust the randomization ratio. The number of subjects who were planned 
to be randomized into the dropped dosing regimen can be allocated to one of the other active 
dosing groups. The interim analysis will also serve as the formal venue to assess study status and 
possibly add once daily dosing of 50 mg and/or 200 mg of JNJ-70033093 based on available 
efficacy and safety data. If PK/PD analysis results are available at the time of the interim 
analysis, the results will be included in the review. Additional interim analyses will be 
conducted, as needed, at the discretion of the OC. A futility analysis will also be included as part 
of the interim analysis, which may lead to stopping the entire study. These decisions will be 
made only after taking the safety and efficacy profiles of JNJ-70033093 into account. Further 
details related to the first interim analysis and any subsequent interim analyses as determined to 
be appropriate by the OC as well as the decision guidelines will be specified in the OC charter.
9.4.1.
Committees
An OC, Steering Committee, and independent CEC will be established as noted in Committees 
Structure in Section 10.3, Appendix 3, Regulatory, Ethical, and Study Oversight Considerations.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS


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10.1.
Appendix 1: Abbreviations
ALT
alanine aminotransferase
anti-FXa
anti-Factor Xa
aPTT
activated partial thromboplastin time
ASO
antisense oligonucleotide
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-24h
area under the concentration versus time curve from 0 to 24 hours of the last measurable 
concentration
∋-hcg
beta-human chorionic gonadotropin
BID
twice daily
BMS
Bristol-Meyers Squibb Company
CEC
Clinical Events Committee
CI
confidence interval
Cmax
maximum plasma concentration
CSR
clinical study report
CYP
cytochrome P450
DDI
drug-drug interaction
DOAC
direct oral anticoagulant
DVT
deep vein thrombosis
ECAT
electrically induced carotid artery thrombus
eCRF
electronic case report form
eDC
electronic data capture
ESRD
end-stage renal disease
FSH
follicle stimulating hormone
FXa
Factor Xa
FXI
Factor XI
FXIa
Factor XIa
GCP
Good Clinical Practice
hs-cTnT
high-sensitive cardiac troponin T
IB
Investigator’s Brochure
IC50
concentration at which 50% inhibition was observed
ICF
informed consent form
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
INR
international normalized ratio
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous
IWRS
interactive web response system
Ki
inhibition constant
LMWH
low molecular-weight heparin
MATE
multidrug and toxin extrusion
MCP-Mod
multiple comparison procedures and modeling
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MINS
myocardial injury in noncardiac surgery
mITT
modified intent-to-treat
MRP
multiple drug-resistance protein
NSAID
nonsteroidal anti-inflammatory drug
NTCP
sodium-taurocholate cotransporting polypeptide
NOAEL
no observed adverse effect level
OAT
organic anion transporter
OATP
organic anion-transporting polypeptide
OC
Operations Committee
OCT
organic cation transporter


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PD
pharmacodynamic(s)
PE
pulmonary embolism
P-gp
p-glycoprotein
PK
pharmacokinetic(s)
PQC
Product Quality Complaint
PROBE
prospective, randomized, open-label, blinded endpoint
PT
prothrombin time
RBC
red blood cell
SAP
Statistical Analysis Plan
SC
subcutaneous
SD
standard deviation
SmPC
Summary of Product Characteristics
SUSAR
suspected unexpected serious adverse reaction
TGA
thrombin generation assay
TKR
total knee replacement
UGT
uridine diphosphate glucuronosyltransferase
ULN
upper limit of normal
UV
ultraviolet
VTE
venous thromboembolism
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman of childbearing potential
x
times




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10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
REGULATORY AND ETHICAL CONSIDERATIONS
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.
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 
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) involve 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.
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.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study-site:


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!
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.
!
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
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)
!
IB (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


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!
Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)
!
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 IB 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).


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At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion.
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 4.2.1, Study-Specific Ethical Design 
Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1, Study-Specific Ethical 
Design Considerations.
FINANCIAL DISCLOSURE
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
INFORMED CONSENT PROCESS
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 and prior to TKR surgery. 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 


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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.
DATA PROTECTION
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 
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 PD, biomarker, and PK 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.


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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-70033093, to 
understand thrombosis, to understand differential intervention responders, and to develop 
tests/assays related to JNJ-70033093 and VTE prophylaxis. The research may begin at any time 
during the study or the post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 7.2.1, Withdrawal of Consent for the Use of Research 
Samples).
COMMITTEES STRUCTURE
Operations Committee
An OC will be established for this study. The OC, consisting of clinicians with expertise in 
thrombosis, thromboprophylaxis, hematology, orthopedic surgery, and clinical studies, and also 
including 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 3 to 8 weeks on a periodic basis
!
Reviewing the interim analysis data and making dose decisions, including but not limited to 
deciding whether to proceed with optional dose regimen and at what dose(s)
The details of the OC function and composition, as well as dose decision guidelines will be 
described in the OC charter.
Steering Committee
A Steering Committee with expertise in thrombosis, thromboprophylaxis, hematology, 
orthopedic surgery, and clinical studies will be commissioned to provide scientific leadership the 
study. The Steering Committee 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. 
The Steering Committee will receive recommendations from the OC regarding suggested 
modifications to the study based on the review of the unblinded data by the OC. The sponsor, in 
collaboration with the Steering Committee, 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 Steering Committee will be 
documented in a separate charter.
Independent Clinical Events Committee
An independent CEC will be established to review, adjudicate, and classify endpoint events as 
they become available in a blinded, consistent, and unbiased manner according to the definitions 


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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:
!
Venography assessment 
!
Suspected symptomatic DVT
!
Suspected symptomatic PE
!
Suspected bleeding events
!
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. The CEC will remain 
blinded to treatment assignment. 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 the interim 
analysis. The CEC-adjudicated events will be used in the final analysis.
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA
All information, including but not limited to information regarding JNJ-70033093 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-70033093, 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 biomarker 
analyses performed after the CSR has been issued will be reported in a separate report and will 
not require a revision of the CSR. 


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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 (ICMJE) 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 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 after the study 
end date, 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 ICMJE Recommendations for the Conduct, Reporting, Editing and 
Publication of Scholarly Work in Medical Journals, which state that the named authors must
have made a significant contribution to the conception or design of the work; or the acquisition, 
analysis, or interpretation of the data for the work; and drafted the work or revised it critically for 
important intellectual content; and given final approval of the version to be published; and 
agreed to be accountable for all aspects of the work in ensuring that questions related to the 
accuracy or integrity of any part of the work are appropriately investigated and resolved.
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.
DATA QUALITY ASSURANCE
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 clinical 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. 


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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. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources. 
CASE REPORT FORM COMPLETION
Case report forms are prepared and provided by the sponsor for each subject in electronic format. 
All data relating to the study must be recorded in eCRF. All eCRF 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 eCRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an 
eCRF, 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 eCRF. 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 eDC tool. If corrections to an eCRF 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.
SOURCE DOCUMENTS
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; 
intervention
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 and will be described in the monitoring 
guidelines (or other equivalent document).


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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 eCRF 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 eCRF 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 
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.
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 
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.


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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.
STUDY AND SITE CLOSURE
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


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10.4.
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
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 intervention. 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 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.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to All 
Adverse Events under Section 8.3.2, Time Period and Frequency for Collecting Adverse Events
and Serious Adverse Events Information, 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.*
*Medical and scientific judgement 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 


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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-70033093, the expectedness of an 
adverse event will be determined by whether or not it is listed in the IB. For enoxaparin, the 
expectedness of an adverse event will be determined by whether or not it is listed in the SmPC.
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 below (see Attribution Definitions).
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 
treatment(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 treatment(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 
treatment(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 treatment(s), concomitant disease(s). The 
relationship in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
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.


