Clinical trial NCT02846532
Conditions: Thrombosis
Keywords: Thromboembolism Fontan Procedure Children
Sponsor: Janssen Research & Development, LLC
Start date: 2016-11-16; Completion date: 2020-07-16
Enrollment: 112 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The Purpose of this study is to characterize the single and multiple-dose pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/ PD) profiles after oral rivaroxaban therapy administered to pediatric participants 2 to 8 years of age with single ventricle physiology who have completed the Fontan procedure within 4 months prior to enrollment (Part A) and to evaluate the safety and efficacy of rivaroxaban, administered twice daily (exposure matched to rivaroxaban 10 milligram \[mg\] once daily in adults) compared to acetylsalicylic acid (ASA), given once daily (approximately 5 milligram per kilogram \[mg/kg\]) for thromboprophylaxis in pediatric participants 2 to 8 years of age with single ventricle physiology who have completed the Fontan procedure within 4 months prior to enrollment.

Detailed description:
Part A: This part includes a 12-day Initial PK, PD, and Safety Assessment Period. Participants in Part A will not participate in Part B. Randomization in Part B of this study will begin once the cumulative data from the Initial PK, PD, and Safety Assessment Period in Part A are deemed acceptable by the Independent Data Monitoring Committee. Part A of the study will consist of an up to 21-day Screening Period, a 12-day Initial PK, PD, and Safety Assessment Period, a 12-month Open-Label Treatment Period, and a 30-day Follow-Up phone contact. Part B: Participants will be randomly assigned to two treatment groups and randomization ratio will be 2:1 for rivaroxaban and ASA. ASA will be used as control. There will be an up to a 21-day Screening Period, a 12 month Open-Label Treatment Period and a 30-day Follow-Up phone contact.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Rivaroxaban intervention 2: Acetylsalicylic Acid
Intervention descriptions: intervention 1: Participants will receive oral suspension containing rivaroxaban 1 milligram per milliliter (mg/ml) twice daily in Part A and Part B. Following total daily doses of Rivaroxaban will be administered based on the weight of the participants: 7 to \<8 kilogram (kg) will receive 2.2 milligram (mg); 8 to \<10 kg will receive 3.2 mg; 10 to\<12 kg will receive 3.4 mg; 12 to \<20 will receive 4.0 mg and 20 to \<30 will receive 5.0 mg. intervention 2: Participants will receive 5 milligram per kilogram (mg/kg) of acetylsalicylic acid once daily up to 12 months in Part B.

Protocol documents:
Prot_000.pdf: 
1
Status: Approved,  Date: 27 July 2017
Janssen Research & Development *
Clinical Protocol
A Prospective, Open-Label, Active-Controlled Study to Evaluate the Pharmacokinetics, 
Pharmacodynamics, Safety, and Efficacy of Rivaroxaban for Thromboprophylaxis in 
Pediatric Subjects 2 to 8 Years of Age after the Fontan Procedure
UNIVERSE Study
Protocol 39039039CHD3001; Phase 3
BAY59-7939/18226
Amendment INT-2
JNJ-39039039; BAY 59-7939   (rivaroxaban)
*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 Infectious Diseases BVBA; Janssen 
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout 
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information 
page that accompanies the protocol.  
This compound is approved in adults for marketing in 6 indications in the United States and 
7 indications in the European Union.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER:         2015-002610-76
Status:
Approved
Date:
27 July 2017
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-99005906, 5.0
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.
NCT02846532


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 4
PROTOCOL AMENDMENTS....................................................................................................................... 5
SYNOPSIS.................................................................................................................................................... 8
TIME AND EVENTS SCHEDULE .............................................................................................................. 16
ABBREVIATIONS ...................................................................................................................................... 20
1.
INTRODUCTION................................................................................................................................ 21
1.1.
Background .................................................................................................................................... 21
1.1.1.
Pediatric Patients with Single Ventricle Physiology – The Fontan Procedure - Scope of 
the Problem ................................................................................................................................ 21
1.1.2.
Human Pharmacokinetics in Adults............................................................................................ 22
1.1.3.
Efficacy and Safety Profile Based on Adult Clinical Studies ...................................................... 22
1.1.4.
Physiology-Based Pharmacokinetics ......................................................................................... 23
1.1.5.
Efficacy and Safety Profile Based on Pediatric Clinical Studies................................................. 24
1.2.
Comparator Agent.......................................................................................................................... 25
1.3.
Overall Rationale for the Study...................................................................................................... 25
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 27
2.1.
Objectives ...................................................................................................................................... 27
2.2.
Hypothesis ..................................................................................................................................... 27
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 27
3.1.
Overview of Study Design.............................................................................................................. 27
3.2.
Study Design Rationale.................................................................................................................. 31
4.
SUBJECT POPULATION.................................................................................................................. 33
4.1.
Inclusion Criteria ............................................................................................................................ 33
4.2.
Exclusion Criteria ........................................................................................................................... 34
4.3.
Prohibitions and Restrictions ......................................................................................................... 36
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 36
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 36
7.
TREATMENT COMPLIANCE............................................................................................................ 38
8.
PRESTUDY, CONCOMITANT AND POSTSTUDY THERAPY ........................................................ 38
9.
STUDY EVALUATIONS .................................................................................................................... 40
9.1.
Study Procedures........................................................................................................................... 40
9.1.1.
Overview..................................................................................................................................... 40
9.1.2.
Screening Period ........................................................................................................................ 40
9.1.3.
Open-label Treatment Period ..................................................................................................... 41
9.1.3.1.
Part A....................................................................................................................................... 41
9.1.3.2.
Part B....................................................................................................................................... 42
9.1.4.
Unscheduled Visits ..................................................................................................................... 43
9.1.5.
Posttreatment Period (Follow-Up Contact)................................................................................. 43
9.1.6.
Transthoracic Echocardiograms................................................................................................. 44
9.2.
Pharmacokinetics/Pharmacodynamics Evaluations ...................................................................... 44


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9.3.
Safety Evaluations/Outcomes........................................................................................................ 47
9.3.1.
Bleeding Events.......................................................................................................................... 47
9.3.2.
Approach to the Subject with a Bleeding Event ......................................................................... 47
9.3.3.
Other Safety Assessments ......................................................................................................... 48
9.4.
Efficacy Evaluations/Outcomes ..................................................................................................... 50
9.5.
Sample Collection and Handling.................................................................................................... 50
9.6.
Study Booklet................................................................................................................................. 51
9.7.
Committees .................................................................................................................................... 51
9.7.1.
Executive Committee.................................................................................................................. 51
9.7.2.
Independent Data Monitoring Committee................................................................................... 51
9.7.3.
Data Review Committee............................................................................................................. 51
9.7.4.
Central Independent Adjudication Committee............................................................................ 52
9.7.5.
Steering Committee.................................................................................................................... 52
9.7.6.
Sponsor Committee.................................................................................................................... 52
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 52
10.1.
Completion ..................................................................................................................................... 52
10.2.
Discontinuation of Study Drug ....................................................................................................... 52
10.2.1.
Temporary Discontinuation of Study Drug.................................................................................. 53
10.2.2.
Permanent Discontinuation of Study Drug ................................................................................. 53
10.3.
Withdrawal from the Study............................................................................................................. 54
11.
STATISTICAL METHODS................................................................................................................. 55
11.1.
Analysis Populations and Periods.................................................................................................. 55
11.1.1.
Subject Information..................................................................................................................... 55
11.1.2.
Analysis Sets .............................................................................................................................. 55
11.1.3.
Analysis Periods ......................................................................................................................... 56
11.2.
Sample Size Determination ........................................................................................................... 56
11.3.
Pharmacokinetics/Pharmacodynamics Analyses .......................................................................... 56
11.4.
Safety Analyses ............................................................................................................................. 56
11.5.
Efficacy Analysis ............................................................................................................................ 57
12.
ADVERSE EVENT REPORTING ...................................................................................................... 58
12.1.
Definitions ...................................................................................................................................... 58
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 58
12.1.2.
Attribution Definitions.................................................................................................................. 59
12.1.3.
Severity Criteria .......................................................................................................................... 60
12.2.
Special Reporting Situations.......................................................................................................... 60
12.3.
Procedures..................................................................................................................................... 61
12.3.1.
All Adverse Events...................................................................................................................... 61
12.3.2.
Serious Adverse Events ............................................................................................................. 62
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 63
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 63
13.1.
Procedures..................................................................................................................................... 64
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 64
14.
STUDY DRUG INFORMATION......................................................................................................... 64
14.1.
Physical Description of Study Drug(s) ........................................................................................... 64
14.2.
Packaging ...................................................................................................................................... 64
14.3.
Labeling.......................................................................................................................................... 64
14.4.
Preparation, Handling, and Storage............................................................................................... 64
14.5.
Drug Accountability ........................................................................................................................ 65
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 65
16.
ETHICAL ASPECTS ......................................................................................................................... 66
16.1.
Study-Specific Design Considerations........................................................................................... 66
16.2.
Regulatory Ethics Compliance....................................................................................................... 68


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16.2.1.
Investigator Responsibilities ....................................................................................................... 68
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 68
16.2.3.
Informed Consent/Assent ........................................................................................................... 70
16.2.4.
Privacy of Personal Data ............................................................................................................ 71
16.2.5.
Country Selection ....................................................................................................................... 71
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 71
17.1.
Protocol Amendments.................................................................................................................... 71
17.2.
Regulatory Documentation ............................................................................................................ 72
17.2.1.
Regulatory Approval/Notification ................................................................................................ 72
17.2.2.
Required Prestudy Documentation............................................................................................. 72
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 73
17.4.
Source Documentation................................................................................................................... 73
17.5.
Case Report Form Completion ...................................................................................................... 74
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 75
17.7.
Record Retention ........................................................................................................................... 75
17.8.
Monitoring ...................................................................................................................................... 76
17.9.
Study Completion/Termination....................................................................................................... 76
17.9.1.
Study Completion/End of Study.................................................................................................. 76
17.9.2.
Study Termination....................................................................................................................... 76
17.10.
On-Site Audits ................................................................................................................................ 77
17.11.
Use of Information and Publication................................................................................................ 77
REFERENCES............................................................................................................................................ 79
INVESTIGATOR AGREEMENT ................................................................................................................. 88
LIST OF ATTACHMENTS
Attachment 1:
Volume of Blood to be Collected ................................................................................ 81
Attachment 2:
Post-Fontan Echocardiographic Examination protocol .............................................. 82
Attachment 3:
Estimated glomerular filtration rate (eGFR)................................................................ 84
Attachment 4:
Amendment 1 changes............................................................................................... 85
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES
Table 1: 
Dosing Table for Rivaroxaban Administration .......................................................................... 37
Table 2: 
Sampling Schedule of the Initial PK, PD, and Safety Assessment Period (Day 1 and 
Day 4-6) (Part A)a ..................................................................................................................... 46
FIGURES
Figure 1: 
Schematic Overview of Study 39039039CHD3001.................................................................. 30


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PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
30 June 2015
INT-1
7 April 2016
INT-2
27 July 2017
Amendments below are listed beginning with the most recent amendment.
Amendment 2 (27 July 2017)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.  
The overall reason for the amendment: The overall reason for the amendment is to address the feedback received 
from Investigators, regulatory authorities and ethics committees.
Applicable Section(s)
Description of Change(s)
Rationale:  A working hypothesis for the study was added based on an expected similar FXa inhibition response 
between children and adults.
Synopsis; Section 2.2 Hypothesis
The working hypothesis was added.
Rationale: Additional clarification provided for subjects participating in Part B.
Synopsis; Section 9.1.2, Screening 
Period and Section 9.1.3.2, Open-
label Treatment Period, Part B
Clarification relating to when subjects may be enrolled and randomized 
in Part B.
Rationale:  List of committees commissioned for the study was revised and the role of Sponsor Committee was 
added.
Synopsis; 3.1 Overview of Study 
Design, Committees and Advisors
The Sponsor Committee was added to the list of committees 
commissioned for the study.
Section 9.7.2, Independent Data 
Monitoring Committee; 9.7.6 
Sponsor Committee
Clarified and defined the role of the Sponsor Committee.
Rationale: Exclusion Criteria revised to include detail and further clarification
Synopsis, Section 4.2. Exclusion 
Criteria 
Exclusion Criterion #5, additional clarification was provided to allow for 
continual treatment of heparin or LMWH during the screening period.  
Exclusion Criteria #8, replaced creatinine clearance with estimated 
glomerular filtration rate (eGFR). 
Exclusion Criteria #10, added text “or has or is recovering from chicken 
pox or flu-like symptoms” for subjects participating in Part B. 
Exclusion Criteria #11, known allergies, hypersensitivity or intolerance 
to ASA was added.
Rationale: Addition of study booklet as source documentation for dosage and administration of study drug
Synopsis Dosage and Administration; 
Section 6. Dosage and 
Administration
Text “as described in the study booklet” added to the information 
regarding dosage to be given to subjects randomized to acetylsalicylic 
acid.


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Applicable Section(s)
Description of Change(s)
Rationale: Selected time points were revised and study procedures were clarified.
Time and Events Schedule, Part A
Removed the requirement for subject information to be entered into 
IWRS for phone contacts.
Protocol activities were further clarified by modifying or adding more 
detailed footnotes (footnotes j, l, q, r and s), eg, deletion of text and 
addition of language, “at month 3 only serum chemistry laboratory tests 
are done”.
Time and Events Schedule Part A and 
Part B
Removal of review of the core laboratory decision for final eligibility 
since enrollment can be done with local reader.
Time and Events Schedule Part B
Protocol activities were further clarified by modifying or adding more 
detailed footnotes (footnotes b, j, m, r, s, t, u, v and w), eg, some text 
deleted or added. 
Time and Events Schedule, Part B, 
Section 9.2. 
Pharmacokinetics/Pharmacodynamics
Instructions for PT, aPTT and/or PK and anti-FXa samples to be 
obtained at specific time points pre-dose and post dose. 
Rationale:  Additional information regarding current anticoagulant use in children was added. 
Section 1.3, Overall Rationale for the 
Study
Further details related to current treatment guideline recommendations 
were included.
Rationale: Instructions on vomiting after dosing were given.
Section 6, Dosage and 
Administration
Instructions were added to explain the procedure to be followed if the 
subject vomits and/or spits up the dose within a specified time frame. 
Rationale: Clarification of concomitant medication and prohibited medications 
Section 8, Prestudy, Concomitant
Therapy and Post study Therapy
Clarification of the definition of concomitant medications, “concomitant 
medications include all medications received between the first dose and 
the last dose of study drug”.
Also, text was revised to include “any anticoagulant/antiplatelet 
medication initiated at the end of the study treatment period will also be 
documented (see Section 9.1.5)”.
Details were added to clarify prohibited medication use for all subjects 
in the study. 
Clarification of time point for allowed therapy of ASA during the 
screening period and up to 24 hours prior to the first dose of study drug 
at Day 1 Visit was added. 
Additional clarification was provided to allow for continual treatment of 
heparin or LMWH during the screening period
Occasional use of NSAID was explained under Allowed Therapy. 
Rationale: Additional details related to study design and post-treatment procedure clarified.
Section 9.1.2, Screening Period
More details related to screening evaluations for subjects participating in 
Part B was added. 


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Applicable Section(s)
Description of Change(s)
Section 9.1.2, Screening Period; 
Section 9.1.3.2, Open-label 
Treatment Period, Part B
Clarification regarding the time point for when the first dose of study 
drug should be given was added.
Section 9.1.5, Posttreatment Period 
(Follow-Up Contact); Transition at 
End of Treatment
Additional clarification was included to specify time periods for post 
treatment follow up contact in both Part A and Part B. Also, instructions 
for the use of any anticoagulant/antiplatelet medication initiated at the 
end of the study treatment period was added.
Rationale: Additional instructions provided in case of a bleeding event.
Section 9.3.2, Approach to the 
Subject with a Bleeding Event
Instructions were added to explain the procedure to be followed if 
bleeding cannot be controlled. 
Rationale: Clinical laboratory tests were specified 
Section 9.3.3, Other Safety 
Assessments
A full list of clinical laboratory tests for safety assessment was provided.
Rationale: Revised time point to better align with study design.
Section 9.7.4, Central Independent 
Adjudication Committee 
Replaced post randomization with post enrollment, since randomization 
is utilized only in Part B. 
Rationale: Method of electronic serious adverse event reporting revised
Section 12.3.1, All Adverse Events
Updated the process to report serious adverse events, including those 
spontaneously reported to the investigator within 30 days after the last 
dose of study drug.
Rationale: Consistent with the latest prescribing information additional storage instructions were added.
Section 14.4, Preparation, Handling, 
and Storage
Specific temperature parameters for rivaroxaban and ASA were added.
Rationale: Study-Specific Materials updated
Section 15, Study-Specific Materials
As the Diagnostic Testing Manual is no longer applicable, it was 
removed from the list of study-specific materials. Ancillary supplies 
were added.
Use of an iPad® as a study management tool provided to the investigator 
applies to Part A of the study only.
Rationale: Additional details in the attachment sections were provided.
Attachment 1, Volume of Blood to be 
Collected
The number of samples per subject and volume of blood to be collected 
for Part B was modified.
Attachment 2, Post-Fontan 
Echocardiographic Examination 
protocol 
A note was provided to refer to the Technical Reference Manual for 
further details.   
Attachment 3, Estimated glomerular 
filtration rate (eGFR)
Added the headings to describe original and updated Schwartz formula 
for clarity.
Rationale: Minor edits made for clarity.
Throughout the
protocol
Minor, consistency and logical clarifications were made throughout the 
document, which do not affect the overall study concept.
Please note that description of changes for INT-1 can be found in Attachment 4.