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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 judgement in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
SPECIAL REPORTING SITUATIONS
Safety events of interest on a sponsor study drug in an interventional study that may require 
expedited reporting or safety evaluation include, but are not limited to:
!
Overdose of a sponsor study drug 
!
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.
PROCEDURES
All Adverse Events
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.
For all studies with an outpatient phase, including open-label studies, 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


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!
Subject number
!
Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
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 Week 6, whether or not the event is expected 
or associated with the study drug, is considered a serious adverse event.
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.
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, 


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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.
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 8.3.2, Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information). A sample of the suspected product should be maintained for further 
investigation if requested by the sponsor.
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.


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10.5.
Appendix 5: Contraceptive and Barrier Guidance and Collection of 
Pregnancy Information
Subjects must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria. 
Pregnancy information will be collected and reported as noted in Section 8.3.6, Pregnancy, and 
Section 10.4, Appendix 4 Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-Up, and Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Woman Not of Childbearing Potential
!
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
!
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.
!
permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral 
tubal occlusion/ligation procedures, and bilateral oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman 
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually 
active becomes active), a woman must begin a highly effective method of contraception, as 
described throughout the inclusion criteria.


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Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT (PREFERRED METHOD FOR COMPOUNDS WITH POSSIBLE OR 
UNKNOWN TOXICITY AND RECOMMENDED METHOD FOR COMPOUNDS WITH 
SUSPECTED OR DEMONSTRATED TOXICITY)
Highly Effective Methods That Are User Independent Failure rate of ≤1% per year when used 
consistently and correctly.
!
Implantable progestogen-only hormone contraception associated with inhibition of ovulationb
!
Intrauterine device (IUD)
!
Intrauterine hormone-releasing system (IUS)
!
Bilateral tubal occlusion
!
Vasectomized partner
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, 
additional highly effective method of contraception should be used.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly.
!
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb
) oral
) intravaginal
) transdermal
) injectable
!
Progestogen-only hormone contraception associated with inhibition of ovulationb
) oral
) injectable
!
Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the subject.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY 
(not considered to be highly effective - failure rate of >1% per year)
!
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary 
mode of action.
!
Male or female condom with or without spermicidec
!
Cap, diaphragm, or sponge with spermicide
!
A combination of male condom with either cap, diaphragm, or sponge with spermicide 
(double-barrier methods)c
!
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
!
Withdrawal (coitus-interruptus)
!
Spermicides alone
!
Lactational amenorrhea method (LAM)
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 


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consistent with local regulations regarding the use of contraceptive methods for subject in clinical 
studies.
b) Hormonal contraception may be susceptible to interaction with the study drug, which may reduce 
the efficacy of the contraceptive method. In addition, consider if the hormonal contraception may 
interact with the study drug.
c) Male condom and female condom should not be used together (due to risk of failure with friction).


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10.6.
Appendix 6: Definition of Bleeding Events
1.
Major Bleeding in Surgical Setting35
a.
Fatal bleeding, and/or
b.
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
c.
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
d.
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 
e.
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 Bleeding28
A modified version of clinically relevant nonmajor bleeding criteria used in the ADVANCE-2 
study, in tandem with clinical judgement, will be used to classify bleeding events:
!
Acute clinically overt bleeding
)
Does not satisfy additional criteria required for the bleeding event to be defined as a 
major bleeding event and is still considered clinically relevant. Examples are listed 
below: 
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


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∗
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)
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, 
computed tomography, magnetic resonance imaging) 
Note: Any overt bleeding not meeting major or clinically relevant nonmajor criteria will be 
assessed27 as minimal bleeding.


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10.7.
Appendix 7: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).


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Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques in dose-response 
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15.
Francis CW, Davidson BL, Berkowitz SD, et al. Ximelagatran versus warfarin for the prevention of venous 
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16.
Fuji T, Fujita S, Tachibana S, Kawai Y. A dose-ranging study evaluating the oral factor Xa inhibitor edoxaban 
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Fuji T, Wang CJ, Fujita S, et al. Safety and efficacy of edoxaban, an oral factor Xa inhibitor, versus enoxaparin 
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18.
Gailani D, Gruber A. Factor XI as a therapeutic target. Arterioscler Thromb Vasc Biol. 2016;36(7):1316-1322.
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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(3 Suppl):338S-400S.


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20.
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American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. 
J Arthroplasty. 2009;24(1):1-9.
21.
Investigator’s Brochure: JNJ-70033093; Edition 5. Janssen Research & Development, LLC. (16 May 2019)
22.
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.
23.
Kearon C. Noninvasive diagnosis of deep venous thrombosis. McMaster Diagnostic Imaging Practice 
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24.
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thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786.
25.
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.
26.
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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.
27.
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.
28.
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.
29.
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(PREvention oF Thromboembolic Events-European Registry in Atrial Fibrillation). J Am Heart Assoc. 
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venous thromboembolism events. Blood. 2017;129:1210-1215.
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Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg. 1972;4:134 144.
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35.
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Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis 
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in surgical patients. J Thromb Haemost. 2010;8(1):202-204.
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venous thromboembolism prevention studies? J Thromb Haemost. 2005;3:1099-1102.
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Shnerb Ganor R, Harats D, et al. Factor XI deficiency protects against atherogenesis in Apolipoprotein E/
Factor XI double knockout mice. Arterioscler Thromb Vasc Biol. 2016;36(3):475-481.
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thromboprophylaxis clinical trials for the accurate evaluation of deep vein thrombosis. Br J Radiol. 
2007;80(959):859-865.
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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, 
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SAP_003.pdf: 
1
Status: Approved, Date: 26 September 2019
Janssen Research & Development
Statistical Analysis Plan
A Randomized, Open-Label, Study Drug-Dose Blind, Multicenter Study to Evaluate the 
Efficacy and Safety of JNJ-70033093 (BMS-986177), an Oral Factor XIa Inhibitor, Versus 
Subcutaneous Enoxaparin in Subjects Undergoing Elective Total Knee Replacement Surgery
Protocol 70033093THR2001; Phase II
JNJ-70033093
Status:
Approved
Date:
26 September 2019
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-ERI-197223295, 1.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
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.
NCT03891524


JNJ-70033093
Statistical Analysis Plan 70033093THR2001
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Status: Approved, Date: 26 September 2019
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
ABBREVIATIONS ........................................................................................................................................ 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Trial Objectives ................................................................................................................................ 5
1.2.
Trial Design ...................................................................................................................................... 6
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 8
1.4.
Sample Size Justification ................................................................................................................. 8
1.5.
Randomization and Blinding ............................................................................................................ 9
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 9
2.1.
Visit Windows................................................................................................................................... 9
2.2.
Pooling Algorithm............................................................................................................................. 9
2.3.
Analysis Sets.................................................................................................................................. 10
2.3.1.
All Randomized Analysis Set...................................................................................................... 10
2.3.2.
Intent-to-treat Analysis Set ......................................................................................................... 10
2.3.3.
Efficacy Analysis Sets................................................................................................................. 10
2.3.3.1.
Primary Efficacy Analysis Set.................................................................................................. 10
2.3.3.2.
Secondary Efficacy Analysis Sets ........................................................................................... 11
2.3.4.
Safety Analysis Set..................................................................................................................... 11
2.3.5.
Pharmacokinetics Analysis Set .................................................................................................. 11
2.3.6.
Pharmacodynamics Analysis Set ............................................................................................... 12
2.4.
Definition of Subgroups.................................................................................................................. 12
2.5.
Study Day and Relative Day .......................................................................................................... 12
2.6.
Baseline and Endpoint ................................................................................................................... 13
2.7.
Imputation Rules for Missing Date/Time........................................................................................ 13
3.
PERIODIC AND INTERIM ANALYSES ............................................................................................15
3.1.
Interim Analyses............................................................................................................................. 15
4.
SUBJECT INFORMATION................................................................................................................ 16
4.1.
Demographics and Baseline Characteristics ................................................................................. 16
4.2.
Disposition Information................................................................................................................... 16
4.3.
Treatment Compliance................................................................................................................... 17
4.4.
Extent of Exposure......................................................................................................................... 17
4.5.
Protocol Deviations ........................................................................................................................ 17
4.6.
Prior and Concomitant Medications ............................................................................................... 18
5.
EFFICACY ......................................................................................................................................... 18
5.1.
Analysis Specifications................................................................................................................... 18
5.1.1.
Level of Significance................................................................................................................... 18
5.1.2.
Data Handling Rules................................................................................................................... 18
5.2.
Primary Efficacy Endpoint(s).......................................................................................................... 18
5.2.1.
Analysis Methods........................................................................................................................ 18
5.3.
Major Secondary Efficacy Endpoints ............................................................................................. 19
5.3.1.
Analysis Methods........................................................................................................................ 20
5.4.
Exploratory Efficacy Variable(s)..................................................................................................... 20
5.4.1.
Definition..................................................................................................................................... 20
5.4.2.
Analysis Methods........................................................................................................................ 20
6.
SAFETY............................................................................................................................................. 20
6.1.
Principal Safety (Bleeding) Endpoint ............................................................................................. 21
6.1.1.
Principal Safety (Bleeding) Analysis Methods............................................................................ 21
6.2.
Major Secondary Safety (Bleeding) Endpoints ..............................................................................21
6.2.1.
Major Secondary Safety (Bleeding) Endpoints Analysis Methods ............................................. 22


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6.3.
Adverse Event................................................................................................................................ 22
6.4.
Clinical Laboratory Tests................................................................................................................ 23
6.5.
Vital Signs ...................................................................................................................................... 23
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 23
7.1.
Pharmacokinetics........................................................................................................................... 23
7.2.
Pharmacodynamics........................................................................................................................ 24
7.3.
Pharmacokinetic/Pharmacodynamic Relationships....................................................................... 24
8.
BIOMARKERS................................................................................................................................... 24
REFERENCES............................................................................................................................................ 25
ATTACHMENTS......................................................................................................................................... 26
Attachment 1:
Medications of Special Interest ..................................................................................26
LIST OF IN-TEXT TABLES
Table 1:
Assumed Total VTE Event Rates by Treatment Group in Sample Size Determination ............. 9
Table 2:
Definition of Subgroups............................................................................................................. 12
Table 3:
Demographic Variables and Baseline Characteristics.............................................................. 16
LIST OF IN-TEXT FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................... 8
Figure 2:
Canonical Candidate Emax Dose-response Models Used in the MCP-Mod Analysis ............... 19


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Statistical Analysis Plan 70033093THR2001
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Status: Approved, Date: 26 September 2019
ABBREVIATIONS
AE
adverse event
ALT/SGPT
APAC
alanine aminotransferase
Asia Pacific
AST/SGOT
aspartate aminotransferase
ATC
anatomic and therapeutic class
BID
twice daily
BMI
CEC
body mass index
Clinical events committee
CI
confidence interval
CRF
CRNM
case report form
clinically relevant non-major
CSR
Clinical Study Report
CV
coefficient of variation
DPS
DVT
Data Presentation Specifications
Deep vein thrombosis
(e)CRF
(electronic) case report form
FAS
full analysis set
FDA
Food and Drug Administration
ICH
International Conference on Harmonization
IQ
interquartile
IWRS
LATAM
interactive web response system
Latin America
MCP-Mod
multiple comparison procedures and modeling
MedDRA
Medical Dictionary for Regulatory Activities
MINS
(m)ITT
N
NA
OC
Myocardial injury in noncardiac surgery
(Modified) intent-to-treat
Total number
North America
Operations committee
PD
PE
Pharmacodynamic
pulmonary embolism
PI
principal investigator
PK
pharmacokinetic(s)
PP
per protocol
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
SDS
standard deviation
Secure Data Supplier
SMQs
standardized MedDRA queries
TEAE
TKR
VTE
treatment-emergent adverse event
Total knee replacement
Venous thromboembolism
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary


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Status: Approved, Date: 26 September 2019
1.
INTRODUCTION
This Statistical Analysis Plan (SAP) specifies definitions of analysis sets, key derived variables, 
and statistical methods for analysis of efficacy and safety for the
Phase 2 study
70033093THR2001. This SAP is based on the Clinical Protocol 70033093THR2001 amendment 
1 dated September 10, 2019. Titles, mock-ups and programming instructions for all statistical 
outputs (tables, figures and listings) will be provided in a separate document entitled Data 
Presentation Specifications (DPS). This SAP and its associated DPS will be used to generate a 
topline report and a Clinical Study Report (CSR) after database lock.
1.1.
Trial Objectives
Primary Objective
!
To determine the efficacy of JNJ-70033093 in preventing total VTE events (proximal and/or 
distal DVT [asymptomatic confirmed by venography assessment or objectively confirmed 
symptomatic], nonfatal PE, or any death) during the treatment period
Secondary Objectives
!
To assess the dose-response of JNJ-70033093 for the occurrence of the endpoint of any 
bleeding events during the treatment period
!
To determine the efficacy of JNJ-70033093 in preventing total VTE events during the full 
study period
!
To assess the dose-response of JNJ-70033093 for the rate of any bleeding throughout the 
full study period
!
To assess the dose-response of JNJ-70033093 for the prevention of major VTE (death, 
asymptomatic or symptomatic proximal DVT or nonfatal PE) during the treatment period 
and throughout the full study period
!
To assess the effect of individual doses of JNJ-70033093 compared with enoxaparin for both 
efficacy and safety endpoints
!
To compare the effect of JNJ-70033093 with enoxaparin for the individual components of 
the total VTE endpoint
!
To assess the PK of JNJ-70033093 in men and women undergoing primary unilateral TKR 
surgery and the relation of these measures to efficacy and safety endpoints (e.g., exposure-
response analyses)
Exploratory Objectives
!
To evaluate PD to assess its relationships to PK and the relation of these measures to 
efficacy and safety endpoints (e.g., exposure-response analyses). 
!
To evaluate exploratory biomarkers to assess their relationship to the probability of total 
VTE during the treatment period.
!
To explore the presence and incidence of asymptomatic myocardial injury in noncardiac 
surgery (MINS) as it relates to total knee arthroplasty.
The full study period and the treatment period are defined in Section 2.3.