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SYNOPSIS
STUDY TITLE
A 
Prospective, 
Open-Label, 
Active-Controlled 
Study 
to 
Evaluate 
the 
Pharmacokinetics, 
Pharmacodynamics, Safety, and Efficacy of Rivaroxaban for Thromboprophylaxis in Pediatric Subjects 2 
to 8 Years of Age after the Fontan Procedure
DESCRIPTION OF THE COMPOUND
Rivaroxaban is an oral, highly selective direct Factor Xa (FXa) inhibitor.  Inhibition of FXa interrupts the 
intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and 
development of thrombi. The clinical development program for rivaroxaban is extensive, covering the 
prevention and treatment of multiple thrombosis-mediated conditions. Rivaroxaban is marketed under the 
trade name XARELTO® and has been approved for multiple adult indications worldwide. As of 
September 2015, more than 60, 000 subjects have been treated with rivaroxaban in clinical trials (Phase 1 
through Phase 4), covering several indications, including the prophylaxis of venous thromboembolism 
(VTE) in adults undergoing elective hip or knee replacement surgery, the treatment of deep vein 
thrombosis (DVT) and/or pulmonary embolism (PE) and the reduction in the risk of recurrence of DVT 
and PE, and to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation (NVAF).
XARELTO is also approved in the European Union (EU) for the prevention of atherothrombotic events 
(cardiovascular death, myocardial infarction, or stroke) after an acute coronary syndrome in adults with 
elevated cardiac biomarkers.
OBJECTIVES AND HYPOTHESIS
Primary Objectives
Part A
To characterize the single- and multiple-dose pharmacokinetics (PK) and PK/pharmacodynamics (PD) 
profiles after oral rivaroxaban therapy administered to pediatric subjects 2 to 8 years of age with single 
ventricle physiology who have completed the Fontan procedure within 4 months prior to enrollment.
Part B
To evaluate the safety and efficacy of rivaroxaban, administered twice daily (exposure matched to 
rivaroxaban 10 mg once daily in adults) compared to acetylsalicylic acid (ASA), given once daily 
(approximately 5 mg/kg) for thromboprophylaxis in pediatric subjects 2 to 8 years of age with single 
ventricle physiology who have completed the Fontan procedure within 4 months prior to enrollment.
Secondary Objectives
Part A
To assess the safety and tolerability of rivaroxaban treatment.
Part B
To further characterize the PK and PK/PD profiles of rivaroxaban.


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Hypothesis
Children with congenital heart disease (CHD) who underwent the Fontan procedure will respond to FXa 
inhibition by rivaroxaban in a similar manner as seen in adults. This hypothesis is supported by ex vivo 
spiking experiments, which covered the entire rivaroxaban concentration in clinical studies ranging up to 
500 ng/mL, and in which similar exposure-response relationships existed in healthy children and adults of 
different age groups (23 days to 23 months, 2 to 6 years, 7 to 11 years, 12 to 16 years, and adults).1,2
No statistical hypothesis testing is planned for this study.
OVERVIEW OF STUDY DESIGN
This is a prospective, open-label, active-controlled, multicenter study designed to evaluate the PK and 
PK/PD profiles, safety, and efficacy of rivaroxaban for thromboprophylaxis in pediatric subjects 2 to 
8 years of age with single ventricle physiology who have completed the Fontan procedure within 
4 months prior to enrollment.
This study consists of 2 parts:

Part A: This is the 12-month, non-randomized, open-label part of the study, which includes a 12-day 
Initial PK, PD, and Safety Assessment Period. An internal Data Review Committee (DRC) will 
assess by Day 12 the single- and multiple-dose rivaroxaban PK, PD, and the initial safety and 
tolerability data available from each subject, prior to the subject continuing in the study to complete 
the planned 12 months of open-label rivaroxaban therapy of Part A. Subjects in Part A will not 
participate in Part B.
Randomization in Part B of this study will begin once the cumulative data from the Initial PK, PD,
and Safety Assessment Period in Part A are deemed acceptable by the Independent Data Monitoring 
Committee (IDMC).

Part B: This is the randomized, open-label, active-controlled part of the study that will evaluate the 
safety and efficacy of rivaroxaban compared to ASA for thromboprophylaxis for 12 months. 
Subjects randomized to rivaroxaban will also have PK and PD assessments.
Subjects Participating in Part A 
Part A of the study will consist of an up to 21-day Screening Period, a 12-day Initial PK, PD, and Safety 
Assessment Period, a 12-month Open-Label Treatment Period, and a 30-day Follow-Up Contact 
(phone contact). Approximately 10 pediatric subjects are planned to be enrolled in Part A.
Parental informed consent/child assent (as appropriate, typically at age ≥7 years or as defined by local 
regulations) must be obtained prior to performing any study-specific procedures. The screening 
assessments will take place after the Fontan procedure and up to 21 days before the first dose of 
rivaroxaban. During the screening period, baseline laboratory blood testing will be done and a 
transthoracic echocardiogram will be performed to rule out thrombosis. Laboratory parameters obtained 
as part of the post-surgery standard-of-care may be used for screening if they have been done within 
21 days prior to receiving the first dose of rivaroxaban. The most recent post-Fontan clinical laboratory 
results will be used for screening if there are multiple laboratory results. Subjects who do not meet all of 
the enrollment criteria for the study may be rescreened 1 additional time as long as enrollment is within 
4 months of their Fontan procedure. Subjects who are rescreened will be assigned a new subject number, 
undergo the informed consent process, and then restart a new screening phase.


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Subjects who meet all of the inclusion and none of the exclusion criteria will be enrolled and will receive 
the first dose of rivaroxaban oral suspension on Day 1 (on site). Rivaroxaban will be given twice daily for 
12 days (+9 days). Pharmacokinetic and PD samples will be collected on Day 1 and Day 4 (+2 days) of 
rivaroxaban administration. An internal DRC will assess before the subject returns for Day 12 the PK, 
PD, and the safety data available from each subject, prior to the subject continuing in the study to 
complete the planned 12 months of open-label rivaroxaban therapy. The subjects who are allowed to 
continue the 12-month treatment will also have PK and PD samples collected at Month 3 and Month 12. 
Safety and efficacy will be evaluated throughout the study. The assessment criteria will be described in 
the DRC charter.
Randomization in Part B of this study will begin once the cumulative data from the Initial PK, PD, and 
Safety Assessment Period in Part A are deemed acceptable by the IDMC. The decision tree of
rivaroxaban exposure acceptability criteria will be described in the IDMC charter.
Subjects Participating in Part B
For subjects randomized into Part B, there will be an up to 21-day Screening Period, a 12-month 
Open-Label Treatment Period, and a 30-day Follow-Up Contact (phone contact). Approximately 
90 subjects who meet all the inclusion and none of the exclusion criteria will be randomly assigned in a 
2:1 ratio to receive rivaroxaban oral suspension and ASA for 12 months.
Parental informed consent/child assent (as appropriate, typically at age ≥7 years or as defined by local 
regulations) must be obtained prior to performing any study-specific procedures. Subjects will undergo 
the same screening evaluations as in Part A. Eligible subjects will be enrolled and randomized on Day 1 
and will receive their first dose of study drug on site at this visit. Subjects may be enrolled and 
randomized on the business day prior to Day 1 to facilitate logistics, provided the investigator ensures that 
the subject meets all eligibility criteria prior to randomization. Pharmacokinetic and PD samples will be 
obtained on Day 1, Month 3, and Month 12 for subjects randomized to rivaroxaban only. Safety and 
efficacy will be evaluated throughout the study for all subjects.
Early Study Medication Discontinuation
For subjects in Part A and Part B who prematurely discontinue study drug for any reason, the Early Study 
Medication Discontinuation (ESMD) visit will be performed as soon as possible after discontinuation. A 
Follow-Up Contact (phone contact) will be performed 30 days following the last dose of study drug and 
at Month 12, the end of the planned treatment period.
Note: An exception are subjects who are enrolled after local reading of the Screening transthoracic 
echocardiogram rules out thrombosis, and subsequently reported to have thrombosis after central reading 
by the core laboratory of the same transthoracic echocardiogram. These subjects will be withdrawn from 
the study when the result of the echocardiogram by the core laboratory becomes available. Subjects will 
be asked to return for the ESMD visit as soon as possible. They will not be required to have a repeat 
transthoracic echocardiogram as part of the ESMD. Subjects will go on to receive proper care according 
to the healthcare provider’s judgment. They will be contacted by phone approximately 30 days (+/-
7 days) after last dose of study drug (Follow-Up Contact). An ESMD Month 12 follow up visit will not be 
required.
Committees
An Executive Committee (EC), an internal DRC, IDMC, Central Independent Adjudication Committee 
(CIAC), Steering Committee (SC), and a Sponsor Committee will be commissioned for this study.


JNJ-39039039; BAY 59-7939   (rivaroxaban)
Clinical Protocol 39039039CHD3001 - Amendment INT-2
11
Approved, Date: 27 July 2017
SUBJECT POPULATION
Pediatric subjects 2 to 8 years of age who have single-ventricle physiology and who have completed the 
Fontan procedure within 4 months prior to enrollment are potentially eligible for Part A or Part B of this 
study.  
Subjects must satisfy all of the following criteria to be enrolled in the study:
Inclusion Criteria
1.
Boys or girls 2 to 8 years of age with single ventricle physiology and who have completed the initial 
Fontan procedure within 4 months prior to enrollment 
2.
Considered to be clinically stable by the investigator and able to tolerate oral or enteral 
administration of a suspension formulation and oral/enteral feedings
3.
Satisfactory initial post-Fontan transthoracic echocardiographic screening as defined in the 
Post-Fontan Echocardiographic Examination Research Protocol
4.
Parent/legally acceptable representative must sign an informed consent form (ICF) and child assent 
will also be provided, if applicable, according to local requirements
Subjects who meet any of the following criteria will be excluded from participating in the study:
Exclusion Criteria
1.
Evidence of thrombosis, including those that are asymptomatic confirmed by post-Fontan procedure
transthoracic echocardiogram, or other imaging techniques, during the screening period of the study
2.
History of gastrointestinal disease or surgery associated with clinically relevant impaired absorption 
3.
History of or signs/symptoms suggestive of protein-losing enteropathy
4.
Active bleeding or high risk for bleeding contraindicating antiplatelet or anticoagulant therapy, 
including a history of intracranial bleeding
5.
Criterion modified per Amendment INT-2
5.1   Indication for anticoagulant or antiplatelet therapy other than current study, however:

A subject who has received vitamin K antagonist (VKA) after the Fontan procedure may be 
eligible provided that the subject has discontinued VKA before the screening visit.  Baseline 
laboratory samples must be obtained at least 7 days after the last dose of VKA.

A subject who is receiving ASA at the time of the screening visit may be eligible and may 
continue receiving ASA provided the last dose is taken at least 24 hours prior to the first dose of 
study drug.

A subject who is receiving heparin or LMWH after the Fontan procedure may be eligible and 
may continue receiving either of these anticoagulants during the screening period provided the 
study drug (rivaroxaban or ASA) is started 0 to 2 hours prior to the next scheduled 
administration of either of these anticoagulants and omit their administration thereafter. 
6.
Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs)
7.
Platelet count <50 x 109/L at screening 
8.
Criterion modified per Amendment INT-2
8.1   Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2


JNJ-39039039; BAY 59-7939   (rivaroxaban)
Clinical Protocol 39039039CHD3001 - Amendment INT-2
12
Approved, Date: 27 July 2017
9.
Known clinically significant liver disease (eg, cirrhosis, acute hepatitis, chronic active hepatitis, or
alanine aminotransferase (ALT) >3x upper limit of normal (ULN) with concurrent total bilirubin 
>1.5x ULN with direct bilirubin >20% of the total at screening)
10. Criterion modified per Amendment INT-2
10.1   Known contraindication to ASA, or has or is recovering from chicken pox or flu-like 
symptoms (subjects participating in Part B only)
11. Criterion modified per Amendment INT-2
11.1   Known allergies, hypersensitivity, or intolerance to rivaroxaban, ASA or its excipients
12. Inability to cooperate with study procedures
13. Combined P-glycoprotein (P-gp) and strong cytochrome P450 3A4 (CYP3A4) inhibitors (such as but 
not limited to ketoconazole, telithromycin, or protease inhibitors) use within 4 days before 
enrollment, or planned use during the study. Itraconazole use within 7 days before enrollment or 
planned use during the study.
14. Combined P-gp and strong CYP3A4 inducers (such as but not limited to rifampin/rifampicin, 
rifabutin, rifapentine, phenytoin, phenobarbital, carbamazepine, or St. John's Wort) use within 
2 weeks before enrollment, or planned use during the study.
15. Planned use of drugs that are moderate CYP3A4 inhibitors (such as erythromycin) during the Initial
PK, PD, and Safety Assessment Period of Part A only
16. Participation in a clinical study with an investigational drug or medical device in the previous 30 
days prior to enrollment
17. 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
18. Family member of an 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
DOSAGE AND ADMINISTRATION
Rivaroxaban: The rivaroxaban dose to be used in this study was determined via an adapted 
Physiologically-based Pharmacokinetics (PBPK) modeling approach. Rivaroxaban will be administered 
twice daily in an open-label fashion as a 0.1% (1 mg/ml) oral suspension with target exposure (area under 
the plasma concentration time curve from 0 to 24 hours [AUC0-24]) at steady state matching to that of 
rivaroxaban 10 mg total daily dose in adults (age- and body weight-adjusted dosing). Because children 
with an estimated glomerular filtration rate below 30 mL/min/1.73 m2 are excluded from the study, dose 
reduction for impaired renal function is not required. Rivaroxaban will be taken in the morning and in the 
evening (approximately 12 hours apart) and at approximately the same times each day as described in the 
study booklet. Dose adjustment, due to increased body weight, will be made at Month 6 (both Part A and 
Part B).
ASA: Acetylsalicylic acid will be provided as 81-mg or 100-mg tablets according to local practice. 
Subjects randomized to ASA will receive approximately 5 mg/kg of ASA to a maximum of 1 whole tablet 
as a single daily dose as described in the study booklet. Tablets can be split in half, if necessary (eg,
children weighing ≤10 kg), to meet the daily dose, and the dose must be documented. It is recommended 
that tablets are not split more than in half. Dose adjustments due to increased body weight will be made at 
Month 6 as appropriate.
Temporary discontinuation of study drug is allowed for events, such as intercurrent illnesses. In this case, 
standard clinical practice should be followed.


JNJ-39039039; BAY 59-7939   (rivaroxaban)
Clinical Protocol 39039039CHD3001 - Amendment INT-2
13
Approved, Date: 27 July 2017
PHARMACOKINETIC/PHARMACODYNAMIC EVALUATIONS
Blood samples for rivaroxaban PK and PD, including rivaroxaban plasma concentration, absolute 
prothrombin time (PT), activated partial thromboplastin time (aPTT), and anti-FXa activity measurements 
will be taken from pediatric subjects enrolled in Part A on Day 1 and Day 4 and for subjects continuing in 
Part A, at Month 3 and Month 12, and for subjects randomized to rivaroxaban in Part B on Day 1, 
Month 3, and Month 12. The dosing, exact time of rivaroxaban administration and PK and PD blood 
sampling will be documented in the electronic case report form (eCRF).
Sampling Schedule of the Initial PK, PD, and Safety Assessment Period (Day 1 and Day 4-6) (Part A)a
Visit 2-D1/
Day 1
Visit 2-D4/
Day 4b
Postdosec
0.5-1.5 hours
Postdosec
1.5-4 hourse
Predosec,d
Postdosec
0.5-1.5 hours
Postdosec
1.5-4 hourse
Postdosec
6.0-8 hours
PKf
0.6 ml
0.6 ml
0.6 ml
0.6 ml
0.6 ml
0.6 ml
PD-1g
1.4 ml
1.4 ml
1.4 ml
1.4 ml
1.4 ml
1.4 ml
PD-2h
1.4 ml
1.4 ml
-
-
-
1.4 ml
D1=Day 1; D4=Day 4; PD=pharmacodynamics; PK=pharmacokinetics.
a) Subjects continuing in Part A will also have additional PK and PD assessments at Months 3 and 12.
b) Visit 2-D4 can be performed on Days 4, 5, or 6.
c) Sampling times are relative to morning dose.
d) Up to 3 hours predose. 
e) Allow at least 30 minutes from the previous sample.
f) Blood volume per PK sample for rivaroxaban plasma concentration is approximately 0.6 mL; total blood volume 
for all PK samples is 3.6 mL (Day 1: 1.2 mL; Day 4: 2.4 mL); sites will send samples to the central laboratory on 
the day of collection for liquid chromatography/mass spectrometry/mass spectrometry (LC-MS/MS) 
determination. 
g) PD-1 assessments will include prothrombin time (PT) and activated partial thromboplastin time (aPTT). Blood 
volume per PD-1 sample is approximately 1.4 mL; total blood volume for all PD-1 samples is 8.4 mL 
(Day 1: 2.8 mL; Day 4: 5.6 mL). Sites will send samples to the central laboratory after Day 4 of collection. 
h) PD-2 assessment will be anti-FXa activity. Blood volume per PD-2 sample is approximately 1.4 mL; total blood 
volume for all PD-2 samples is 4.2 mL (Day 1: 2.8 mL; Day 4: 1.4 mL). Sites will send samples to the central 
laboratory.