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1.2.
Trial Design
This is an open-label, study drug-dose blind, active-controlled, multicenter, dose-ranging study 
of JNJ-70033093 in subjects undergoing primary unilateral elective TKR surgery. The study uses 
the prospective, randomized, open-label, blinded endpoint (PROBE) design. Men and women 
who are ∀50 years of age are eligible to participate if they are considered medically stable and 
appropriate for anticoagulant prophylaxis as determined by the investigator and on the basis of 
clinical laboratory tests performed as part of screening for elective TKR surgery. A target of 
900 subjects will be randomly assigned to treatment in this study, with an option to increase the 
randomization target to approximately 1,200 subjects based on the possible addition of QD dose 
groups, and/or evaluability rate.
Subjects meeting all of the enrollment criteria will be eligible to enter the study. The study will 
be conducted in 3 phases, which includes an up to 30-day screening phase before surgery, a 
10- to 14-day postoperative dosing phase, and a 4-week #10 days 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 participation following randomization 
will be approximately 6 weeks.
Screening for eligible subjects will be performed within and including 30 days before 
administration of the first dose of postoperative study drug. Eligible subjects will be randomly 
assigned to treatment with either JNJ-70033093 or enoxaparin postoperatively following 
unilateral elective TKR surgery. Subjects will know the treatment to which they were assigned 
but subjects randomly assigned to JNJ-70033093 will remain blinded to the dose and frequency 
(i.e., BID versus QD).
First dosing of both study drugs will occur while the subject is still hospitalized, with 
administration beginning a minimum of 12 hours and a maximum of 24 hours after the end of 
TKR surgery, which is defined as the time of wound closure, and must be the first anticoagulant 
administered postoperatively.
Enoxaparin may be initiated preoperatively at least 12 hours prior to the surgical procedure in 
accordance with local standard-of-care. Sites that routinely administer preoperative enoxaparin 
should continue their standard practice for all study subjects at that site. Per standard-of-care, 
study drug should not be used for the preoperative dose of enoxaparin for subjects in either 
treatment group.
Following discharge or transfer to an alternate facility, subjects will continue to take the assigned 
study drug for a total of 10 to 14 days. Unilateral venography assessment of the operated leg will 
be performed within 1 calendar day after the last dose of either JNJ-70033093 or enoxaparin is 
taken. 
Subjects will return to the study site 6 weeks after the TKR surgery for study-related evaluations 
and procedures as described in the Schedule of Activities. Safety evaluations will include the 
monitoring of all adverse events (AE), including nonserious adverse events, serious adverse 
events (SAE), adverse events of interest (i.e., bleeding events, liver enzyme elevations and 


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clinical liver events, wound or joint complications), clinical laboratory tests (i.e., hematology, 
clinical chemistry, urinalysis), and physical examinations. 
An Operations Committee (OC), Steering Committee, and independent Clinical Events 
Committee (CEC) will be commissioned for this study. The OC will be unblinded and the 
Steering Committee will be blinded to the dose and frequency of JNJ-70033093, unless the OC 
finds it necessary to consult with and unblind select members of the Steering Committee. If any
members of the Steering Committee are unblinded to the dose and frequency of JNJ-70033093, 
they will no longer be involved in the operational conduct of the study. The CEC will be blinded 
to both the study drug and the dose. The OC will be responsible for reviewing ongoing safety 
and efficacy data by unblinded subject treatment assignments approximately every 3 to 8 weeks
on a periodic basis. 
Unblinded periodic and interim analyses will be conducted by the OC for the purposes of safety 
oversight and as part of the adaptive approach. The first interim analysis will be triggered when 
approximately 300 subjects (approximately 50 subjects in each of the JNJ-70033093 BID 
treatment groups) will have completed venography or have had a symptomatic VTE event. Both 
periodic and the interim analyses results will be used to guide the decision to drop a dose of 
JNJ-70033093 and/or readjust the randomization ratio. The number of subjects who were 
planned to be randomized into the dropped dosing regimen can be allocated to one of the other 
dosing groups. The interim analysis will also serve as the formal venue to assess study status and 
possibly add once-daily dosing of JNJ-70033093 based on available efficacy and safety data. If 
PK/PD analysis results are available at the time of the interim analysis, the results will be 
included in the review.
Additional interim analyses will be conducted, as needed, at the discretion of the OC.
A diagram of the study design is provided in Figure 1.


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Figure 1:
Schematic Overview of the Study
1.3.
Statistical Hypotheses for Trial Objectives
The study objectives include proof-of-efficacy and estimation of dose-response relationship in 
total VTE. This objective can be achieved either by showing a statistically significant dose-
response trend (i.e., the alternative hypothesis is that there exists monotone dose-response trend), 
or by showing a statistically lower total VTE event rate in combined BID data compared with 
30% (i.e., the alternative hypothesis is that the event rate of combined BID dose is less than 
30%). The rate of 30% is a conservative estimate of the total VTE rate in subjects given placebo. 
The trend test consists of contrast tests defined by prespecified candidate models (4 Emax dose-
response modules with varying degrees of ED50, Figure 2), which provide estimates of dose-
response (taking BID and once daily into consideration). 
1.4.
Sample Size Justification
A target of 900 subjects will be randomly assigned to treatment in this study, with an option to 
increase the randomization target to approximately 1,200 subjects based on interim analysis 
results and/or evaluability rate.
Assuming the evaluability rate (rate of subjects with a valid assessment of potential efficacy 
outcome and who take at least 1 dose of study drug) is 80%, if the true underlying total VTE 
event rates are as shown in Table 1, the study is expected to have over 99% power to declare 
proof-of-efficacy at 1-sided 5% significance level. Proof-of-efficacy is defined as either a 
statistically significant dose-response trend or primary endpoint event rate for the combined BID 
JNJ-70033093 groups that is statistically lower than 30%. The exact power will vary because of 
the nature of the adaptive study design. 


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The highest dose of JNJ-70033093 with acceptable safety will be compared against enoxaparin.
For example, if the highest dose for acceptable safety is 200 mg BID, the number of evaluable 
subjects at this dose and enoxaparin groups is expected to be 120 and 240 subjects respectively, 
the power to detect a statistically significantly lower total VTE event rate against enoxaparin, at 
1-sided 5% significance level, is over 90%.
Table 1:
Assumed Total VTE Event Rates by Treatment Group in Sample Size 
Determination
JNJ-70033093
Enoxaparin
25 mg
50 mg
100 mg
200 mg
40mg once 
daily
BID
18%
14.5%
12.5%
11.0%
Once daily
24%
14%
23.8%
BID = twice daily, VTE = venous thromboembolism
1.5.
Randomization and Blinding
Randomization
Initially, subjects will be assigned in a 1:1:1:1:2 ratio into 1 of 5 treatment groups, including 
4 dose regimens of JNJ-70033093 and enoxaparin 40 mg once daily based on an algorithm 
implemented in the interactive web response system (IWRS). Following the decision of altering 
randomization scheme by dropping and/or adding treatment arms, and/or changing 
randomization ratio, the IWRS will be updated for randomization accordingly. Subjects will be 
stratified by region using dynamic central randomization to minimize the imbalance in the 
distribution of the number of subjects across study drug groups. Based on the algorithm, the 
IWRS will assign a unique treatment code, which will dictate the treatment assignment and 
matching study drug kit for the subject.
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 dosing blind 
for an individual subject. More details of blinding in the subject level could be found in 
Section 6.3 of the protocol amendment 1.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
As subjects do not always adhere to the protocol visit schedule, the following rules are applied to 
assign actual visits to analysis visits. If a subject has 2 or more actual visits in one scheduled 
visit, the earliest visit will be used as the protocol visit for that analysis visit. This is mainly for 
the lab test analyses for the changes from baseline.
2.2.
Pooling Algorithm 
Not applicable.