JNJ-39039039; BAY 59-7939   (rivaroxaban)
Clinical Protocol 39039039CHD3001 - Amendment INT-2
14
Approved, Date: 27 July 2017
SAFETY EVALUATIONS/OUTCOMES
The primary safety outcome will be major bleeding events, as defined below. Clinically relevant 
non-major bleeding events and trivial (minimal) bleeding will be secondary safety outcomes.
The safety and tolerability of rivaroxaban will also be evaluated by assessing adverse events and clinical 
laboratory values. 
Bleeding events will be adjudicated by the CIAC using the International Society on Thrombosis and 
Hemostasis (ISTH) recommendations.
Major bleeding is defined as overt bleeding and:

Associated with a fall in hemoglobin of 2 g/dL or more; or

Leading to a transfusion of the equivalent of 2 or more units of packed red blood cells or whole 
blood in adults; or

Occurring in a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, 
intramuscular with compartment syndrome, retroperitoneal; or

Contributing to death.
Clinically relevant non-major bleeding is defined as overt bleeding not meeting the criteria for major 
bleeding but associated with:

Medical intervention, or

Unscheduled contact (visit or telephone call) with a physician, or

(Temporary) cessation of study treatment, or 

Discomfort for the subject such as pain, or 

Impairment of activities of daily life (such as loss of school days or hospitalization).
Trivial (minimal) bleeding is defined as any other overt bleeding event that does not meet criteria for 
clinically relevant non major bleeding.
EFFICACY EVALUATIONS/OUTCOMES
The primary efficacy outcome will be any thrombotic event (venous or arterial), defined as:

The appearance of a new thrombotic burden within the cardiovascular system on either routine 
surveillance or clinically indicated imaging, or

The occurrence of a clinical event known to be strongly associated with thrombus (such as 
cardioembolic stroke, pulmonary embolism).
Subjects who develop either a symptomatic or asymptomatic thrombotic event during the study must 
permanently discontinue the study drug. All available imaging results (eg, transthoracic or 
transesophageal echocardiograms, or MRIs), should be sent to the CIAC. After cessation of the study 
drug, it is at the investigator’s discretion to continue with other antithrombotic therapy. The investigator 
should document this therapy in the eCRF. Thrombotic events will not be reported as adverse events or 
serious adverse events, as they will be reported as efficacy outcomes.
Transthoracic echocardiograms will be centrally read by an echocardiographic core laboratory. All 
thrombotic events and the primary cause of any death will be adjudicated by the CIAC.


JNJ-39039039; BAY 59-7939   (rivaroxaban)
Clinical Protocol 39039039CHD3001 - Amendment INT-2
15
Approved, Date: 27 July 2017
STATISTICAL METHODS
Sample Size Determination
A total of at least 100 pediatric subjects overall are planned to be enrolled in this study. The total sample 
size does not originate from a formal sample size calculation but is based on regulatory feedback to obtain 
sufficient safety data in this pediatric population. No statistical hypothesis will be tested in either part of 
this study.  
The sample size of approximately 10 subjects for Part A is considered adequate for the initial assessment 
of the rivaroxaban PK in the studied pediatric subjects and determine the dosing regimen to be studied in 
Part B. Approximately 90 subjects will be enrolled into Part B of the study.    
Pharmacokinetics, Pharmacodynamics, Safety, and Efficacy Analyses
No statistical hypothesis will be tested in Part A or Part B. 
Descriptive statistics will be used to summarize rivaroxaban PK data for each time interval. 
Pharmacodynamics measurements, including PT, aPTT, and anti-FXa activity will be plotted against 
rivaroxaban plasma concentrations and will also be summarized by timepoint.
Rivaroxaban PK parameters, including AUC0-24, maximum plasma concentration (Cmax) after single dose,
and AUC0-24, Cmax, and minimum plasma concentration (Cmin) at steady sate, will be derived by model-
based methods. Pharmacokinetics/PD relationship will be quantified. Results from PK and PK/PD 
analyses will be reported separately from the Clinical Study Report.
For both parts of the study, safety and efficacy (adverse events, bleedings, and thrombotic events) will be 
summarized.
EudraCT NUMBER: 2015-002610-76


JNJ-39039039; BAY 59-7939   (rivaroxaban)
Clinical Protocol 39039039CHD3001 - Amendment INT-2
16
Approved, Date: 27 July 2017
TIME AND EVENTS SCHEDULE 
TIME & EVENTS SCHEDULE – SUBJECTS PARTICIPATING IN PART A  
Screening 
Perioda
Initial PK, PD, and SafetyAssessment Period
Rivaroxaban Oral Suspension
12-month Open-Label Treatment Periodb
Rivaroxaban Oral Suspension
Follow-Up 
Contactc
ESMD 
Month 12 
Follow-Upd
Visit 
Visit 1
Visit 2-D1
Visit 2-D4
Visit 2-D12
Visit 3
Visit 4
Visit 5
Phone 
Contact 
Phone 
Contact
Time
Up to 21 Days
Day 1e
Day 4
Day 12
Month 3
Month 6
Month 
12
ESMDf
30-days after 
last dose
Visit Type/ Window
Visit
Visit
Visit
+2 days
Visit
+9 days
Visit
±7 days
Visit
±7 days
Visit
±7 days
Phone contact
±7 days
Visit
±14 days
Screening/Administrative
Informed consent (ICF)/assentg
X
Enter subject information into IWRS
X
X
X
X
X
X
X
Inclusion/exclusion criteriah
X
Review medical history, demographics 
X
Obtain blood pressure, heart rate
X
Obtain body weight, height
X
X
X
X
X
Record prestudy medications
X
Obtain baseline transthoracic echocardiograma
X
Enrollment
X
Rivaroxaban Administration
Dispense rivaroxaban
X
Xi
X
X
Rivaroxaban administration at the sitej
X
X
X
Rivaroxaban drug accountability
X
X
X
X
X
X
Rivaroxaban dose adjustment due to growth
X
Provide Study booklet
X
Safety and Efficacy Assessments
Assess study outcome eventsk
X
X
X
X
X
X
X
X
Xl
Adverse events assessmentm
X
X
X
X
X
X
X
X
X
Review concomitant medications
X
X
X
X
X
X
X
X
X
Physical examination
X
Xn
X
Xn
Xn
X
X
Transthoracic echocardiogramo
Xa
X
X
X
Hematology, serum chemistry p,q, PT, aPTT 
X
X
X
X
PK/PD
Obtain PK and PD samples at the following 
timepointsr :
    Up to 3 hours pre-dose
X
Xs
Xt
    0.5-1.5 hour postdose
Xs
X
X
    1.5-4 hours postdose
Xu,s
Xu 
    2.5-4 hours postdose
X
    6-8 hours postdose
Xs
Key:  AM=Ante Meridian (morning); aPTT= activated partial thromboplastin time; CBC= complete blood count; D1=Day 1; D4=Day 4; DRC=Data Review Committee; ESMD=Early Study 
Medication Discontinuation; IDMC = Independent Data Monitoring Committee; IWRS= interactive web response system; PD= pharmacodynamics, PK=pharmacokinetics; PT= prothrombin time


JNJ-39039039; BAY 59-7939   (rivaroxaban)
Clinical Protocol 39039039CHD3001 - Amendment INT-2
17
Approved, Date: 27 July 2017
a) Screening procedures can be performed up to 21 days prior to Day 1/enrollment. For screening, the subjects transthoracic echocardiogram may be read locally 
to rule out thrombosis and proceed to enrollment of the subject if no thrombosis is reported and inclusion/exclusion criteria are satisfied. The transthoracic 
echocardiogram should also be sent to the core laboratory if subject is enrolled. See Section 9.1.6 for further instructions. Note: Hospital laboratory, local 
laboratory results or central laboratory results are acceptable at screening, and the most recent clinical laboratory results will be used for screening if there are 
multiple laboratory results. Subjects who do not meet all of the enrollment criteria for the study may be rescreened 1 additional time as long as enrollment is 
within 4 months of their Fontan procedure. Subjects who are rescreened will be assigned a new subject number, undergo the informed consent process, and 
then restart a new screening phase.
b) This period will include subjects who complete the Initial PK, PD, and Safety Assessment Period and are allowed to continue on open-label rivaroxaban oral 
suspension twice-daily therapy to complete 12 months.
c) Regardless of treatment duration, all subjects will have a Follow-Up Contact, 30 days after the last dose (+/- 7 days).
d) Only for subjects with ESMD. These subjects will also be contacted to determine vital status and efficacy outcomes at the end of the planned treatment period 
(Month 12).
e) Fontan procedure completed within 4 months prior to enrollment (Visit 2).
f) For subjects who prematurely discontinue study drug for any reason, the ESMD visit procedures will be performed as soon as possible after discontinuation.
See Section 3.1 for detailed instructions for subjects returning for the ESDM because of core laboratory reading of the baseline transthoracic echocardiogram.
g) Must be signed before first study-related activity.
h) Minimum criteria for the availability of documentation supporting the eligibility criteria are described in Section 17.4, Source Documentation. Check clinical 
status again before first dose of study medication.
i) Rivaroxaban will be dispensed to those subjects who complete the Day 1 and Day 4 visits and after review and approval of their individual Day 1 and Day 4 
PK, PD and safety data by the DRC.  
j) Rivaroxaban (AM dose) to be administered at the site.
k) If a suspected outcome event (thrombotic or bleeding event) occurs, the adjudication package is to be completed. 
l) Only vital status and thrombotic events (no bleeding events) will be assessed and an adjudication package will be completed.
m) Adverse event assessment includes a review of all ongoing and new adverse events since the last visit for all visits through Month 12.
n) A physical examination will be symptom-driven.   
o) Transthoracic echocardiograms will be obtained at screening, Month 6, and Month 12, or ESMD and whenever medically necessary, and results sent to the 
core laboratory. For screening see footnote ‘a’.
p) Hematology (complete blood count [CBC] with differential, platelet count); blood chemistry (liver function tests [alanine aminotransferase, ALT; aspartate 
aminotransferase, AST; total and direct bilirubin; alkaline phosphatase] and creatinine).
q) Hematology and serum chemistry testing are done at screening (testing should be done after the Fontan procedure and results should be available within 
21 days prior to Day 1, at Month 12 and ESMD visit). At Month 3 only serum chemistry laboratory tests are done. Prothrombin time and aPTT tests 
(should be done at screening visit only). Note: Hospital laboratory, local laboratory results, or central laboratory results are acceptable at screening, and the 
most recent clinical laboratory results will be used for screening if there are multiple laboratory results.  
r) Pharmacokinetics and (PT and aPTT) samples will be collected at all timepoints for central testing. If a subject experiences a major bleeding event while being 
treated with rivaroxaban, obtain PK and PD samples (see also Section 9.3.2 for approach to the subject with a bleeding event and Section 9.5 for sample 
instructions).
s) Anti- factor Xa [FXa] assay samples will be collected only at these specific time points.
t) To be collected at any timepoint during the visit (PK, PT, aPTT, hematology and chemistry testing). Parent/legally acceptable representative should document 
timing of the administered AM study drug dose. 
u) Allow at least 30 minutes from the previous sample.


JNJ-39039039; BAY 59-7939   (rivaroxaban)
Clinical Protocol 39039039CHD3001 - Amendment INT-2
18
Approved, Date: 27 July 2017
TIME & EVENTS SCHEDULE – SUBJECTS PARTICIPATING IN PART B  
Screening 
Perioda
Open-Label Treatment Periodc
Follow-Up 
Contactd
ESMD 
Month 12 
Follow-Upe
Visit 
Visit 1
Visit 2
Phone 
Contact 
Visit 3
Visit 4
Visit 5
Phone 
Contact 
Phone 
Contact
Time
Up to 21 days
Day 1f
Day 12
Month 3
Month 6
Month 12
ESMDg
30-days 
after last 
dose
Visit Type/Window
Visit
Visit
Phone contact
+9 days
Visit
±7 days
Visit
±7 days
Visit 
±7 days
Phone 
contact 
±7 days
Visit
±14 days
Screening/Administrative
Informed consent (ICF)/assent h
X
Enter subject information into IWRS
X
Xj
X
X
X
X
Inclusion/exclusion criteriai
X
Review medical history, demographics 
X
Obtain blood pressure, heart rate
X
Obtain body weight, height
X
X
X
X
X
Record prestudy medications
X
Obtain baseline transthoracic echocardiogram a
X
Enrollment
Xb
Study Drug Administration
Randomization
Xj 
Dispense study drug
X
X
X
Study drug administration at the sitek
X
X
Study drug accountability
X
X
X
X
Study drug dose adjustment due to growth
X
Provide Study booklet
X
Safety and Efficacy Assessments
Assess study outcome eventsl
X
X
X
X
X
X
X
Xm 
Adverse events assessment n
X
X
X
X
X
X
X
X
Review concomitant medications
X
X
X
X
X
X
X
X
Physical examination
X
Xo
Xo
Xo
X
X
Transthoracic echocardiogramp 
X a
X
X
X
Hematology, serum chemistry q,r
Xr
X
X
PK/PD – Rivaroxaban Subjects Only
Obtain PK and PD samples at the following 
timepointss
    Up to 3 hours pre-dose
Xv
Xw
Xt
    0.5-1.5 hour postdose
Xw
Xw
    1.5-4 hours postdose
Xw, u
    2.5-4 hours postdose
Xw
Key:  AM=Ante Meridian (morning); aPTT= activated partial thromboplastin time; D1=Day 1; D4=Day 4; DRC=Data Review Committee; ESMD=Early Study Medication Discontinuation; IWRS=interactive 
web response system; PD= pharmacodynamics (PT and aPTT testing); PK= pharmacokinetics; PT= prothrombin time


JNJ-39039039; BAY 59-7939   (rivaroxaban)
Clinical Protocol 39039039CHD3001 - Amendment INT-2
19
Approved, Date: 27 July 2017
a) Screening procedures can be performed up to 21 days prior to Day 1/enrollment. For screening, the subjects transthoracic echocardiogram may be read locally to rule 
out thrombosis and proceed to enrollment of the subject if no thrombosis is reported and inclusion/exclusion criteria are satisfied.  The transthoracic echocardiogram 
should also be sent to the core laboratory if subject is enrolled.  See Section 9 for further instruction. Note: Hospital laboratory, local laboratory results or central 
laboratory results are acceptable at screening, and the most recent clinical laboratory results will be used for screening if there are multiple laboratory results.
Subjects who do not meet all of the enrollment criteria for the study may be rescreened 1 additional time as long as enrollment is within 4 months of their Fontan 
procedure. Subjects who are rescreened will be assigned a new subject number, undergo the informed consent process, and then restart a new screening phase.
b) Subjects will undergo the same screening evaluations as in Part A except for PT and aPTT testing which will be performed on Day 1 prior to first dose of study drug. 
c) Subjects will receive either rivaroxaban oral suspension twice-daily or acetylsalicylic acid (ASA) approximately 5 mg/kg/day.
d) Regardless of treatment duration, all subjects will have a Follow-Up Contact, 30 days after the last dose (+/- 7 days).
e) Only for subjects with ESMD. These subjects will also be contacted to determine vital status and efficacy outcomes at the end of the planned treatment period 
(Month 12).
f) Fontan procedure completed within 4 months prior to enrollment (Visit 2).
g) For subjects who prematurely discontinue study drug for any reason, the ESMD visit procedures will be performed as soon as possible after discontinuation. See 
Section 3.1 for detailed instructions for subjects returning for the ESDM because of core laboratory reading of the baseline transthoracic echocardiogram.
h) Must be signed before first study-related activity.
i) Minimum criteria for the availability of documentation supporting the eligibility criteria are described in Section 17.4, Source Documentation. Check clinical status 
again before first dose of study medication.
j) Subjects will be enrolled and randomized on Visit 2/Day 1 after meeting inclusion and exclusion criteria. Subjects may be enrolled and randomized on the business
day prior to Day 1 to facilitate logistics provided the investigator ensures that the subject meets all eligibility criteria prior to randomization. The first dose of study 
drug will be administered on site on Day 1 if the subject is still eligible.
k) For subjects randomized to rivaroxaban, the AM dose will be administered at the site.
l) If a suspected outcome event (thrombotic or bleeding event) occurs, the adjudication package is to be completed.
m) Only vital status and thrombotic events (no bleeding events) will be assessed and an adjudication package will be completed.
n) Adverse event assessment includes a review of all ongoing and new adverse events since the last visit for all visits through Month 12.
o) Physical examination of the subject will be symptom-driven.   
p) Transthoracic echocardiograms will be obtained at screening, Month 6 and Month 12, or ESMD and whenever medically necessary, and results sent to core 
laboratory. For screening see footnote ‘a’.
q) Hematology (complete blood count [CBC] with differential, platelet count); blood chemistry (liver function tests [alanine aminotransferase, ALT; aspartate 
aminotransferase, AST; total and direct bilirubin, alkaline phosphatase] and creatinine).
r) Hematology and serum chemistry testing at screening (testing should be done after the Fontan procedure and results should be available within 21 days prior to
randomization, at Month 12 and ESMD visit). Note: Hospital laboratory, local laboratory results or central laboratory results are acceptable at screening, and the 
most recent clinical laboratory results will be used for screening if there are multiple laboratory results.  
s) If a subject experiences a major bleeding event while being treated with rivaroxaban, obtain PK and PD samples (see also Section 9.3.2 for approach to the subject 
with a bleeding event and Section 9.5 for sample instructions).
t) To be collected at any timepoint during the visit (PK, PT,and aPTT). Parent/legally acceptable representative should document timing of the administered AM study 
drug dose.
u) Allow at least 30 minutes from previous sample.
v) Only PT and aPTT samples will be collected.
w) PK,  PT, aPTT, and anti- FXa assay samples will be collected.