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2.3.
Analysis Sets
Each analysis involves the following two aspects:
!
The analysis set, which specifies those subjects who will be included in an analysis.
!
The observation (or analysis) period, which specifies the time window within which data
will be included in an analysis.
The following analysis sets: All Randomized Analysis Set, Intent-to-treat Analysis set (ITT), 
Safety Analysis Set, modified Intent-To-Treat Analysis Set (mITT), Per Protocol (PP) Analysis 
Set, and PK/PD Analysis Sets, will be used.
Associated with the analysis sets, three Analysis periods are defined as follows.
!
Day 14: this period is defined as from Day 1 to Day 17 (inclusive).
!
Week 6: this period is defined as from Day 1 to the last contact date.
!
On-treatment: this period is defined as from Day 1 to last dose date + 2 days.
Day 1 refers to date of the first dose of study drug administration or the surgery date if the 
subject didn’t take any study drug (see Section 2.5); Day 14 period and On-treatment period refer 
to the treatment period in different scenarios; Week 6 period refers to the full study period.
2.3.1.
All Randomized Analysis Set
The all randomized analysis set includes all subjects who were randomized in the study
regardless of whether they took study drug.
2.3.2.
Intent-to-treat Analysis Set
The Intent-to-treat (ITT) (as termed Full Analysis Set [FAS] in the International Conference on 
Harmonization [ICH] E9 guideline) analysis set includes all randomized subjects who have 
signed an informed consent form.
2.3.3.
Efficacy Analysis Sets
2.3.3.1.
Primary Efficacy Analysis Set
The modified Intent-to-treat (mITT) analysis set includes all ITT subjects who received at least 1 
dose of study drug with an evaluable venography assessment or a confirmed symptomatic VTE 
event or any death as adjudicated by CEC. This will be identified as mITT (CEC).
Evaluable venography assessment at Day 14 is defined as the venography assessment with an 
evaluable result of the leg between Day 8 and Day 17. Subjects with unevaluable venography 
result as deemed by the CEC will be excluded from the primary efficacy analysis set mITT
(CEC).
Primary efficacy analysis is based on the mITT analysis set associated with Day 14 analysis 
period.


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In addition, the following distinctions will be implemented in data summary outputs whenever
needed.
!
Modified intent-to-treat analysis set (mITT) (Investigator) will be associated with 
investigator reported results.
!
Modified intent-to-treat analysis set (mITT) (Best available) will be associated with the best
available results, where best available event is defined as follows:
o
If an event is CEC adjudicated, then best available event is the CEC adjudicated 
event.
o
Otherwise, if an event is not CEC adjudicated, then best available event is the
investigator reported event.
The mITT (Best available) analysis set will only be applicable to the interim analyses and the 
planned periodic reviews. At the time of database lock at the end of the study, all CEC 
adjudication of events will be completed. Hence, after the database lock, the mITT (Best 
available) analysis set will be identical to the mITT (CEC) analysis set.
2.3.3.2.
Secondary Efficacy Analysis Sets
The mITT analysis set at Week 6 is defined as the mITT analysis set at Day 14 plus the subjects 
who had no evaluable venography results at Day 14 visit but had symptomatic events or had 
evaluable venography results after Day 14 visit. The efficacy analysis based on this analysis set 
is associated with the Week 6 analysis period.
Per Protocol (PP) analysis set includes all mITT subjects with no key protocol deviations. Key
protocol deviations are defined as follows,
!
Developed withdrawal criteria but not withdrawn
!
Randomized but did not satisfy key criteria
!
Received a disallowed concomitant treatment
!
Received study drug which is different from the treatment group randomized by the IWRS 
or an incorrect dose of study drug
!
Was randomized but did not receive study drug
Key criteria are specified in the major protocol deviation document (TV-FRM-04718).
2.3.4.
Safety Analysis Set
The safety analysis set includes all ITT subjects who received at least 1 dose (partial or 
complete) of study drug.
2.3.5.
Pharmacokinetics Analysis Set
The PK analysis set consists of subjects who have received at least 1 dose of JNJ-70033093 and 
have at least one valid blood sample drawn for PK analysis.


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2.3.6.
Pharmacodynamics Analysis Set
The PD analysis set is defined as subjects who have received at least 1 dose of study drug and at 
least one valid blood sample drawn for PD analysis.
2.4.
Definition of Subgroups
The following subgroups (see Table 2) will be used to summarize the total VTE efficacy and any 
bleeding event data.
Table 2:
Definition of Subgroups
Subgroup
Variant
Definition
Region
!
Western Europe (Belgium, Greece, Israel, Italy, Portugal, South Africa, Spain)
!
Eastern Europe (Bulgaria, Hungary, Lithuania, Latvia, Poland, Russia, 
Turkey, Ukraine)
!
APAC (Asia Pacific: Australia, Japan, Malaysia, Thailand)
!
LATAM (Latin America: Argentina, Brazil, Mexico)
!
NA (North America: Canada and USA)
Age Group
!
50 - <65 years
!
65 - <75 years
!
≥75 years
Sex
!
Female
!
Male
Race
!
White
!
Asian
!
African American
!
Others
BMI
!
underweight <18.5 kg/m2
!
normal 18.5-<25 kg/m2
!
overweight 25-<30 kg/m2
!
obese ≥30 kg/m2
D-Dimer
!
≥2X ULN*
!
< 2X ULN*
Renal function (Creatinine 
Clearance Level) 
!
30-<50 ml/min
!
50-<80 ml/min
!
≥80 ml/min
Surgery duration
!
< 2 hours
!
≥2 hours
Tourniquet use
!
Yes
!
No
Aspirin/nonsteroidal anti-
inflammatory drugs at 
baseline
!
Yes
!
No
*ULN = upper limit of normal
2.5.
Study Day and Relative Day
Day 1 refers to the date of the first dose of study drug administration or the surgery date if the 
subject didn’t take any study drug. All efficacy and safety assessments at all visits will be 
assigned a day relative to this date.


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Study day or relative day for a visit is defined as:
!
Visit date - date of Day 1 + 1, if visit date ≥date of Day 1
!
Visit date - date of Day 1, if visit date < date of Day 1.
There is no 'Day 0'.
The last contact date is defined as the maximum of the following dates,
!
Dates of all study-related visits (including scheduled or unscheduled visits);
!
Dates of all study-related procedures, findings and events, including, but not limited to AE, 
concomitant medications, disposition, clinical laboratories, and death.
2.6.
Baseline and Endpoint
Baseline is defined as the last observation prior to the first dose of study drug or the surgery if no 
study drug is taken.
Endpoint is defined as the available postbaseline result within the analysis period. Unscheduled 
visit results are included in this definition.
2.7.
Imputation Rules for Missing Date/Time
Partial (missing) first dose (postoperative) date will be imputed as follows:
!
If the partial date is missing day only, it will be set to:
o
First day of the month of the partial date, if month/year of the partial date is 
different than the month/year of the surgery day;
o
The surgery day if the month/year of the partial date is the same as the month/year 
of the surgery day.
!
If the partial date is missing both day and month, it will be set to:
o
January 1 of the year of the partial date, if the year of this date is after the year of
the surgery day;
o
The surgery day, if the partial date is the same year of the surgery day.
Completely missing first dose (postoperative) dates will not be imputed for the safety population.
Partial last dose date will be imputed as follows: 
!
If the partial last dose date is missing day only, it will be set to the earliest of 
o
the last day of the month of the partial last dose date;
o
the surgery day + 14 days;
o
the evaluable venography day.
!
If the partial last dose date is missing both day and month, it will be set to the earliest of 
o
December 31 of the year of the partial last dose date;


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o
the surgery day + 14 days;
o
the evaluable venography day.
!
Completely missing last dose dates will not be imputed for the safety population.
Partial AE onset dates will be imputed as follows:
!
If the onset date of an AE is missing day only, it will be set to:
o
First day of the month that the AE occurred, if month/year of the onset of AE is 
different than the month/year of the first dose date;
o
The first dose date, if the month/year of the onset of AE is the same as month/year 
of the first dose date and month/year of the AE resolution date is different;
o
The first dose date or the day of AE resolution date, whichever is earliest, if 
month/year of the onset of AE and month/year of the first dose date and month/year 
of the AE resolution date are same;
!
If the onset date of an AE is missing both day and month, it will be set to, but no later than 
the AE resolution date:
o
January 1 of the year of onset date, as long as this date is on or after the first dose 
date;
o
Month and day of the first dose date, if this date is the same year that the AE 
occurred;
o
Last day of the year if the year of the AE onset is prior to the year of the first dose
date;
!
Completely missing onset dates will not be imputed.
Partial AE resolution dates not marked as ongoing will be imputed as follows:
!
If the resolution date of an AE is missing day only, it will be set to the earliest of the last day 
of the month of occurrence of resolution or the day of the date of death, if the death occurred 
in that month;
!
If the resolution date of an AE is missing both day and month, it will be set to the earliest of 
December 31 of the year or the day and month of the date of death, if the death occurred in 
that year.
!
Completely missing resolution dates will not be imputed.
Missing times of AE onset/resolution dates will be imputed as follows:
!
A missing time of onset of an AE will be set to the earlier of:
o
00:01 as long as the date is after Day 1;
o
The time of the first dose or the time of surgery for untreated subjects if this is the 
same day of Day 1.