JNJ-39039039; BAY 59-7939   (rivaroxaban)
Clinical Protocol 39039039CHD3001 - Amendment INT-2
20
Approved, Date: 27 July 2017
ABBREVIATIONS
ACS
acute coronary syndrome
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time 
ASA
acetylsalicylic acid
AST
aspartate aminotransferase
AUC
area under the plasma concentration time curve
AUC0-24
area under the plasma concentration time curve from 0 to 24 hours
CBC
complete blood count
CHD
congenital heart disease
CIAC
Central Independent Adjudication Committee
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
CrCl
creatinine clearance
CRF
case report form 
CYP3A4
cytochrome P450 3A4
D
Day
DRC
Data Review Committee
EC
Executive Committee
eCRF
electronic case report form
eDC
electronic data capture
eGFR
estimated glomerular filtration rate
ESMD
early study medication discontinuation 
EU
European Union
FXa
factor Xa 
GCP
Good Clinical Practice
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
INR
international normalized ratio
IRB
Institutional Review Board
ISTH
International Society on Thrombosis and Hemostasis
IWRS
interactive web response system
LC-MS/MS
liquid chromatography/mass spectrometry/mass spectrometry
LMWH
low molecular-weight heparin
MedDRA
Medical Dictionary for Regulatory Activities
NSAID
non-steroidal anti-inflammatory drug
NVAF
non-valvular atrial fibriallation
PBPK
physiologically-based pharmacokinetics 
PD
pharmacodynamic(s)
P-gp
P-glycoprotein 
PK
pharmacokinetic(s)
PQC
product quality complaint
PT
prothrombin time
SAP
Statistical Analysis Plan
SC
Steering Committee
SCr
serum creatinine
SUSAR
suspected unexpected serious adverse reaction
ULN
upper limit of normal
VKA
vitamin K antagonist 
VTE
venous thromboembolism


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1.
INTRODUCTION
Rivaroxaban is an oral, highly selective direct Factor Xa (FXa) inhibitor. Inhibition of FXa
interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both 
thrombin formation and development of thrombi. The clinical development program for 
rivaroxaban is extensive, covering the prevention and treatment of multiple thrombosis-mediated 
conditions through a joint collaboration agreement between Bayer HealthCare AG and Ortho 
McNeil Pharmaceuticals, Inc (now Janssen Research and Development, LLC). Rivaroxaban has 
been approved in multiple indications worldwide under the trade name XARELTO®. As of 
September 2015, more than 60,000 subjects have been treated with rivaroxaban in clinical trials 
(Phase 1 through Phase 4), covering several indications, including the prophylaxis of venous 
thromboembolism (VTE) in adults undergoing elective hip or knee replacement surgery, the
treatment of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and the reduction in 
the risk of recurrence of DVT and PE, and to reduce the risk of stroke and systemic embolism in 
non-valvular atrial fibrillation XARELTO is also approved in the EU for the prevention of 
atherothrombotic events (cardiovascular death, myocardial infarction, or stroke) after an acute 
coronary syndrome in adults with elevated cardiac biomarkers. 
Rivaroxaban is currently being studied in pediatric subjects with VTE (see Section 1.1.4, 
Physiology-Based Pharmacokinetics). It has been well tolerated in a Phase 2 and Phase 3 study 
in pediatric subjects for the treatment and secondary prevention of VTE (studies ongoing).
For the most comprehensive nonclinical and clinical information regarding rivaroxaban, refer to 
the latest version of the Investigator's Brochure.14
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Background
1.1.1.
Pediatric Patients with Single Ventricle Physiology – The Fontan 
Procedure - Scope of the Problem 
The Fontan procedure has become the most common procedure performed for congenital heart 
disease (CHD) after the age of 2 years and is the final palliative surgery for children with single 
ventricle physiology.10,19 Improvements in early outcomes have led to an increase in the number 
of patients surviving into adulthood after this palliative procedure.15 In response to the need for 
population-based data, Fontan patient registries have been established in North America 
(Society of Thoracic Surgeons Congenital Heart Surgery Database, STS-CHSDB), Europe 
(EACTS Congenital Database) and Australia and New Zealand (Fontan Registry). Collectively, 
these registries reported about 1,460 Fontan procedures per year during 2007 to 2011, which 
captured the majority of the Fontan procedures performed in those regions.3,16,31
Thrombosis remains an important complication for patients with single ventricle physiology 
following the Fontan procedure; however, the true frequency of thrombotic events is not well 
known.21,22 Several studies have estimated that the prevalence of thrombosis events occurring 
post-Fontan procedure ranges from 17% to 33%, with a reported mortality of 25% due to an 


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associated post-Fontan thromboembolism.4,9,30 The risk of thrombotic complications is higher 
within 6 months after the Fontan procedure and the risk diminishes but persists over the first 
2.5 years thereafter.18
1.1.2.
Human Pharmacokinetics in Adults
Rivaroxaban is rapidly absorbed after oral administration, with peak plasma concentrations 
occurring approximately 2 to 4 hours postdose. Rivaroxaban is a low clearance drug (clearance is 
approximately 10 L/h or 0.14 L/h/kg) and does not undergo any relevant first-pass metabolism. 
The terminal elimination half-life of rivaroxaban ranges from 5 to 9 hours in healthy young male 
subjects and from 11 to 13 hours in healthy elderly subjects (aged 65 to 83 years). Due to the 
multiple elimination pathways of rivaroxaban, there are few clinically relevant drug-drug 
interactions. 
In drug-drug interaction studies evaluating the concomitant use with drugs that are combined 
P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) inhibitors, increases in rivaroxaban 
exposure were observed. Similar increases in pharmacodynamic effects (ie, FXa inhibition and 
prothrombin time [PT] prolongation) were also observed. Significant increases in rivaroxaban 
exposure may increase bleeding risk.
In a drug interaction study, coadministration of rivaroxaban (20-mg single dose with food) with a 
drug that is a combined P-gp and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once 
daily) led to an approximate decrease of 50% and 22% in area under the plasma concentration 
curve (AUC) and maximum plasma concentration (Cmax), respectively. Similar decreases in PD 
effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.
1.1.3.
Efficacy and Safety Profile Based on Adult Clinical Studies
The efficacy and safety of rivaroxaban have been studied in several large clinical development 
programs for the prevention and treatment of multiple thrombosis-mediated conditions. 
The highlights of relevant studies are:

The pooled analysis of 4 studies comprising the RECORD program involving 
12,729 subjects undergoing hip or knee arthroplasty demonstrated that rivaroxaban given at 
a dose of 10 mg once daily compared with enoxaparin given at a dose of 30 mg twice daily 
or 40 mg once daily for 30 days significantly reduced the risk of symptomatic VTE and 
mortality (0.8% absolute risk decrease). Rivaroxaban increased the risk of bleeding slightly 
compared with enoxaparin (0.2% absolute risk increase in major bleeding events).

The ROCKET AF study involving 14,264 patients with NVAF at high risk of stroke 
demonstrated that rivaroxaban 20 mg once daily (15 once daily in subjects with an estimated 
glomerular filtration rate of 30 to 49 ml/min) compared with warfarin (target international 
normalized ratio [INR] 2.0 to 3.0) for a mean of 19 months was non inferior for the 
prevention of stroke or systemic embolism (hazard ratio 0.88; 95% confidence interval: 0.74
to 1.03), with a significant reduction in life-threatening, intracranial and fatal bleeding and a 
favorable effect on mortality, but more transfusions and hemoglobin decreases of >2 gm/dl.  


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
The EINSTEIN VTE treatment studies involving 9,447 subjects with VTE demonstrated 
that rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily compared 
with initial low molecular-weight heparin (LMWH) followed by warfarin (INR 2.0 to 3.0) 
was associated with a similar or reduced risk of recurrent VTE with a similar or reduced rate 
of major bleeding during up to 12 months. Overall bleeding rates were similar with 
rivaroxaban compared to enoxaparin/ vitamin K antagonists (VKA), and showed a clinically 
important reduction in major bleeding risk. 

Rivaroxaban has been studied for reduction of the risk of thrombotic cardiovascular (CV) 
events in patients with acute coronary syndrome (ACS) (ST segment elevation myocardial 
infarction, non-ST-segment elevation myocardial infarction, or unstable angina) in 
combination with acetylsalicylic acid (ASA) alone or with ASA plus a thienopyridine 
(clopidogrel or ticlopidine) in the ATLAS program. The ATLAS ACS 2 TIMI 51 study 
randomized a total of 15,526 subjects and demonstrated that rivaroxaban 2.5 mg or 5 mg 
twice daily compared with placebo reduced the risk of CV death, MI, or stroke by 16% in 
patients with a recent ACS, most of whom (92%) were also receiving dual antiplatelet 
therapy. The incidences of all categories of treatment-emergent bleeding were consistently 
higher in subjects treated with rivaroxaban compared with placebo. The higher rates of 
bleeding with rivaroxaban were expected, since in this study rivaroxaban was compared to 
placebo on the background of standard antiplatelet therapy.

The MAGELLaN study compared VTE prophylaxis with oral rivaroxaban 10 mg once daily 
for 35 days with enoxaparin 40 mg daily for 10 days in subjects who were hospitalized for a 
medical illness. The MAGELLaN study randomized 8,101 subjects and met both of its 
primary efficacy objectives (ie, for rivaroxaban versus enoxaparin/placebo noninferiority at 
Day 10, and superiority at Day 35). Although bleeding rates in MAGELLaN were low 
overall, the incidences of clinically relevant bleeding events were increased in rivaroxaban 
treated subjects compared to enoxaparin. 
In addition to bleeding, other adverse reactions associated with rivaroxaban include nausea, 
fever, kidney and liver impairment, dyspepsia, allergic reactions including skin reactions, 
itching, rash, hives, swelling of face, lips, mouth, tongue, skin or throat, and cholestasis.
Postmarketing data gathered subsequently to the pivotal studies do not change the favorable 
benefit-risk assessment of rivaroxaban in the approved indications. 
For the most comprehensive description of the safety profile of rivaroxaban, refer to the latest 
version of the Investigator's Brochure for rivaroxaban.14
1.1.4.
Physiology-Based Pharmacokinetics
The rivaroxaban doses that are being tested in the pediatric VTE treatment studies were derived 
using Physiologically-based Pharmacokinetics (PBPK) modeling (ie, extrapolation of the known 
pharmacokinetic (PK) properties of the drug into the pediatric population by way of physiology 
based translational approaches).6,7 The primary goal for dosing is to achieve in pediatric patients 
an equivalent exposure (as measured by AUC) to the 20 mg once daily dose regimen that has 
demonstrated effectiveness for treatment of VTE in adults. The term ‘equivalent exposure’ is 
used to indicate the achievement of a similar area under the plasma concentration curve from 


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0 to 24 hours (AUC0-24) value between pediatric and adult subjects. For assessing dose linearity, 
pediatric doses that provide equivalent exposure to the rivaroxaban 10-mg once daily regimen in 
adults are also being evaluated in the Phase 1 study conducted by Bayer Healthcare. Based on 
the current knowledge of the coagulation system in the pediatric population, the expectation is 
that children will respond to FXa inhibition in a similar manner to adults. This hypothesis is 
supported by ex-vivo spiking experiments, which covered the entire rivaroxaban concentration in 
clinical studies ranging up to 500 ng/mL, and in which similar exposure-response relationships 
existed in healthy children and adults of different age groups (23 days to 23 months, 2 to 6 years, 
7 to 11 years, 12 to 16 years, and adults).1,2,25
1.1.5.
Efficacy and Safety Profile Based on Pediatric Clinical Studies 
Rivaroxaban is currently being developed for the treatment of VTE in pediatric subjects 
(EINSTEIN Junior program). The VTE treatment pediatric clinical development program was 
designed in a comprehensive, staggered and stepwise approach to establish pediatric age-specific 
dosing recommendations and to explore the comparative safety and efficacy of rivaroxaban to 
the standard-of-care therapy in children from birth to <18 years. As of 29 March 2016, 
223 pediatric subjects have received at least one dose of rivaroxaban in these pediatric trials. 
The VTE treatment program is comprised of 7 studies of which 1 study has been completed, 5 
are ongoing and 1 is planned to start in 2017.

Two Phase 1 studies: 

Study #12892 is a Phase 1 study in pediatric subjects from 6 months to 18 years of age, 
which recently completed enrollment. This Phase 1 study was designed to evaluate the 
safety profile of a single dose of rivaroxaban ready to use suspension and confirm the 
age- and body-weight adjusted pediatric dose recommendations equivalent to 10 and 
20 mg single dose in adults derived from adult data and PBPK modeling. 

Study #17992 is another Phase 1 single-dose study evaluating rivaroxaban granules for 
oral suspension formulation in pediatric subjects from 6 months to 12 years with 
previous thrombosis, currently starting enrollment. 
A total of 78 children have received a single dose of rivaroxaban in these Phase 1 studies.

Two Phase 2 studies (Study #14373 and #14374) are enrolling pediatric subjects from 
6 months to 18 years of age. Both studies investigate the safety, tolerability, effectiveness 
and pharmacokinetics and pharmacodynamics of a 30-day treatment of age- and body weight 
adjusted rivaroxaban. The pediatric dose targets an adult exposure of 20 mg in children with 
various manifestations of thrombosis. 
A total of 57 pediatric subjects have received rivaroxaban in these Phase 2 studies.

Study #14372 is a Phase 3 study in pediatric subjects from 6 months to <18 years. It is a 3 to 
12 month, open-label, active-controlled, randomized study of the safety, efficacy and the 
pharmacokinetic and pharmacodynamic properties of oral rivaroxaban in pediatric subjects 
with various manifestations of venous thrombosis. The study is currently enrolling the age 
cohort 12 to 18 years. A total of 87 subjects have received rivaroxaban.


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
Study # 17618 is a Phase 1/2 7-day study of safety, efficacy and the pharmacokinetic and 
pharmacodynamic properties of oral rivaroxaban in pediatric subjects from birth to 6 months 
with catheter-related arterial or venous thrombosis. Pediatric subjects will be receiving an 
age- and body weight-adjusted dose of rivaroxaban (20 mg equivalent). Enrollment is 
currently starting, and 1 subject has received rivaroxaban.