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If a missing time is associated with a partial or missing date, the date will be imputed prior to 
imputing the time.
3.
PERIODIC AND INTERIM ANALYSES 
The OC will be responsible for reviewing ongoing safety and efficacy data by unblinded subject 
treatment assignments approximately 3 to 8 weeks on a periodic basis. The first interim analysis 
will be triggered when approximately 300 subjects (approximately 50 subjects in each of the 
JNJ-70033093 BID treatment groups) will have completed the venography or have had a 
symptomatic VTE event. Additional interim analyses will be conducted, as needed, at the 
discretion of the OC.
Both periodic reviews and interim analyses will require an independent Statistical Support Group 
(SSG). Details of the operation of the OC are provided in the OC Charter. There will be no 
separate OC SAP.
3.1.
Interim Analyses
The unblinded interim analyses will be conducted by the OC as part of the adaptive approach 
that may be used to guide decisions to drop a dose of JNJ-70033093, and/or adjust the 
randomization ratio based on available efficacy and safety 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. Note, it is not intended that the study will stop early due to 
statistically significant dose-response trend
!
Determine if a dose 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. 
Subjects randomization will be balanced in the active dose groups until the first OC committee 
review. Regarding adaptation guidelines, including futility, adding/dropping a dose, modification 
of the randomization ratio, see Section 7 of the OC Charter.
The first interim analysis will be triggered when approximately 300 subjects (approximately 
50 subjects in each of the JNJ-70033093 BID treatment groups) will have completed the 
venography or have had a symptomatic VTE event. Before the first interim analysis OC 
meeting, a data cut-off date will be identified, and data cleaning efforts will be intensified in 
preparation for the creation of analysis data sets. The study programming team will transfer the 
blinded data to the SSG, and the IWRS vendor (Bracket) will transfer the randomization code to 
Secure Data Supplier (SDS). The SSG will then obtain the treatment assignment dataset from the 
SDS prior to the interim analysis and the unblinded report will be provided to the OC.


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Additional interim analyses will be conducted, as needed, at the discretion of the OC. These 
decisions will be made only after taking the safety and efficacy profiles of JNJ-70033093 into 
account.
The significance level will not be adjusted for the final analysis.
4.
SUBJECT INFORMATION
The number of subjects in each analysis set will be summarized and listed by separate treatment 
groups, combined active treatment groups and overall group. In addition, the distribution of 
subjects by region, country, and site ID will be presented unless otherwise noted.
4.1.
Demographics and Baseline Characteristics
Table 3 presents a list of the demographic variables and baseline characteristics that will be 
summarized for the ITT, mITT, PP and safety analysis sets. 
Table 3:
Demographic Variables and Baseline Characteristics
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (total number 
[N], mean, standard deviation 
[SD]).
Weight (kg)
Height (cm)
Body Mass Index (BMI) (kg/m2)
Categorical Variables
Age (50 - <65 years, 65 - <75 years and ≥75 years)
Frequency distribution with the 
number and percentage of subjects 
in each category.
Sex (male, female)
Racea (White, Asian, African American and others)
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
BMI (underweight <18.5 kg/m2, normal 18.5-<25 kg/m2, overweight 25-
<30 kg/m2, obese ≥30 kg/m2)
Renal function (CrClb 30-<50 ml/min, 50-<80 ml/min, ≥80 ml/min)
D-Dimer (≥2X ULNc, < 2X ULN)
Surgery duration (< 2 hours, ≥2 hours)
Tourniquet use (Yes, No)
Aspirin/nonsteroidal anti-inflammatory drugs at baseline (Yes, No)
Reason for surgery (Osteoarthritis, Rheumatoid arthritis, Osteonecrosis 
and Other)
a If multiple race categories are indicated, the Race is recorded as 'Multiple'
b CrCl = creatinine clearance. cULN = upper limit of normal
4.2.
Disposition Information
Screened subjects and reason for screen failures will be summarized.
The number of subjects in the following disposition categories will be summarized throughout 
the study:
!
Subjects randomized
!
Subjects randomized signing informed consent forms


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!
Subjects received study drug
!
Subjects completed the study
!
Subjects who prematurely discontinued study drug
!
Subjects who completed study drug
!
Reasons for discontinuation of study drug
!
Subjects who terminated study prematurely
!
Reasons for termination of study
Listings of subjects will be provided for the following categories:
!
Subjects who prematurely discontinued study drug
!
Subjects who terminated study prematurely
!
Subjects who were unblinded to the dose level during the study period
!
Subjects who were randomized yet did not receive study drug.
4.3.
Treatment Compliance
Study drug compliance rate (%) will be calculated as: 100 * the actual number of days of study 
drug taken / the supposed number of days of study drug taken. More specifically, the actual 
number of days of study drug taken will be calculated as the minimum of [Day 10 date, last dose 
date, and the first primary efficacy outcome date] – first dose date + 1 – dose interruption days 
up to day 10. The supposed number of days of study drug taken will be calculated as the
minimum of [day 10 date, and the first primary efficacy outcome date] - first dose date + 1.
Study drug compliance will be summarized descriptively. 
4.4.
Extent of Exposure
The number and percentage of subjects who receive study drug will be summarized. Descriptive 
statistics (N, mean, SD) for study drug duration will be presented for the safety analysis set. 
4.5.
Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
subjects’ rights, safety or well-being, or the integrity and/or result of the clinical study. Subjects 
with major protocol deviations will be identified prior to database lock and the subjects with 
major protocol deviations will be summarized by category.
!
Developed withdrawal criteria but not withdrawn
!
Randomized but did not satisfy criteria
!
Received a disallowed concomitant treatment
!
Received wrong treatment or incorrect dose


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!
Others
4.6.
Prior and Concomitant Medications
Prior and Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). Prior medications are defined as any therapy used before Day 1. 
Concomitant medications are defined as any therapy used with a period overlapping with the 
period between the first dose and last dose of study drug, including those that started before and 
continued after the first dose of study drug.
Summaries of concomitant medications will be presented by anatomic and therapeutic class
(ATC) term. The proportion of subjects who receive each concomitant medication will be 
summarized as well as the proportion of subjects who receive at least 1 concomitant medication. 
In addition, concomitant medications of special interest will be presented (see Attachment 1).
Prior medications will be summarized by ATC term.
5.
EFFICACY
5.1.
Analysis Specifications
5.1.1.
Level of Significance
The primary hypothesis is that JNJ-70033093 reduces the risk of total VTE during the treatment 
period. This can be achieved by showing either a statistically significant dose-response trend 
(1-sided 5% significance level) or an event rate for the combined BID groups of JNJ-70033093 
that is statistically lower than 30% (1-sided 5% significance level). The family wise error rate 
will be controlled at 1-sided 10%.
5.1.2.
Data Handling Rules
Unless otherwise stated, all efficacy analyses and summaries will be performed using the 
treatment groups assigned by IWRS.
5.2.
Primary Efficacy Endpoint(s)
The primary efficacy endpoint is the total VTE, which is a composite of the proximal DVT
(asymptomatic or symptomatic), distal DVT (asymptomatic or symptomatic), non-fatal PE and 
death.
5.2.1.
Analysis Methods
The primary hypothesis, as defined in Section 5.1.1., will be tested with its two components, 
respectively. The first component, the total VTE event rate lower than 30% in the combined BID 
doses of JNJ-70033093 in the mITT analysis set and Day 14 analysis period, will be tested at a
1-sided 5% significance level. In other words, the following hypothesis will be tested:
: 	
  
	 ≥0.3 Versus : 	
  
	 < 0.3
Binomial test will be employed to test the hypothesis.