Study #17625 is a Phase 3 study in pediatric subjects from birth to 6 months planned to start 
in 2017.
In the ongoing rivaroxaban studies in pediatric subjects, rivaroxaban has been well tolerated; 
there have been no cases of drug-related death and no major bleeding events. 
No recurrences of VTE have been observed during rivaroxaban treatment in phase 2 studies. In 
the Phase 3 study 14372 with a 2:1 randomization to the rivaroxaban and standard of care arm, 
there were 3 outcomes in the rivaroxaban arm (including 1 recurrence that occurred during the 
initial heparin treatment, ie, before rivaroxaban was started) and 1 outcome in the standard of 
care arm. The side effect profile of rivaroxaban has been similar to the side effect profile in 
adults. In summary, these data support a positive risk/benefit assessment.
1.2.
Comparator Agent
Acetylsalicylic acid (ASA)
Acetylsalicylic acid is a nonsteroidal anti-inflammatory drug (NSAID). The mechanism of action 
of ASA is suppression of prostaglandins and thromboxanes production by irreversible 
inactivation of the cyclooxygenase enzyme required for prostaglandin and thromboxane 
synthesis.
Acetylsalicylic acid is indicated as a pain reliever for the temporary relief of minor aches and
pains. It also has an antiplatelet effect and at lower doses can be used as a long-term treatment to 
help prevent heart attacks, strokes, and blood clot formation in patients at high risk of developing 
blood clots.
Adverse reactions associated with the use of ASA include allergic reactions, an increased risk of 
gastrointestinal bleeding, and Reye's syndrome.
Further information regarding low dose ASA can be found in the local approved product label.
1.3.
Overall Rationale for the Study
Despite continuous improvements in the medical management of pediatric patients with CHD, 
the risk of thrombotic events remains an important complication for pediatric patients following 
the Fontan procedure.21
The National Heart, Lung and Blood Institute (NHLBI) convened a Working Group in 2012 to 
explore the issues related to thrombosis in children with CHD.19 The report from the Working 
Group identified single ventricle patients as a priority population and further noted that studies to 
evaluate thromboprophylaxis in this patient population both before and after the Fontan 
procedure were a top research priority. Therefore, there is an important unmet medical need for 


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additional therapies with well controlled studies upon which to base treatment decisions for 
thromboprophylaxis in children after the Fontan procedure. 
There has been only 1 prospective study of anticoagulation prophylaxis in Fontan patients, which 
included 111 pediatric subjects that were randomized to treatment with ASA or heparin/warfarin 
for 2 years. The study did not reach the targeted recruitment goal of 242 subjects. Thrombotic 
events (venous and arterial) were the primary endpoints in the study. Results demonstrated a 
peak incidence of VTE in the first 6 months, and no significant difference in event rates between 
the treatment groups with thrombosis occurring in 21% of ASA-treated subjects and 24% of 
warfarin-treated subjects. The study found no difference in risk of thrombosis between subjects 
randomized to warfarin at the 2 years study endpoint. All of the thrombotic events in the study 
were venous events (no arterial events).20 Although there was no difference between warfarin 
and ASA, the event rate supports the decision to include an active comparator for which there is 
a perceived equipoise. 
To date, no consensus exists in the literature or in routine clinical practice as to the optimal type 
or duration of antithrombotic therapy for thromboprophylaxis after Fontan surgery and much of 
the data for pediatric recommendations is still extrapolated from adult data.11,18
Current 
guidelines recommend the use of ASA, or unfractionated heparin followed by vitamin K 
antagonist (VKA) for thromboprophylaxis in pediatric subjects after the Fontan procedure.12,11,18
While these recommendations are based on available literature and experts opinion and are 
routinely followed by pediatric hematologists and other health care providers, currently there are 
no anticoagulants approved for use in children for treatment or prophylaxis of thromboembolism 
in the United States  or European Union . Instead, anticoagulants (namely, VKAs and heparins) 
are currently used off-label in children. Furthermore, there is a negligible amount of published 
data on the safety and efficacy of novel oral anticoagulation agents in children for whom 
anticoagulation is recommended.
This study aims to provide safety and efficacy information on the use of rivaroxaban, an oral 
anticoagulant, compared to ASA, an antiplatelet, in this population.


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2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives  
Primary Objectives
Part A
To characterize the single- and multiple-dose PK and PK/ PD profiles after oral rivaroxaban 
therapy administered to pediatric subjects 2 to 8 years of age with single ventricle physiology 
who have completed the Fontan procedure within 4 months prior to enrollment.
Part B
To evaluate the safety and efficacy of rivaroxaban, administered twice daily (exposure matched 
to rivaroxaban 10 mg once daily in adults) compared to ASA, given once daily (approximately 
5 mg/kg) for thromboprophylaxis in pediatric subjects 2 to 8 years of age with single ventricle 
physiology who have completed the Fontan procedure within 4 months prior to enrollment.
Secondary Objectives
Part A
To assess the safety and tolerability of rivaroxaban treatment.
Part B
To further characterize the PK and PK/PD profiles of rivaroxaban.
2.2.
Hypothesis
Children with CHD who underwent a Fontan procedure will respond to FXa inhibition by 
rivaroxaban in a similar manner as seen in adults. This hypothesis is supported by ex vivo 
spiking experiments, which covered the entire rivaroxaban concentration in clinical studies 
ranging up to 500 ng/mL, and in which similar exposure-response relationships existed in 
healthy children and adults of different age groups (23 days to 23 months, 2 to 6 years, 7 to 11 
years, 12 to 16 years, and adults).1,2
There is no statistical hypothesis testing for this study.  
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a prospective, open-label, active-controlled, multicenter study designed to evaluate the 
PK and PK/PD profiles, safety, and efficacy of rivaroxaban for thromboprophylaxis in pediatric 
subjects 2 to 8 years of age with single ventricle physiology who have completed the Fontan 
procedure within 4 months prior to enrollment.


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This study consists of 2 parts:

Part A: This is the 12-month, non-randomized, open-label part of the study, which includes a 
12-day Initial PK, PD, and Safety Assessment Period. An internal Data Review Committee 
(DRC) will assess before the subject returns for Day 12 the single- and multiple-dose 
rivaroxaban PK, PD, and the initial safety and tolerability data available from each subject, 
prior to the subject continuing in the study to complete the planned 12 months of open-label 
rivaroxaban therapy of Part A. Subjects in Part A will not participate in Part B. 
Randomization in Part B of this study will begin once the cumulative data from the Initial 
PK, PD, and Safety Assessment Period in Part A are deemed acceptable by the Independent 
Data Monitoring Committee (IDMC).

Part B: This is the randomized, open-label, active-controlled part of the study that will 
evaluate the safety and efficacy of rivaroxaban compared to ASA for thromboprophylaxis 
for 12 months. Subjects randomized to rivaroxaban will also have PK and PD assessments.
Subjects Participating in Part A 
Part A of the study will consist of an up to 21-day Screening Period, a 12-day Initial PK, PD, and 
Safety Assessment Period, a 12-month Open-Label Treatment Period, and a 30-day Follow-Up
Contact (phone contact) (see Time and Events Schedule). Approximately 10 pediatric subjects 
are planned to be enrolled in Part A.
Parental informed consent/child assent (as appropriate, typically at age ≥7 years or as defined by 
local regulations) must be obtained prior to performing any study-specific procedures. The 
screening assessments will take place after the Fontan procedure and up to 21 days before the 
first dose of rivaroxaban. During the screening period, baseline laboratory blood testing will be 
done and a transthoracic echocardiogram will be performed to rule out thrombosis. Laboratory 
parameters obtained as part of the post-surgery standard-of-care may be used for screening if 
they have been done within 21 days prior to receiving the first dose of rivaroxaban. The most 
recent post-Fontan clinical laboratory results will be used for screening if there are multiple 
laboratory results. Subjects who do not meet all of the enrollment criteria for the study may be 
rescreened 1 additional time as long as enrollment is within 4 months of their Fontan procedure.
Subjects who are rescreened will be assigned a new subject number, undergo the informed 
consent process, and then restart a new screening phase.
Subjects who meet all of the inclusion and none of the exclusion criteria will be enrolled and will 
receive the first dose of rivaroxaban oral suspension on Day 1 (on site). Rivaroxaban will be 
given twice daily for 12 days (+9 days). Pharmacokinetic and PD samples will be collected on 
Day 1 and Day 4 (+2 days) of rivaroxaban administration. An internal DRC will assess before 
the subject returns for Day 12 the PK, PD, and the safety data available from each subject, prior 
to the subject continuing in the study, to complete the planned 12 months of open-label 
rivaroxaban therapy. The subjects who are allowed to continue the 12-month treatment will also 
have PK and PD samples collected at Month 3 and Month 12. Safety and efficacy will be 
evaluated throughout the study. The assessment criteria will be described in the DRC charter.


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Randomization in Part B of this study will begin once the cumulative data from the Initial PK, 
PD, and Safety Assessment Period in Part A are deemed acceptable by the IDMC. The decision 
tree of rivaroxaban exposure acceptability criteria will be described in the IDMC charter. The 
IDMC may stop enrollment into Part A and begin enrollment into Part B without changes, 
recommend to continue enrollment into Part A, or adjust the dose in Part B, depending on the 
results obtained.
Subjects Participating in Part B
For subjects randomized into Part B, there will be an up to a 21-day Screening Period, a 
12-month Open-Label Treatment Period and a 30-day Follow-Up Contact (phone contact) (see 
Time & Events Schedule). Subjects who do not meet all of the enrollment criteria for the study 
may be rescreened 1 additional time as long as enrollment is within 4 months of their Fontan 
procedure. Subjects who are rescreened will be assigned a new subject number, undergo the 
informed consent process, and then restart a new screening phase. Approximately 90 subjects 
who meet all of the inclusion and none of the exclusion criteria will be randomly assigned in a 
2:1 ratio to receive rivaroxaban oral suspension and ASA for 12 months.
Parental informed consent/child assent (as appropriate, typically at age ≥7 years or as defined by 
local regulations) must be obtained prior to performing any study-specific procedures. Subjects 
will undergo the same screening evaluations as in Part A. Eligible subjects will be enrolled and 
randomized on Day 1 and will receive their first dose of study drug on site at this visit. 
Pharmacokinetic and PD samples will be obtained on Day 1, Month 3, and Month 12 for subjects 
randomized to rivaroxaban only. Safety and efficacy will be evaluated throughout the study for 
all subjects.
Early Study Medication Discontinuation
For subjects in Part A and Part B who prematurely discontinue study drug for any reason, the 
Early Study Medication Discontinuation (ESMD) visit will be performed as soon as possible 
after discontinuation. A Follow-Up Contact (phone contact) will be performed 30 days following 
the last dose of study drug and at Month 12, the end of the planned treatment period. After 
cessation of the study drug, it is at the investigator’s discretion to continue with other 
antiplatelet/anticoagulant therapy. Every attempt must be made to ensure the subject is not lost to 
follow up.  
Note: An exception are subjects who are enrolled after local reading of the Screening 
transthoracic echocardiogram rules out thrombosis, and subsequently reported to have 
thrombosis after central reading by the core laboratory of the same transthoracic 
echocardiogram. These subjects will be withdrawn from the study when the result of the 
echocardiogram by the core laboratory becomes available. Subjects will be asked to return for 
the ESMD visit as soon as possible. They will not be required to have a repeat transthoracic 
echocardiogram as part of the ESMD. Subjects will go on to receive proper care according to the 
healthcare provider’s judgment. They will be contacted by phone approximately 30 days (+/-
7 days) after last dose of study drug (Follow-Up Contact). An ESMD Month 12 follow up visit 
will not be required.


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No interim analysis will be performed for this Study. An IDMC will monitor the subject’s safety 
and give recommendations to the Executive Committee (EC). The IDMC has the responsibility 
to provide the EC and the sponsor with recommendations related to the protection of the 
pediatric subject’s safety, including stopping recruitment and study treatment. For that purpose, 
the IDMC will regularly review all incidences of serious adverse events, thrombotic events and 
bleeding events. Organizational aspects, responsibilities, and processes will be described in the 
IDMC charter.
Committees and Advisors
An EC, an internal DRC, IDMC, a Central Independent Adjudication Committee (CIAC),
Steering Committee (SC), and a Sponsor Committee, will be commissioned for this study. Refer 
to Section 9.7, Committees, for details.
A diagram of the study design is provided below in Figure 1.
Figure 1: 
Schematic Overview of Study 39039039CHD3001
Key: BID=twice daily, DRC= Data Review Committee, IDMC=Independent Data Monitoring Committee, PD= 
pharmacodynamics, PK= pharmacokinetic(s)
Note: An internal DRC will assess by Day 12 the PK, PD, and the safety data from each subject, prior to the subject 
continuing in the study to complete the planned 12 months of open-label rivaroxaban therapy. 
Enrollment in Part A will end, and enrollment in Part B will start, once the cumulative data from all subjects in 
the Initial PK, PD, and Safety Assessment Period of Part A are deemed acceptable by the IDMC.


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3.2.
Study Design Rationale
Study Population
Young pediatric subjects who have recently completed the initial Fontan procedure were chosen 
for this study because they are a population with a high thrombotic risk and for whom there is 
scant evidence-based information regarding thromboprophylaxis. Much of the data for pediatric 
recommendations for thromboprophylaxis are still extrapolated from adult data. Alternative 
thromboprophylaxis strategies should be studied in the post-Fontan population in light of the 
high prevalence of thrombotic events, difficulties achieving consistent protection with current
anticoagulant therapy, and the considerable residual risk that remains in children treated with 
warfarin or ASA. Results from this study would therefore fulfill an unmet medical need. 
Two-Part Study 
Because this is the first clinical study of rivaroxaban in pediatric post-Fontan subjects, this study 
is designed to first, evaluate the single- and multiple-dose PK properties of rivaroxaban in this 
population (Part A) to confirm the dose scheme chosen, and, second, to evaluate the safety and 
efficacy profiles of rivaroxaban when used for thromboprophylaxis for 12 months and compare 
them to those of ASA (Part B). Enrollment in Part B will begin once the cumulative data from 
the Initial PK, PD, and Safety Assessment Period in Part A are assessed by the IDMC. 
Dose and Dosing Regimen, Treatment Period
Because patients with known thrombosis will not be allowed to be enrolled in this study, this 
population will more closely be similar to a prophylaxis population than a treatment population.
The rivaroxaban dose to be used in this study was determined via an adapted PBPK modeling 
approach based on previously established and validated rivaroxaban PBPK modeling, used for 
the VTE pediatric studies and adapted to reflect the special physiology of the pediatric 
post-Fontan population.26,24 Rivaroxaban will be administered to the pediatric post-Fontan 
population as age- and body weight-adjusted dosing targeting exposure (as measured by AUC0-24 
at steady state), matching that of rivaroxaban 10 mg total daily dose in adults that has been 
shown to be safe and effective for thromboprophylaxis in adult subjects after major orthopedic 
surgery (Phase 3 RECORD studies).32
The pediatric PBPK model was also used to compare once- or twice-daily dosing options. 
Twice-daily dosing was chosen because it provided both, a lower Cmax that stayed completely 
within the adult reference range and a higher trough plasma concentration (Ctrough) that was 
sufficiently high to not fall below the lower adult PBPK modeling range. 
No relevant difference in Cmax is expected between the first dosing day and steady state in the 
population targeted in this study.
These subjects will be followed for 1 year because thrombus formation is most significant 
immediately following the Fontan procedure and has been noted to peak within the first 
postoperative year in particular.16,17


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PK and PD Sampling Scheme
Pharmacokinetic and PD samples will be drawn on Day 1 and Day 4 of rivaroxaban treatment in 
Part A with the main goal of obtaining initial assessment of rivaroxaban exposure. 
Pharmacokinetic and PD samples will also be drawn at Month 3 and Month 12, to further enrich 
and refine the initial PK/PD model and to evaluate any adjustment in dose made at Month 6 due 
to the subjects’ weight gain. 
Comparator Selection
Subjects in Part B are randomized to ASA as the appropriate comparator to allow for the 
evaluation of benefit/risk of rivaroxaban as a thromboprophylactic agent in pediatric subjects 
who have single-ventricle physiology and who have completed the Fontan procedure. This 
decision was made based on careful consideration of the literature, existing guidelines for the 
standard-of-care practice, and current clinical practice in many centers. 
Current American College of Chest Physicians 2012 guidelines recommend ASA, or
unfractionated heparin followed by warfarin for this patient population.12 The American Heart 
Association, in a statement in 2013, suggested that long-term antiplatelet therapy for prevention 
of thrombosis is reasonable after the Fontan procedure and that prophylaxis with warfarin or 
LMWH may be reasonable after the Fontan procedure for patients with anatomic or 
hemodynamic risk factors.11 However, controversy remains in clinical practice as to the optimal 
prevention strategy to be followed, as there are no evidence-based recommendations.11,12 The 
only prospective, multicenter, randomized study published showed a similar cumulative risk for 
thrombosis between ASA (5 mg/kg/day) and heparin/warfarin treatment.20 In a secondary 
analysis of this study, risk reduction was observed in a small subset of subjects in the warfarin 
group who had adequate INR levels and in those on ASA, compared with subjects in the 
warfarin group with a high prevalence of sub therapeutic INR measurements (<30% INR 
measurements within the target range).18 These subjects had a significantly greater risk of 
thrombosis than those subjects who received ASA therapy alone. Because the factors associated 
with poorly controlled warfarin therapy in these subjects have not been identified yet, the authors 
of the study concluded that ASA might be the best current strategy to prevent thrombosis for this 
patient population.18 Using ASA as the comparator in this study will allow a descriptive 
comparison of results across 2 different drug classes: antiplatelet versus anticoagulant therapy 
within the period of highest incidence of thrombosis (up to 12 months after Fontan procedure). 
A new oral anticoagulant such as rivaroxaban, which demonstrated in studies in adults to be 
noninferior regarding efficacy but with more predictable and stable PK and easier to dose, may 
be a potential alternative to ASA or VKA treatment in the post-Fontan population. 


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Open-label and Randomization
Randomization will be used in Part B to minimize bias in the assignment of subjects to treatment 
groups, to increase the likelihood that known and unknown subject attributes (eg, demographic 
and baseline characteristics) are evenly balanced across treatment groups, and to enhance the 
validity of the descriptive comparisons between treatment groups. Open-label treatment will be 
used to allow for further evaluation of the PK and PK/PD profiles of rivaroxaban throughout the 
study.
Safety Assessments
As with any anticoagulant agent, the use of rivaroxaban is associated with an increased risk of 
bleeding events. Bleeding events will be assessed using the International Society on Thrombosis 
and Hemostasis (ISTH) classification to be consistent with the other rivaroxaban pediatric VTE 
treatment studies.5,27 All bleeding events will be adjudicated by the CIAC.
Efficacy Assessment
The efficacy outcomes of any thrombotic event (venous or arterial), defined as the appearance of 
a new thrombotic burden within the CV system on either routine surveillance or clinically 
indicated imaging, or the occurrence of a clinical event known to be strongly associated with 
thrombus (such as cardioembolic stroke, pulmonary embolism), are accepted, validated, clinical 
endpoints for the evaluation of thromboprohylaxis. All transthoracic echocardiograms will be 
taken under a standardized protocol and will be read in a blinded manner at a central laboratory 
to minimize inter-site variability and bias.
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 21 days before administration of the 
study drug.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed.
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, 
Sample Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
1.
Boys or girls 2 to 8 years of age with single ventricle physiology and who have 
completed the initial Fontan procedure within 4 months prior to enrollment 
2.
Considered to be clinically stable by the investigator and able to tolerate oral or enteral 
administration of a suspension formulation and oral/enteral feedings 


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3.
Satisfactory initial post-Fontan transthoracic echocardiographic screening as defined in 
the Post-Fontan Echocardiographic Examination Research Protocol 
4.
Parent/legally acceptable representative must sign an informed consent form (ICF) and 
child assent will also be provided, if applicable, according to local requirements. 
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study.
1.
Evidence of thrombosis, including those that are asymptomatic confirmed by post-
Fontan procedure transthoracic echocardiogram, or other imaging techniques, during the 
screening period of the study
2.
History of gastrointestinal disease or surgery associated with clinically relevant 
impaired absorption 
3.
History of or signs/symptoms suggestive of protein-losing enteropathy 
4.
Active bleeding or high risk for bleeding contraindicating antiplatelet or anticoagulant 
therapy, including a history of intracranial bleeding
5.
Criterion modified per Amendment INT-2
5.1.   Indication for anticoagulant or antiplatelet therapy other than current study, 
however:

A subject who has received VKA after the Fontan procedure may be eligible 
provided that the subject has discontinued VKA before the screening visit. 
Baseline laboratory samples must be obtained at least 7 days after the last dose 
of VKA.

A subject who is receiving ASA at the time of the screening visit may be 
eligible and may continue on ASA provided the last dose is taken at least 
24 hours prior to the first dose of study drug.

A subject who is receiving heparin or LMWH after the Fontan procedure may 
be eligible and may continue receiving either of these anticoagulants during the 
screening period provided the study drug (rivaroxaban or ASA) is started 0 to 2 
hours prior to the next scheduled administration of either of these 
anticoagulants and omit their administration thereafter.  
6.
Chronic use of NSAIDs
7.
Platelet count <50 x 109/L at screening
8.
Criterion modified per Amendment INT-2


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8.1.   Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 (Attachment 3)
9.
Known clinically significant liver disease (eg, cirrhosis, acute hepatitis, chronic active 
hepatitis, or alanine aminotransferase (ALT) >3x upper limit of normal (ULN) with 
concurrent total bilirubin >1.5x ULN with direct bilirubin >20% of the total at 
screening)
10.
Criterion modified per Amendment INT-2
10.1.   Known contraindication to ASA, or has or is recovering from chicken pox or flu-
like symptoms (subjects participating in Part B only)
11.
Criterion modified per Amendment INT-2
11.1.   Known allergies, hypersensitivity, or intolerance to rivaroxaban, ASA or its 
excipients (Investigator's Brochure)14
12.
Inability to cooperate with study procedures
13.
Combined P-gp and strong CYP3A4 inhibitors (such as but not limited to ketoconazole, 
telithromycin, or protease inhibitors) use within 4 days before enrollment, or planned 
use during the study. Itraconazole use within 7 days before enrollment or planned use 
during the study
14.
Combined P-gp and strong CYP3A4 inducers (such as but not limited to 
rifampin/rifampicin, rifabutin, rifapentine, phenytoin, phenobarbital, carbamazepine, or 
St. John's Wort) use within 2 weeks before enrollment, or planned use during the study
15.
Planned use of drugs that are moderate CYP3A4 inhibitors (such as erythromycin) 
during the Initial PK, PD, and Safety Assessment Period of Part A only
16.
Participation in a clinical study with an investigational drug or medical device in the 
previous 30 days prior to enrollment
17.
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
18.
Family member of an 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
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's status changes (including laboratory results or receipt of additional medical records) 
after screening but before the first dose of study drug is given such that he or she no longer meets
all eligibility criteria, then the subject should be excluded from participation in the study. 
Section 17.4, Source Documentation, describes the required documentation to support meeting 


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the enrollment criteria. Subjects who do not meet all of the enrollment criteria for the study may 
be rescreened 1 additional time as long as enrollment is within 4 months of their Fontan 
procedure. Subjects who are rescreened will be assigned a new subject number, undergo the 
informed consent process, and then restart a new screening phase.
Modification of an effective preexisting therapy should not be made for the explicit purpose of 
entering a subject into the study.
4.3.
Prohibitions and Restrictions 
Refer to Section 8, Prestudy and Concomitant Therapy, for details regarding prohibited and 
restricted therapy during the study.
5.
TREATMENT ALLOCATION AND BLINDING
Subjects in Part A will not be randomized.
Treatment Allocation
Procedures for Randomization in Part B
Subjects will be randomly assigned to 1 of 2 treatment groups based on a computer-generated 
randomization schedule prepared before the study by or under the supervision of the sponsor. 
The randomization ratio will be 2:1 for rivaroxaban and ASA. The randomization will be 
balanced by using randomly permuted blocks. Based on this randomization code, the study drug 
will be packaged and labeled for each subject. Study drug code numbers will be preprinted on 
the study drug labels and assigned as subjects qualify for the study and are assigned to treatment.
The interactive web response system (IWRS) will assign a unique treatment code for each 
subject, which will dictate the treatment assignment and matching study drug kit for the subject. 
The requestor must use his or her own user identification and personal identification number 
when contacting the IWRS to receive the relevant subject details to uniquely identify the subject.
Blinding
As this is an open-label study, blinding procedures are not applicable.
6.
DOSAGE AND ADMINISTRATION
Rivaroxaban: The rivaroxaban dose to be used in this study was determined via an adapted 
PBPK modeling approach.26 Rivaroxaban will be administered twice daily in an open-label 
fashion as a 0.1% (1 mg/ml) oral suspension with target exposure (AUC0-24 at steady state)
matching to that of rivaroxaban 10 mg total daily dose in adults (age- and body weight-adjusted 
dosing [see Table 1]). Because children with an estimated glomerular filtration rate below 
30 mL/min/1.73 m2 are excluded from the study, dose reduction for impaired renal function is 
not required. Rivaroxaban will be taken in the morning and in the evening (approximately 
12 hours apart) at approximately the same times each day as described in the study booklet. Dose 
adjustment, due to increased body weight, will be made at Month 6 (both Part A and Part B).


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Table 1: 
Dosing Table for Rivaroxaban Administration 
Body weight [kg]a
BID Doseb 
[mg or mL]
Total Daily Dosec
[mg]
7 to <8
1.1
2.2
8 to <10
1.6
3.2
10 to<12
1.7
3.4
12 to <20
2.0
4.0
20 to <30
2.5
5.0
BID=twice daily
a) For subjects with body weight outside of the range provided in this table, please 
contact the sponsor for dosing information.
b) Oral suspension 0.1% (1 mg/mL)
c) Equivalent to exposure of 10 mg once daily in adults
  
ASA: Acetylsalicylic acid will be provided as 81-mg or 100-mg tablets according to local 
practice. Subjects randomized to ASA will receive approximately 5 mg/kg of ASA to a 
maximum of 1 whole tablet as a single daily dose as described in the study booklet. Tablets can 
be split in half, if necessary (eg. children weighing ≤10 kg), to meet the daily dose, and the dose 
must be documented. It is recommended that tablets are not split more than in half. Dose 
adjustments due to increased body weight, will be made at Month 6.
Temporary discontinuation of the study drug is allowed for events, such as intercurrent illnesses. 
In this case, standard clinical practice should be followed. See Section 10.2.1, Temporary 
Discontinuation of Study Treatment. All interruptions of study drug must be recorded in the 
eCRF.
Throughout the study, study drug will be dispensed at appropriate intervals (see the Time and 
Events Schedule) to ensure that subjects have adequate quantities of study drug between study 
visits. Study-site personnel will instruct parents/legally acceptable representatives on the proper 
administration and storage of study drug for at-home use.
Detailed instructions on the administration of the oral suspension will be provided in the study 
booklet.
Missed Dose
Rivaroxaban: is taken in a twice daily regimen. A missed morning dose should be taken 
immediately when it is noticed, any time during the calendar day, which could include taking it 
together with the evening dose. A missed evening dose should only be taken in the same evening. 
On the following day, the subject should continue with the regular twice daily regimen. A missed 
dose from a previous calendar day should not be taken.


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ASA: if a dose of ASA is missed the subject should take the missed dose immediately when it is 
noticed within the same calendar day. On the following day, the subject should continue with the 
regular once daily regimen. A missed dose from a previous calendar day should not be taken.
Intentional stopping of study drug by the subject, unintentional stopping of study drug for more 
than 7 consecutive days, or temporary stopping of study drug as directed by the investigator or 
other physician will be documented. Study drug interruptions will be recorded in the eCRF. 
Vomiting and/or Spitting After Dosing
If the subject immediately vomits and/or spits up the dose within 30 minutes after receiving a 
dose of study medicine (rivaroxaban or ASA), a second dose should be given. If the subject 
vomits more than 30 minutes after the first dose, a second dose must not be given to replace it. 
The parent should contact the study team if the subject spits up the dose or vomits after receiving 
the study medicine multiple times either the same day or on different days.
7.
TREATMENT COMPLIANCE
The IWRS in Part A and Part B will keep track of study drug dispensed to the subjects. 
The investigator or designated study-site personnel will maintain a log of all study drug 
dispensed and returned. Drug supplies for each subject will be inventoried and accounted for 
throughout the study. 
8.
PRESTUDY, CONCOMITANT AND POSTSTUDY THERAPY
Any previous anticoagulant/antiplatelet medication taken after the Fontan procedure and prior to 
first dose of study drug will be documented as prestudy therapy. 
Concomitant medications include all medications received between the first dose and the last 
dose of study drug.
Any anticoagulant/antiplatelet medication initiated after the end of the study treatment period 
will also be documented on the concomitant medication eCRF page (see Section 9.1.5, 
Posttreatment Period [Follow-Up Contact]).
Concomitant therapies (prescription or over-the-counter medications, including vaccines, 
vitamins, herbal supplements) must be recorded throughout the study according to the Time and 
Events Schedule.


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Prohibited Therapy
For All Subjects in the Study:
The use of any other antiplatelet, anticoagulant (other than study drug) taken concomitantly with 
study drug is prohibited.
Chronic NSAID therapy is prohibited during the study.  
Modification of an effective preexisting therapy should not be made for the explicit purpose of 
entering a subject into the study.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered
For Subjects Receiving Rivaroxaban only:
Combined P-gp and strong CYP3A4 inhibitors (such as but not limited to ketoconazole, 
telithromycin, or protease inhibitors) use is prohibited within 4 days before enrollment, or during 
the study. Itraconazole use is prohibited within 7 days before enrollment or during the study.
Combined P-gp and strong CYP3A4 inducers (such as but not limited to rifampin/rifampicin, 
rifabutin, rifapentine, phenytoin, phenobarbital, carbamazepine, or St. John's Wort) use is 
prohibited within 2 weeks before enrollment, or planned use during the study is prohibited.
Planned use of drugs that are moderate CYP3A4 inhibitors (such as erythromycin or 
fluconazole) are not allowed during the Initial PK, PD, and Safety Assessment Period of Part A 
only. However, they are allowed during the 12-month Open-Label Treatment Periods of Part A 
and Part B.
Allowed Therapy
Subjects can receive ASA during the screening period and up to 24 hours prior to the first dose 
of study drug at Day 1 Visit.
A subject who has received VKA after the Fontan procedure may be eligible provided that the 
subject has discontinued VKA before the screening visit. Baseline laboratory samples must be 
obtained at least 7 days after the last dose of VKA. 
A subject who is receiving heparin or LMWH after the Fontan procedure may be eligible and 
may continue receiving either of these anticoagulants during the screening period provided the 
study drug (rivaroxaban or ASA) is started 0 to 2 hours prior to the next scheduled 
administration of either of these anticoagulants and omit their administration thereafter.
Occasional use of NSAID is allowed, but the lowest possible dosage and shortest duration should 
be selected.


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9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of PK, PD, safety, and 
efficacy measurements applicable to this study.
The study consists of 2 parts: 

Part A of the study has an up to 21-day Screening Period, a 12-Month Open-Label 
Treatment Period (which includes a 12-day Initial PK, PD, and Safety Assessment Period), 
and a 30-day Follow-up Contact  

Part B of the study has an up to 21-day Screening Period, a 12-Month Open-Label 
Treatment Period and a 30-day Follow-up Contact  
For each subject in Part A, blood samples will be obtained at the timepoints noted in the Time 
and Events Schedule; the estimated amount of blood drawn in this study will be approximately 
33 mL over 12 months (a maximum of approximately 3.5 mL on each blood draw, except for 1 
blood draw each at the Month 3 and Month 12 visits, where 4.5 ml will be drawn). For details on 
the volumes and types of blood samples to be collected, see table in Attachment 1.  
For each subject in Part B, blood samples will be obtained at the timepoints noted in the Time 
and Events Schedule; the estimated amount of blood drawn in Part B will be approximately 25 
mL over a 12-month period (a maximum of approximately 3.5 ml on each blood draw, except for 
1 blood draw at the Month 12 visit, where 4.3 ml will be drawn). For details, see table in 
Attachment 1.
9.1.2.
Screening Period   
Subjects Participating in Part A 
Parental informed consent/child assent (as appropriate) must be obtained prior to performing any 
study-specific procedures. The screening assessments will take place after the Fontan procedure 
and up to 21 days before the first dose of study drug. During the screening period, baseline 
laboratory blood testing will be done and a transthoracic echocardiogram using a study-specific
protocol (see Attachment 2) will be performed to rule out thrombosis. Laboratory parameters 
obtained as part of the standard-of-care may be used as baseline safety if conducted within 21 
days prior to receiving the first dose of rivaroxaban. The most recent post-Fontan clinical 
laboratory results will be used for screening if there are multiple laboratory results. Subjects who 
do not meet all of the enrollment criteria for the study may be rescreened 1 additional time as 
long as enrollment is within 4 months of their Fontan procedure. Subjects who are rescreened 
will be assigned a new subject number, undergo the informed consent process, and then restart a 
new screening phase.


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All screening activities must be completed before enrollment and the results must be available to 
the investigator for review to ensure that eligibility criteria are met. The IWRS will assign a 
unique subject identification number.
Subjects Participating in Part B
Parental informed consent/child assent (as appropriate) must be obtained prior to performing any 
study-specific procedures. Subjects will undergo the same screening evaluations as in Part A
except for PT and aPTT testing which will be performed on Day 1 prior to first dose of study 
drug.  
All screening activities
related to establishing eligibility must be completed before
randomization and the results must be available to the investigator for review to ensure that 
eligibility criteria are met. Subjects may be enrolled and randomized on the business day prior to 
Day 1 to facilitate logistics provided the investigator ensures that the subject meets all eligibility 
criteria prior to randomization.  The first dose of study drug will be administered on site on Day 
1 if the subject is still eligible.
9.1.3.
Open-label Treatment Period
9.1.3.1.
Part A
There will be up to 7 planned study visits and 1 telephone contact:

Visit 1 - Screening visit (up to 21 days prior to the first dose of study drug)

Visit 2-D1 – Enrollment and PK and PD sampling after first dose of study drug administered 
on site, dispense drug supply (Day 1)

Visit 2-D4 – PK and PD sampling before and after the Day 4 dose of rivaroxaban (Day 4) 

Visit 2-D12 – Communicate to subject if rivaroxaban treatment will be continued. Physical 
examination and dispense 3-month drug supply (Day 12)

Visit 3 – Physical examination, PK, PD, and dispense 3-month drug supply (Month 3)

Visit 4 – Physical examination, transthoracic echocardiogram, adjustment of dose (if 
needed), and dispense 6-month drug supply (Month 6)

Visit 5 - Physical examination, PK, PD, transthoracic echocardiogram, lab testing, final visit 
(Month 12)

Phone call – Follow-Up Contact
Approximately 10 subjects are planned to be enrolled in Part A. Subjects will receive the first 
dose of rivaroxaban on Visit2/Day1 (on site). Any visit may take place while the subject is 
hospitalized.
On Day 1 and Day 4, blood samples for PK and PD assessments will be collected by 
venipuncture. Ideally, an intravenous line could be placed by an experienced pediatric 
phlebotomist on the days of multiple blood draws. For the detailed schedule see Section 9.2,
Pharmacokinetics/Pharmacodynamics Evaluations. 