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The second component, the dose-response trend test based on the MCP-Mod1 framework, will 
consist of contrast tests defined by prespecified candidate models (4 Emax dose-response models 
with varying degrees of ED50, Figure 2), which provide estimates of dose-response (taking BID 
and once daily into consideration). 
The MCP-Mod framework determines a set of optimal model contrasts. Each model will then be 
evaluated for significance of trend, based on its optimal contrast, resulting in four t-test statistics, 
one for each candidate model. The t-test statistics will have been adjusted for the fact that 
multiple candidate models (four) have been included in the trend testing. The efficacy of the drug 
is then established if the maximum of the t-test statistics exceeds the 95th percentile critical value
(one-sided significance level 5%).
Figure 2:
Canonical Candidate Emax Dose-response Models Used in the MCP-Mod Analysis
5.3.
Major Secondary Efficacy Endpoints
Major secondary efficacy endpoints include all individual components of the primary efficacy 
endpoint
!
Proximal DVT
o
Asymptomatic
o
Symptomatic
!
Distal DVT


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o
Asymptomatic
o
Symptomatic
!
Nonfatal PE
!
Any death
!
Major VTE
o
Proximal DVT
o
Nonfatal PE
o
Any death
5.3.1.
Analysis Methods
For the major secondary efficacy endpoints, event rate (incidence) of the total VTE and the 
individual components in the Day 14 period and the Week 6 period will be summarized by 
treatment group for the mITT analysis set. The 95% confidence intervals for the relative risk 
ratio (RR) of each JNJ-70033093 dose group compared with enoxaparin group will also be 
constructed. The relative risk ratios (RR) and their corresponding confidence intervals will be 
calculated using Cochran-Mantel-Haenszel method2,3 with region as a stratification factor. 
Additional sensitivity analyses may be explored in ITT, PP, safety population, and/or a subset of 
the ITT population consisting of subjects with a valid assessment of potential efficacy outcome within
Day 14 and/or Week 6 analysis periods.
5.4.
Exploratory Efficacy Variable(s)
5.4.1.
Definition
The exploratory efficacy variables are defined as
!
To evaluate PD to assess its relationships to PK and the relation of these measures to 
efficacy and safety endpoints (e.g., exposure-response analyses);
!
To evaluate exploratory biomarkers to assess their relationship to the probability of total 
VTE during the treatment period;
!
To explore the presence and incidence of asymptomatic MINS as it relates to total knee 
arthroplasty.
5.4.2.
Analysis Methods
The analysis method for the exploratory efficacy variables will be detailed in separate PK and/or 
PD analysis documents.
6.
SAFETY
All safety analyses will be based on the safety analysis set of actual treatment received, unless 
otherwise specified.


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For all continuous safety variables, descriptive statistics will include N, mean and SD. 
Categorical variables will be summarized using frequency counts and percentages.
6.1.
Principal Safety (Bleeding) Endpoint
The principal safety endpoint is any bleeding event, as adjudicated by CEC, which is defined as 
the composite of major bleeding, clinically relevant non-major (CRNM) bleeding, and minimal 
bleeding events. Major bleeding refers to the ISTH major bleeding in the surgical setting.
6.1.1.
Principal Safety (Bleeding) Analysis Methods
The analysis for safety (bleeding) events has two parts. The first part will focus on the event rate 
(incidence) within specified study period, which will be implemented by comparing the event 
rate of each study drug group with the event rate in the enoxaparin group. The analysis method 
will be the same as the method for major secondary efficacy analysis. Please refer to Section 
5.3.1 for details.
The second part of the analysis will be the analysis of time-to-event data. Specifically, analyses 
based on Kaplan-Meier (K-M) estimates4 of time from day 1 to the first occurrence of any 
bleeding event (composite of major, CRNM and minimal bleeding events) will be implemented
for each JNJ-70033093 dose group and enoxaparin over the on-treatment period and the Week 6
period.
For the time-to-event analyses, subjects who do not experience any bleeding event during the on-
treatment period will be censored at the earliest of the last dose date + 2 days, death date or the 
last contact date. Similarly, subjects who do not experience any bleeding event during the Week 
6 period will be censored at week 6 + 10 days, death date or the last contact date, whichever 
occurs first.
Frequency distribution of per subject total number of bleeding events will be summarized by 
dose group using the counts 0, 1, 2 and ≥3.
Sensitivity analyses of bleeding reported by the investigator and/or by comparing the CEC 
adjudicated event rates in the postoperative period may be presented. Concordance of events 
between CEC and investigator reported may also be assessed.
Estimation of dose-response relationship in any bleeding will also be assessed by MCP-Mod 
approach.
6.2.
Major Secondary Safety (Bleeding) Endpoints
Major secondary safety (bleeding) endpoints include the following components of the principal 
safety endpoint,
!
Major bleeding,
!
Clinically relevant non-major bleeding,
!
Clinically relevant bleeding, including both major and non-major,


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!
Minimal bleeding
6.2.1.
Major Secondary Safety (Bleeding) Endpoints Analysis Methods
The statistical analysis method for the major secondary safety (bleeding) endpoints will be 
similar to the analysis method for the principal safety endpoint. See Section 6.1.1. for details.  
6.3.
Adverse Event
The verbatim terms used in the eCRF by investigators to identify an AE will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the initial 
administration of study drug through the day of last dose plus 2 days is considered as treatment
emergent. If the event occurs on the day of the initial administration of study drug, and either 
event time or time of administration are missing, then the event will be assumed to be treatment
emergent. If the event date is recorded as partial or completely missing, then the event will be 
considered as treatment emergent unless it is known to be prior to the first administration of 
study drug based on the partial date. All reported treatment emergent adverse events (TEAE) will 
be included in the analysis. For each AE, the number and percentage of subjects who experience 
at least 1 occurrence of the given event will be summarized by treatment group. 
Summary tables will be provided for:
!
All AEs, TEAEs, AEs occurred 2 days after the last dose date, and AEs after the first dose 
date.
!
All SAEs, treatment emergent serious adverse events (TESAEs), and SAEs occurred 2 days 
after the last dose date, and SAEs after the first dose date.
!
AEs leading to discontinuation of study drug 
!
TEAEs by severity
Incidence of other TEAEs of interest will be summarized.
As per protocol, AEs of interest include bleeding events, wound or joint complications, liver 
enzyme elevations and clinical liver events. All suspected thrombotic events will also be 
captured as AEs of interest. Subjects with AEs of interest may be counted or listed using 
MedDRA SMQs (e.g., hemorrhage excluding laboratory terms SMQ).
Deaths will be displayed by actual treatment received. Frequencies for the following parameters 
will be included in the summary table:
!
Number of subjects who died
!
Cause of death
!
Relationship to study agent (yes/no)
!
A listing of subjects who died.