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Pharmacokinetic and PD (PT and aPTT tests) blood samples will be sent to the central laboratory 
after the collection of the last sample on Day 4 (ie, after the 6.0 to 8.0 hour sample). Results are 
anticipated to be available for DRC review 4 to 6 days after the samples are received by the 
central laboratory.
An internal DRC will review the subject’s PK, PD and safety data obtained from the Initial PK, 
PD, and Safety Assessment Period prior to allowing the subject to continue on rivaroxaban 
therapy to complete the 12-month period. The sponsor will notify the investigator about the DRC 
decision prior to Visit 2-D12 (+ 9 days). At this visit, the subject will either be informed to 
continue on rivaroxaban in the 12-month Open-Label Treatment Period or be discontinued from 
the study. 
Subjects who continue on in the Open-Label Treatment Period will have up to 3 more planned 
visits: after 3 months (Visit 3), after 6 months (Visit 4), and after 12 months (Visit 5/End of 
Study), and a Follow-Up Contact  (phone contact) will be performed 30 days following the last 
dose of rivaroxaban.  
Transthoracic echocardiograms will be obtained at screening, Month 6, and at the end of the 
study (Month 12) or ESMD (for details see Section 9.1.6, Transthoracic Echocardiograms). PK
and PD blood samples will be collected at Month 3 and at Month 12. Safety and efficacy will be 
evaluated throughout the study.
Enrollment in Part A will end, and enrollment in Part B will start, once the cumulative data from 
the Initial PK, PD, and Safety Assessment Period are deemed acceptable by the IDMC.
Assessment criteria will be described in the IDMC charter.
For Safety and Efficacy evaluations see Section 9.3, Safety Evaluations/Outcomes, and 
Section 9.4, Efficacy Evaluations/Outcomes, respectively.
9.1.3.2.
Part B
Enrollment in Part B of this study will begin after enrollment in Part A ends. This 
recommendation will be made by the IDMC.
There will be up to 5 planned study visits and 2 phone contacts:

Visit 1 – Screening visit (up to 21 days prior to the first dose of study drug)

Visit 2 – enrollment, randomization, PK and PD sampling and first dose of study drug 
administration on site; dispensation of 3-month drug supply (Day 1)

Phone call  - after 12 days of the start of study drug

Visit 3 – Physical examination, PK, PD, and dispense 3-month drug supply (Month 3)

Visit 4 – Physical examination, transthoracic echocardiogram, adjustment of dose (if 
needed), and dispense 6-month drug supply (Month 6) 

Visit 5 – Physical examination, PK, PD, transthoracic echocardiogram, lab testing, final visit 
(Month 12)


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
Phone call – Follow-Up Contact, 30 days after last study drug is taken.
Approximately 90 subjects are planned to be enrolled in Part B. Any visit may take place while 
the subject is hospitalized.
Subjects will be enrolled and randomized on Visit 2/Day 1 after meeting inclusion and exclusion 
criteria. Subjects may be enrolled and randomized on the business day prior to Day 1 to facilitate 
logistics provided the investigator ensures that the subject meets all eligibility criteria prior to 
randomization. The first dose of study drug will be administered on site on Day 1 if the subject is 
still eligible. Subjects will be contacted by phone at approximately 12 days (± 9 days) after the 
first dose to obtain safety and efficacy information after the start of study drug. Visits 3 and 4 are 
treatment visits and occur after 3 months and 6 months of therapy, respectively. Visit 5 is the end 
of study visit (Month 12). Transthoracic echocardiograms will be obtained at screening, at 
Month 6, and at the end of the study (Month 12), or ESMD visit (for details see Section 9.1.6,
Transthoracic Echocardiograms). Safety and efficacy will be evaluated throughout the study.
For subjects randomized to rivaroxaban, blood samples for PK and PD evaluations will be 
collected. For details see Section 9.2, Pharmacokinetics/Pharmacodynamics Evaluations.  
For Safety and Efficacy evaluations see Section 9.3, Safety Evaluations/Outcomes, and 
Section 9.4, Efficacy Evaluations/Outcomes, respectively.
9.1.4.
Unscheduled Visits
Additional site visits may be added as necessary, at the discretion of the investigator.
9.1.5.
Posttreatment Period (Follow-Up Contact)
In both Part A and Part B, all subjects will be contacted by phone at the following time periods:
1.
Subjects who complete the 12-Month treatment period or subjects who are withdrawn from 
the study will receive 1 phone contact: Approximately 30 days (+/-7 days) after last dose 
taken (Follow-Up Contact). A review of safety and efficacy outcomes will be conducted at 
this contact and any concomitant medications will be recorded.
2.
Subjects who permanently discontinue study drug early but continue in (are not withdrawn 
from) the study will receive 2 phone contacts: Approximately 30 days (+/- 7 days) after last 
dose taken (Follow-Up Contact) to review safety and efficacy outcomes and any 
concomitant medications; and at the end of the planned treatment period (ESMD 12 Month 
follow up) to determine their vital status and thrombotic events (no bleeding events).
Transition at End-of-Treatment 
If at the end of study treatment a decision is made to continue a subject on an anticoagulant or 
ASA, the following guidelines are provided:

Subjects who switch from rivaroxaban to heparin/LMWH/fondaparinux can switch at the 
time of the next scheduled dose.


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
Subjects who switch from rivaroxaban to VKA need to continue rivaroxaban for 48 hours 
after the first dose of VKA. After 2 days of co-administration, an INR should be obtained 
prior to the next scheduled dose of rivaroxaban. Co-administration of rivaroxaban and VKA 
is advised to continue until the INR is ≥2.0.

Subjects who switch from rivaroxaban to ASA can switch to ASA at the time of the next 
scheduled dose.
Any anticoagulant/antiplatelet medication initiated at the end of the study treatment period will 
be documented on the concomitant medication eCRF page.
9.1.6.
Transthoracic Echocardiograms 
Transthoracic echocardiograms will be obtained according to the timepoints noted in the Time 
and Events Schedule for the assessment of thrombotic events. For the Screening post-Fontan 
transthoracic echocardiogram, the Post-Fontan Echocardiographic Examination protocol in 
Attachment 2 is to be followed, and the following guidelines will be applicable:

The subject is not to be enrolled if local reading of the Screening transthoracic 
echocardiogram confirms thrombosis. The subject’s transthoracic echocardiogram will not 
need to be sent to the core laboratory.

The subject may be enrolled if local reading of the Screening transthoracic echocardiogram 
rules out thrombosis and the remaining inclusion/exclusion criteria are satisfied. The 
Screening transthoracic echocardiogram is to be sent to the core laboratory for central 
reading.

The subject will be withdrawn from the study if the subject is enrolled after local reading
rules out thrombosis on the transthoracic echocardiogram and subsequently central reading 
by the core laboratory reports a thrombosis from the same transthoracic echocardiogram. 
The reasoning for the early withdrawal will be documented on the eCRF.
The core laboratory report will serve as the baseline for the comparison of the subsequent study 
transthoracic echocardiograms. 
Investigators can image as often as medically necessary or as needed based on their institution’s 
standard-of-care; however, protocol-based imaging must be performed according to the 
timepoints noted in the Time and Events Schedule. Echocardiograms will be sent to a core 
laboratory for blinded reading and to minimize inter-site variability and bias. During the course 
of the study, for subjects who prematurely discontinue study drug for any reason, the final 
echocardiogram will be performed as soon as possible after discontinuation at the ESMD visit. A 
detailed description of the echocardiogram core laboratory process will be provided in a separate 
manual. The Post-Fontan Echocardiographic Examination protocol is provided in Attachment 2.  
9.2.
Pharmacokinetics/Pharmacodynamics Evaluations
Blood samples for rivaroxaban PK and PD, including rivaroxaban plasma concentration, 
absolute PT, activated partial thromboplastin time (aPTT) and anti-FXa activity measurements 
will be taken from pediatric subjects enrolled in Part A and for subjects randomized to 
rivaroxaban in Part B at the timepoints noted in the Time and Events Schedule. Rivaroxaban 


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plasma concentration will be determined using the validated liquid chromatography/mass 
spectrometry/mass spectrometry (LC-MS/MS) method. The dosing, exact time of rivaroxaban 
administration and PK and PD blood sampling will be documented in the eCRF. The exact time 
must be documented even if PK and PD samples are taken outside of the prespecified time 
window.
Ideally, PK and PD blood samples will be collected by venipuncture by an experienced pediatric 
phlebotomist. A local anesthetic cream can be applied at the venipuncture site to decrease
discomfort.
If blood samples are collected via an indwelling cannula, an appropriate amount (eg, 1 mL) of 
fluid slightly greater than the dead space volume of the lock will be removed from the cannula 
before each blood sample is taken (see Section 9.5, Sample Collection and Handling for more 
details).8
Detailed information about the handling and labeling of the samples will be provided in the 
laboratory manual.
Part A
Pharmacokinetic and PD blood samples will be collected on the first day of dosing (Visit 2/D1) 
between 0.5 to 1.5 hours and again between 1.5 to 4.0 hours postdose. Additional samples will 
be collected on Day 4 (Visit 2/D4), just prior to dose administration and again between 0.5 to 
1.5 hours, 1.5 to 4.0 hours, and 6.0 to 8.0 hours postdose. Pharmacokinetic and PD samples will 
be sent to the central laboratory after the collection of the last sample on Day 4 (ie, the 6.0 to 
8.0 hour sample). 
Rivaroxaban plasma concentration will be determined using the validated LC-MS/MS method. 
The blood samples on Day 1 and Day 4 will be taken as specified in Table 2. See Attachment 1
for details.
Pharmacokinetic and PD samples will also be taken at Month 3 and Month 12. See the Time and 
Events Schedule and Attachment 1 for details.
If rivaroxaban is temporarily stopped, PK and PD blood samples should only be obtained if 
rivaroxaban administration has been restarted and sustained for at least 3 days.


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Table 2: 
Sampling Schedule of the Initial PK, PD, and Safety Assessment Period (Day 1 and Day 4-6) 
(Part A)a   
Visit 2-D1/
Day 1
Visit 2-D4/
Day 4b 
Postdosec
0.5-1.5 hours
Postdosec
1.5-4 hourse
Predosec,d
Postdosec
0.5-1.5 hours
Postdosec
1.5-4 hourse
Postdosec
6.0-8 hours
PKf
0.6 ml
0.6 ml
0.6 ml
0.6 ml
0.6 ml
0.6 ml
PD-1g
1.4 ml
1.4 ml
1.4 ml
1.4 ml
1.4 ml
1.4 ml
PD-2h
1.4 ml
1.4 ml
-
-
-
1.4 ml
D1=Day 1; D4=Day 4; PD=pharmacodynamics; PK=pharmacokinetics.
a) Subjects continuing in Part A will also have additional PK and PD assessments at Months 3 and 12. See Time and 
Events Schedule and Section 9.2, Pharmacokinetics/Pharmacodynamics Evaluations, for details. 
b) Visit 2-D4 can be performed on Days 4, 5, or 6.
c) Sampling times are relative to morning dose.
d) Up to 3 hours predose. 
e) Allow at least 30 minutes from the previous sample.
f) Blood volume per PK sample for rivaroxaban plasma concentration is approximately 0.6 mL; total blood volume 
for all PK samples is 3.6 mL (Day 1: 1.2 mL; Day 4: 2.4 mL); sites will send samples to the central laboratory on 
the day of collection for liquid chromatography/mass spectrometry/mass spectrometry (LC-MS/MS)
determination. 
g) PD-1 assessments will include prothrombin time (PT) and activated partial thromboplastin time (aPTT). Blood 
volume per PD-1 sample is approximately 1.4 mL; total blood volume for all PD-1 samples is 8.4 mL 
(Day 1: 2.8 mL; Day 4: 5.6 mL). Sites will send samples to the central laboratory after Day 4 of collection. 
h) PD-2 assessment will be anti-FXa activity. Blood volume per PD-2 sample is approximately 1.4 mL; total blood 
volume for all PD-2 samples is 4.2 mL (Day 1: 2.8 mL; Day 4: 1.4 mL). Sites will send samples to the central 
laboratory.
Part B
Pharmacokinetic and PD samples will also be collected and analyzed for subjects randomized to 
rivaroxaban in Part B. Pharmacokinetic and PD blood samples will be collected on the first day 
of dosing (Visit 2/D1) before first dosing (PT and aPTT only), between 0.5 to 1.5 hours and 
again between 1.5 to 4.0 hours postdose. Additional samples will be collected at Month 3 and 
Month 12. Please see Time and Events Schedule and Attachment 1 for details.
If rivaroxaban was temporarily stopped, PK and PD blood samples for Month 3 and Month 12
should only be obtained if rivaroxaban administration has been restarted and sustained for at 
least 3 days prior to the sampling.


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9.3.
Safety Evaluations/Outcomes
9.3.1.
Bleeding Events
The primary safety outcome will be major bleeding events, as defined below. Clinically relevant 
non-major bleeding events and trivial (minimal) bleeding will be secondary safety outcomes.
Bleeding events will be adjudicated by CIAC using the ISTH recommendations.5,27 The 
following bleeding criteria are consistent across the rivaroxaban pediatric program:
Major bleeding is defined as overt bleeding and:

Associated with a fall in hemoglobin of 2 g/dL or more; or

Leading to a transfusion of the equivalent of 2 or more units of packed red blood cells or 
whole blood in adults ; or

Occurring in a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, 
intramuscular with compartment syndrome, retroperitoneal; or

Contributing to death.
Clinically relevant non-major bleeding is defined as overt bleeding not meeting the criteria for 
major bleeding but associated with:

Medical intervention, or

Unscheduled contact (visit or telephone call) with a physician, or

(Temporary) cessation of study treatment, or 

Discomfort for the subject such as pain, or 

Impairment of activities of daily life (such as loss of school days or hospitalization).
Trivial (minimal) bleeding is defined as any other overt bleeding event that does not meet criteria 
for clinically relevant non major bleeding.
9.3.2.
Approach to the Subject with a Bleeding Event
If a subject has a serious bleed during study treatment, the following routine measures could be 
considered by the treating physician:

Consider usual treatment for bleeding, including blood transfusion, and/or fresh frozen 
plasma if needed

Consider that other causes besides thromboprophylaxis medication can be contributory to 
the seriousness of the bleeding event (eg, thrombocytopenia, and other coagulopathies; 
kidney and liver dysfunction; concomitant medications), and treat accordingly 

Delay the next ASA or rivaroxaban administration or temporarily discontinue treatment, if 
indicated


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
If the subject is treated with rivaroxaban, a blood sample for PK and PD testing should be 
obtained
NOTE: Partial reversal of prothrombin time prolongation has been seen after administration of 
prothrombin complex concentrates (PCCs) in healthy volunteers. The use of other procoagulant 
reversal agents like activated prothrombin complex concentrate (APCC) or recombinant factor 
VIIa (rFVIIa) has not been evaluated.
If severe bleeding cannot be controlled, however, consider administration of one of the following 
procoagulants (both according to the dosages advised in the package insert):

4 factor concentrate 

Recombinant factor VIIa (NovoSeven®) 
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of 
rivaroxaban.
Any products administered to control bleeding should be entered in the CRF.
Parents/ legally acceptable representatives should call the study physician, if the subject has 
signs and symptoms of clinically significant bleeding, for example:

bleeding (eg, nose or gum bleeding) that does not stop within 10 minutes

coughing or throwing up blood

dark-colored urine or black stools

red or black-and-blue marks on the skin that get larger
If the subject has a bleeding incident, the parent/ legally acceptable representatives should 
consult the study physician in addition to their own cardiologist (if different) and always inform 
him/her of the date/time the subject took the last dose of anticoagulant medication. For severe 
bleeding, subjects should be moved to the nearest emergency room.
After resolution of the bleeding event, restarting study drug may be considered based on the 
clinical judgment of the investigator.  
9.3.3.
Other Safety Assessments
The safety and tolerability of rivaroxaban will also be evaluated by assessing other adverse 
events and clinical laboratory test values.
Any clinically relevant changes, including laboratory reports, occurring during the study must be 
recorded on the Adverse Event section of the eCRF. Any clinically significant abnormalities 
persisting at the end of the study/early withdrawal will be followed by the investigator until 
resolution or until a clinically stable endpoint is reached.


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The study includes the evaluations of safety and tolerability according to the time points 
provided in the Time and Events Schedule.
Adverse Events
Adverse events will be reported by the parents/legally acceptable representatives for the duration 
of the study up to the Follow-Up Contact (30-days after last dose). Adverse events will be 
followed by the investigator as specified in Section 12, Adverse Event Reporting.
Clinical Laboratory Tests
The following tests results with reference ranges will be obtained at the visits specified in the 
Time and Events Schedule. Either hospital laboratory/local laboratory results or central 
laboratory results are acceptable at the time of study screening period.  A central laboratory will 
be used during the rest of the study:

Hematology Panel

hemoglobin

hematocrit

red blood cell (RBC) counta

white blood cell (WBC)b count

WBC differentialb:
o
neutrophils
o
lymphocytes
o
monocytes
o
eosinophils
o
basophils

platelet count

Serum chemistry

creatinine (eGFR will be calculated using the original or the modified Schwartz formula 
for pediatric population, see Attachment 3)29

liver function tests (ALT, aspartate aminotransferase [AST], total and direct bilirubin, 
alkaline phosphatase)

PT, aPTT tests 
                                                
a
A RBC evaluation may include abnormalities in RBC count and/or RBC parameters (eg, reticulocyte count) 
and/or RBC morphology, which will then be reported by the laboratory
b
A WBC evaluation may include any abnormal cells, which will then be reported by the laboratory. In addition, 
any other abnormal cells in a blood smear will also be reported.