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6.4.
Clinical Laboratory Tests
Clinical laboratory tests will be displayed for the subjects included in the safety analysis set.
Descriptive statistics will be presented for chemistry, hematology and specific components of 
urinalysis laboratory tests at scheduled time points.
Changes from baseline to scheduled time points will be summarized for chemistry, hematology 
and specific components of urinalysis tests and displayed by treatment group.
Number and percentage of subjects with postbaseline clinically important laboratory values 
and/or markedly abnormal postbaseline values will be presented by treatment group.
Clinically important abnormal laboratory findings to be reported are described below:
!
ALT and/or AST (U/L): ≥3x ULN.
!
Markedly abnormal laboratory findings to be reported are described below:
!
ALT and/or AST (U/L) ≥5x ULN
!
ALT and/or AST (U/L) ≥10x ULN
!
Hemoglobin < 80g/L
!
Platelet < 50,000/uL
A listing of clinically important and/or markedly abnormal laboratory values will be provided.
6.5.
Vital Signs 
Vital signs measurements are not being collected in this study.
7.
PHARMACOKINETICS/PHARMACODYNAMICS
7.1.
Pharmacokinetics
PK analyses will be performed on the PK analysis set, defined as subjects who have received at 
least 1 dose of JNJ-70033093 and have at least 1 valid blood sample drawn for PK analysis.
Descriptive statistics (N, mean, SD, median, range, Coefficient of Variation [CV %] and IQ 
range) will be used to summarize JNJ-70033093 plasma concentrations at each nominal
sampling time point by treatment. 
JNJ-70033093 plasma concentrations below the lower limit of quantitation will not be imputed
and will be noted in the summary statistics. All subjects and samples excluded from the analysis 
will be clearly documented.
Population PK analysis using plasma concentration-time data of JNJ-70033093 will be 
performed using nonlinear mixed-effects modeling. Details will be given in a separate population 
PK analysis plan and the results of the analysis (including the exposure-response analyses) will
be presented in a separate report.


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7.2.
Pharmacodynamics
PD analyses will be performed on the PD analysis set, defined as subjects who have at least one 
valid blood sample drawn for PD.
Descriptive statistics (N, mean, SD, median, range, CV (%) and IQ range) will be used to 
summarize PD response at each nominal sampling time point by treatment group. Changes from 
baseline will be summarized when applicable. 
PD response outside of limit of quantitation will not be imputed and will be noted in the 
summary statistics.
7.3.
Pharmacokinetic/Pharmacodynamic Relationships
Relationships between PD (including aPTT, PT, FXI clotting activity, anti-FXa activity, and 
TGA) and PK will be evaluated. The relationship between PK and efficacy, as well as between
PK and safety endpoints (e.g., exposure-response analyses) will also be evaluated. These 
analyses will be outlined in a separate population PK analysis plan and reported in a separate 
population PK report.
8.
BIOMARKERS
Descriptive statistics (N, mean, SD, median, range, CV (%) and IQ range) will be used to 
summarize exploratory biomarker response (including D dimer, high-sensitive cardiac troponin 
T [hs-cTnT], and FXI antigen) at each nominal sampling time point by treatment group. 
Changes from baseline will be summarized when applicable. 


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REFERENCES
1.
Pinheiro JC, Bornkamp B, Glimm E, Bretz F. 2014. “Model-based dose findings under model uncertainty 
using general parametric models.” Statistics in Medicine. 33:1646-1661.
2.
Cochran, William G. 1954. “Some Methods for Strengthening the Common Chi-Squared Tests.” Biometrics 10 
(4). [Wiley, International Biometric Society]: 417–51.
3.
Mantel, N., and W. Haenszel. 1959. “Statistical Aspects of the Analysis of Data from Retrospective Studies of 
Disease.” Journal of the National Cancer Institute 22 (4): 719–48.
4.
Kaplan, E. L., and Paul Meier. “Nonparametric Estimation from Incomplete Observations.” Journal of the 
American Statistical Association 53, no. 282 (1958): 457–81.


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ATTACHMENTS
Attachment 1: Medications of Special Interest
Concomitant medications of special interest are defined as follows:
Concomitant 
Medication Special 
Interest Category
Standard ATC Group 
Name
ATC Group 
Code
Standard Medication 
Name
ATC code
ANTITHROMBOTIC 
AGENTS
Heparin group
B01AB
heparin
B01AB01
antithrombin III
B01AB02
dalteparin
B01AB04
enoxaparin
B01AB05
nadroparin
B01AB06
parnaparin
B01AB07
reviparin
B01AB08
danaparoid
B01AB09
tinzaparin
B01AB10
sulodexide
B01AB11
bemiparin
B01AB12
Platelet aggregation 
inhibitors excl. heparin
B01AC
clopidogrel
B01AC04
ticlopidine
B01AC05
acetylsalicylic acid
B01AC06
dipyridamole
B01AC07
carbasalate calcium
B01AC08
iloprost
B01AC11
abciximab
B01AC13
eptifibatide
B01AC16
tirofiban
B01AC17
treprostinil
B01AC21
prasugrel
B01AC22
cilostazol
B01AC23
ticagrelor
B01AC24
cangrelor
B01AC25
Enzymes
B01AD
streptokinase
B01AD01
alteplase
B01AD02
anistreplase
B01AD03
urokinase
B01AD04
reteplase
B01AD07
drotrecogin alfa 
(activated)
B01AD10
tenecteplase
B01AD10
Direct thrombin inhibitors
B01AE
desirudin
B01AE01
lepirudin
B01AE02
argatroban
B01AE03
melagatran
B01AE04


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Status: Approved, Date: 26 September 2019
Concomitant 
Medication Special 
Interest Category
Standard ATC Group 
Name
ATC Group 
Code
Standard Medication 
Name
ATC code
ximelagatran
B01AE05
bivalirudin
B01AE06
dabigatran etexilate
B01AE07
Direct factor Xa 
inhibitors
B01AF
rivaroxaban
B01AF01
apixaban
B01AF02
edoxaban
B01AF03
Other antithrombotic 
agents
B01AX
defibrotide
B01AX01
fondaparinux
B01AX05
VITAMIN K AND 
OTHER 
HEMOSTATICS
Local hemostatics
B02BC
thrombin
B02BC06
ANTIFIBRINOLYTIC
S
Amino acids
B02AA
tranexamic acid
B02AA02
aminocaproic acid
B02AA01
NASAL 
DECONGESTANTS 
FOR SYSTEMIC USE
Sympathomimetics
R01BA
phenylpropanolamine
R01BA01
pseudoephedrine
R01BA02
phenylephrine
R01BA03
phenylpropanolamine, 
combinations
R01BA51
pseudoephedrine, 
combinations
R01BA52
OTHER 
ANALGESICS AND 
ANTIPYRETICS
Salicylic acid and 
derivatives
N02BA
carbasalate calcium
N02BA15
carbasalate calcium 
combinations excl. 
psycholeptics
N02BA65
INTESTINAL 
ANTIINFLAMMATO
RY AGENTS
Aminosalicylic acid and 
similar agents
A07EC
sulfasalazine
A07EC01
ANTIINFLAMMATO
RY AND 
ANTIRHEUMATIC 
PRODUCTS
ANTIINFLAMMATORY 
AND 
ANTIRHEUMATIC 
PRODUCTS, NON-
STEROIDS
M01A
Butylpyrazolidines
M01AA
Acetic acid derivatives 
and related substances
M01AB
Oxicams
M01AC
Propionic acid 
derivatives
M01AE


JNJ-70033093
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Status: Approved, Date: 26 September 2019
Concomitant 
Medication Special 
Interest Category
Standard ATC Group 
Name
ATC Group 
Code
Standard Medication 
Name
ATC code
Fenamates
M01AG
Coxibs
M01AH
Other 
antiinflammatory and 
antirheumatic agents, 
non-steroids
M01AX
ANTIINFLAMMATORY
/ANTIRHEUMATIC 
AGENTS IN 
COMBINATION
M01B
Antiinflammatory/anti
rheumatic agents in 
combination with 
corticosteroids
M01BA
Other 
antiinflammatory/antir
heumatic agents in 
combination with 
other drugs
M01BX