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9.4.
Efficacy Evaluations/Outcomes
The primary efficacy outcome will be any thrombotic event (venous or arterial), defined as:

The appearance of a new thrombotic burden within the cardiovascular system on either 
routine surveillance or clinically indicated imaging, or

The occurrence of a clinical event known to be strongly associated with thrombus (such as 
cardioembolic stroke, pulmonary embolism).
Subjects who develop either a symptomatic or asymptomatic thrombotic event during the study 
must permanently discontinue the study drug. All thrombotic events and the primary cause of 
any death will be adjudicated by the CIAC. Transthoracic echocardiograms will be centrally read 
by an echocardiographic core laboratory. All available imaging results (eg, transthoracic or 
transesophageal echocardiograms, or MRIs), should be sent to the CIAC. Sites will be required 
to complete a worksheet, compile an adjudication package, and send it to the adjudication office
within 6 weeks from occurrence of the event.
After cessation of the study drug, it is at the investigator’s discretion to continue with other 
antithrombotic therapy. The investigator should document this therapy in the eCRF. Thrombotic 
events will not be reported as adverse events or serious adverse events, as they will be reported 
as efficacy outcomes, which will be documented in the eCRF.
9.5.
Sample Collection and Handling  
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form.
If blood samples are collected via an indwelling cannula, an appropriate amount (eg, 1 mL) of 
fluid slightly greater than the dead space volume of the lock will be removed from the cannula 
before each blood sample is taken. If a blood sample is taken from a central line, at least 3 mL of 
blood should be withdrawn prior to collecting study blood samples. Investigators should follow 
their institution’s policy for discarding or re-infusing withdrawn blood. Heparin can be used to 
maintain catheter patency; however, before collecting PK/PD samples, the catheter needs to be 
flushed with saline and the first volume of (diluted) blood should be withdrawn, as described 
above.
Refer to the Time and Events Schedule for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual.


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9.6.
Study Booklet
Parents/legally acceptable representatives will receive a study booklet in Part A and Part B 
including information on:

Instructions to return empty study drug packages and unused study drug

Instructions on signs and symptoms of bleeding

Instructions on how to report any adverse event occurring within the reporting period. 
For the rivaroxaban treatment group:

Rivaroxaban will be provided in a glass bottle with a child-resistant screw cap. An adaptor 
and a dosing pipette will be provided to support drug administration. Rivaroxaban should be 
stored according to the label.
For the ASA group:

Acetylsalicylic acid will be provided in child-resistant packaging. The ASA tablets should be 
stored according to the local approved product label.
9.7.
Committees 
9.7.1.
Executive Committee
The EC will provide overall academic leadership for the study and will oversee the conduct of 
the study and the publication of the results. In addition, the EC will receive recommendations 
from the IDMC and SC regarding modifications to the study and will decide whether to accept 
the recommendations. The EC will have 2 co-chairs and will consist of members of academic 
institutions and 1 member from the sponsor.
9.7.2.
Independent Data Monitoring Committee
The IDMC will evaluate PK, PD, safety and efficacy data to ensure subject safety throughout the 
study. The IDMC will be an independent expert advisory group external to the sponsor and 
study. For Part A only, the IDMC will review the cumulative data from the Initial PK, PD, and 
Safety Assessment Period and will provide the recommendation to the EC and Sponsor 
Committee to cease enrollment in Part A and to start enrollment directly into Part B. The IDMC 
will operate for both Part A and Part B. The decision tree of rivaroxaban exposure acceptability 
criteria will be described in the IDMC charter.
9.7.3.
Data Review Committee 
The DRC consists of members from the sponsor not directly involved in the conduct of the 
study, who will evaluate the PK and safety of each subject in Part A, and who will evaluate that 
information relative to the PBPK model predictions. The DRC will assess before the subject 
returns for Day 12 Visit the PK, PD, and the safety data available from each subject, prior to the 
subject continuing in the study to complete the planned 12 months of open-label rivaroxaban
therapy. The DRC will only operate during Part A.


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9.7.4.
Central Independent Adjudication Committee  
The CIAC is comprised of specialist physicians as appropriate and necessary. Committee 
members do not directly enroll subjects in the study, are not involved in the study monitoring, 
and do not have direct operational responsibilities for the conduct of the study. Members will 
review all safety and efficacy outcomes that occur post-enrollment as they become available and 
adjudicate and classify the following events in a consistent and unbiased manner according to 
definitions in the CIAC charter while blinded to treatment assignment: 
Safety and efficacy outcomes include bleeding events, any thrombotic event (venous or arterial), 
other vascular events as listed in Section 9.4, and deaths that occur during the study and the 
30-day post study treatment period. 
The CIAC procedures will be described in the CIAC charter. Adjudication results will be the 
basis for the final analyses.
9.7.5.
Steering Committee
The SC will advise and assist the EC with regard to the scientific and operational aspects of the 
study. Details of the composition, roles, and responsibilities will be documented in the 
SC charter.
9.7.6.
Sponsor Committee
The Sponsor Committee is responsible for communicating the IDMC recommendations within 
the Sponsor and identifying appropriate actions based on the recommendations of the IDMC.
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
A subject will be considered to have completed the study if the subject completes: 

The Follow-Up Contact 30 days after the last dose of study drug taken for subjects who 
complete the 12 month treatment 

The ESMD Month 12 Follow-Up for subjects who discontinue the study drug prematurely
10.2.
Discontinuation of Study Drug
If a subject's study drug must be discontinued before the end of the treatment regimen, this will 
not result in automatic withdrawal of the subject from the study. 


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10.2.1.
Temporary Discontinuation of Study Drug
Study drug may be temporarily discontinued if the subject: 

Undergoes any surgical procedure, or has a medical condition that may require temporary 
interruption of the study drug, or use of prohibited therapy due to bleeding risk, or use of 
other antiplatelet or anticoagulant therapy

Experiences a significant bleeding event

Develops a platelet count <50,000/L

Has any serious adverse event possibly related to or exacerbated by study drug 
administration

Requires a prohibited therapy on a temporary basis (see Section 8, Prestudy and 
Concomitant Therapy)
The investigator should consider stopping the study drug in pediatric subjects with elevated ALT 
values >5 x ULN and are increasing, or if ALT values remain unchanged at >5 x ULN with no 
change in total bilirubin for more than 2 weeks and are considered clinically relevant. In 
addition, investigators should also terminate the study drug in children with worsening clinical 
symptoms of liver injury and no other acceptable explanation. 
The study drug can be resumed at any time when in the opinion of the investigator it is safe to do 
so. Otherwise the subject will be permanently discontinued from study drug. 
10.2.2.
Permanent Discontinuation of Study Drug
A subject's study treatment should be discontinued permanently if:

The investigator believes that for safety reasons (eg, adverse event or persistent 
noncompliance) it is in the best interest of the subject to discontinue study treatment

The subject has a thrombotic event 

The subject develops any condition that requires treatment with anticoagulant or antiplatelet
therapy

The subject has a major bleeding event, eg, intracranial bleeding (for definitions of major 
bleeding see Section 9.3.1, Bleeding Events)

The subject, his or her parents/legally acceptable representatives request to discontinue the 
study drug permanently
For subjects in Part A and Part B who prematurely and permanently discontinue the study drug 
for any reason, the ESMD visit will be performed as soon as possible after discontinuation of the 
study drug. A Follow-Up phone contact will be performed 30 days following the last dose of the 
study drug. In addition, an ESMD Month 12 Follow-Up phone contact will be conducted at the 
end of the planned treatment period. This excludes subjects who are enrolled after local reading 
of the Screening transthoracic echocardiogram rules out thrombosis, and subsequently reported 
to have thrombosis after central reading by the core laboratory of the same transthoracic 
echocardiogram. These subjects will be withdrawn from the study when the result of the 
echocardiogram by the core laboratory becomes available. Subjects will be asked to return for 


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the ESMD visit as soon as possible. They will not be required to have a repeat transthoracic 
echocardiogram as part of the ESMD. Subjects will go on to receive proper care according to the 
healthcare provider’s judgment. They will be contacted by phone approximately 30 days (+/-
7 days) after last dose of study drug (Follow-Up Contact). An ESMD Month 12 follow up visit 
will not be required.
10.3.
Withdrawal from the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent/assent

An internal DRC considers that the subject should not continue rivaroxaban treatment after 
the Initial PK, PD and Safety Assessment Period

The core laboratory reports a thrombosis on the same Screening transthoracic 
echocardiogram that was ruled out by the local reader.  

Other – eg, termination of the study by the sponsor, closing of study sites
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. 
If a subject is withdrawn before the end of the study for reasons other than being lost to 
follow-up, the ESMD assessments should be obtained as soon as possible and a Follow-up phone 
contact will be performed approximately 30 days (+/-7 days) after last dose of study drug. This 
excludes subjects withdrawn after central reading by the core lab reports a thrombosis on 
Screening transthoracic echocardiogram. See Section 10.2, Discontinuation of Study Drug for 
more details. 
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 the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented.
Subjects who withdraw will not be replaced.
If a subject is unwilling or unable to return for follow-up visits in person or have follow-up 
contacts, the sites should collect as much follow-up visit information as possible, including 
contacting the subject or the subject’s representative or health care professional, by telephone or 
by mail, to determine vital status and if an endpoint event has occurred, as agreed to by the 
subject and/or the subject’s representative during the initial informed consent process. If 
applicable, vital status may be obtained by reviewing the subject’s medical or public records 
unless this process is not allowed by local regulations.


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11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the PK, PK/PD, safety, and the 
efficacy data is outlined below. Specific details will be provided in the Statistical Analysis Plan
(SAP), including, if necessary, censoring rules for time-to-event analyses and imputation rules 
for missing or partially missing dates.
The SAP will be finalized prior to first subject enrolled in the study. 
Data from subjects participating in Part A of the study are planned to be combined with data 
from subjects in Part B of the study who were randomized to rivaroxaban. Summaries will also 
be provided based on data from: (a) randomized subjects only (rivaroxaban vs. ASA) from 
Part B, and (b) subjects participating in Part A only.
For both parts of the study, safety and efficacy results (adverse events, bleedings, and thrombotic 
events) will be summarized. All summaries will be presented using appropriate descriptive 
statistics for study variables including demographic and baseline characteristics. Descriptive 
statistics such as mean, median, standard deviation, minimum, and maximum will be used to 
summarize continuous variables. Counts and percentages will be used to summarize categorical 
variables. 
The best available data for safety events will be used by the DRC and IDMC to review subjects 
in the Initial PK, PD, and Safety Assessment Period of Part A. The CIAC-adjudicated results will 
be used in the final analysis for all subjects.
No statistical hypothesis will be tested in this study.
11.1.
Analysis Populations and Periods
11.1.1.
Subject Information
Each summary or analysis involves the following 2 aspects: 1) analysis set, specifying the 
subjects to be included; and 2) analysis period, specifying the time window within which data 
will be included.
Key analysis sets and analysis periods are defined below.
11.1.2.
Analysis Sets  
Full Analysis Set: This analysis set consists of all subjects in Part A who receive at least 1 dose 
of study drug and all subjects in Part B who complete randomization and receive at least 1 dose 
of study drug.


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Safety Analysis Set: This is the same as Full Analysis Set.
PK Analysis Set: All subjects who received at least 1 dose of study drug and have quantifiable 
rivaroxaban plasma concentrations will be included in the descriptive PK analysis. 
PD Analysis Set: All subjects who received at least 1 dose of study drug and have quantifiable 
PT, aPTT, and anti-FXa activity values will be included in the descriptive PD analysis.
11.1.3.
Analysis Periods
On-Treatment Period: This analysis period includes all data from the first dose of study drug to 
2 days after the last dose of the study drug administration (inclusive). 
Up-to-End-of-Treatment Period: This analysis period includes all data from first dose to end of 
treatment visit (Month 12 or ESMD visit).
11.2.
Sample Size Determination
A total of at least 100 pediatric subjects overall are planned to be enrolled in this study. Due to 
the limited availability of the study population and the expected low event rates, this study is not 
powered to test a formal hypothesis for efficacy. The total sample size is based on regulatory 
feedback to obtain sufficient safety data in this pediatric population.
The sample size of approximately 10 subjects for Part A is considered adequate for the initial 
assessment of the rivaroxaban PK in the studied pediatric subjects. Approximately 90 subjects 
will be enrolled into Part B of the study. 
11.3.
Pharmacokinetics/Pharmacodynamics Analyses
Descriptive statistics will be used to summarize rivaroxaban PK data for each time interval. 
Pharmacodynamic measurements, including PT, aPTT, and anti-FXa activity will be plotted 
against rivaroxaban plasma concentrations and will also be summarized by timepoint.
Rivaroxaban PK parameters including AUC0-24, Cmax after single dose and AUC0-24, Cmax, and 
minimum plasma concentration (Cmin) at steady state will be derived through model-based 
methods. The PK/PD relationship will be quantified. Results from PK and PK/PD analyses will 
be reported separately from the Clinical Study Report. When appropriate, PK and PD data 
collected in this study may be used for ad hoc meta-analyses to further explore PK/PD 
relationships of rivaroxaban in pediatric subjects.
11.4.
Safety Analyses  
All safety analyses will be performed on the Safety Analysis Set (described in Section 11.1.2, 
Analysis Sets) and by treatment group as received.


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Bleeding Events
Bleeding events that occur during the On-Treatment Period will be summarized by treatment 
group. Bleeding events observed more than 2 days after stopping the study drug will be 
summarized separately. Individual listings of major and clinically relevant non-major bleeding 
events will be provided. The bleeding events will be adjudicated by the CIAC. 
Cumulative incidences and incidence rates over time based on time to the first bleeding event 
will be provided by treatment group using the Kaplan-Meier method.
Adverse Events
Overall safety will also be assessed by summarizing adverse events by treatment group.
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse 
events are adverse events with onset during the treatment period or that are a consequence of a 
pre-existing 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.
Individual listings of adverse events (including treatment group, age, weight, height, gender, 
adverse event as reported, start, duration, severity, and relationship to the study drug) will be 
provided. The incidence of treatment-emergent adverse events will be summarized by treatment 
using MedDRA preferred terms grouped by primary system organ class.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or a serious adverse event. Additional summaries, listings, or subject narratives may be provided, 
as appropriate.  
Clinical Laboratory Tests   
This study will collect laboratory data at the timepoints specified in the Time and Events 
Schedule. Laboratory data will be summarized by treatment group. 
11.5.
Efficacy Analysis 
Efficacy analyses will be performed on the Full Analysis Set, excluding subjects who start on 
study drug but are discontinued if central reading by the core laboratory reports thrombosis on
the Screening transthoracic echocardiogram. These subjects will be included however in the 
safety analysis. Thrombotic events that occur during the Up-to-End-of-Treatment Period will be 
summarized by treatment received. Events that occur after Up-to-End-of-Treatment Period 
(after Month 12 or ESMD visit) will be summarized separately.
The efficacy outcomes will be adjudicated by CIAC.


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The numbers and percentages of subjects with missing Follow-Up Contact (30-days after last 
dose) will be summarized. Details will be provided in the SAP.
12.
ADVERSE EVENT REPORTING
Parents/legally acceptable representatives will receive a study booklet, specifying for both 
treatment groups important study-related information (see Section 9.6, Study Booklet).  
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.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU 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


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
Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
For the purposes of this study, efficacy outcome events (thrombotic events) will not be reported 
as adverse events or serious adverse events, as they will be reported as efficacy outcomes (See 
Section 12.3.1, All Adverse Events.). 
Serious bleeding events will be considered serious adverse events and must be reported to the 
sponsor in an expedited manner as any other serious adverse events.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event, the event must be reported by the sponsor as a 
serious and unexpected suspected adverse reaction even if it is a component of the study 
endpoint. 
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 rivaroxaban, the expectedness of an adverse 
event will be determined by whether or not it is listed in the Investigator's Brochure.
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed below in Section 12.1.2, Attribution Definitions.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.


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Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria 
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/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

Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study drug

Unexpected therapeutic or clinical benefit from use of a sponsor study drug

Medication error involving product preparation or dose administration of 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 
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12.3.
Procedures
12.3.1.
All Adverse Events  
Adverse events should be reported by the subjects or their parents/legally acceptable
representatives for the duration of the study. 
For the purposes of this study, thrombotic events will be captured in the eCRF and in the 
database as efficacy outcomes only, and will not be reported as adverse events or serious adverse 
events, regardless of seriousness and severity, except for those thrombotic events that ended in 
death. All other thrombotic events will be exempted from expedited reporting.
Any serious adverse events other than thrombotic events will be reported to the sponsor in an 
expedited fashion according to Section 12.3.2, Serious Adverse Events. 
All deaths (including those due to thrombotic causes) will be reported as serious adverse events. 
All bleeding events will be collected on the eCRF as a bleeding event and as an adverse event or
serious adverse event as appropriate. Serious bleeding events must be reported to the sponsor in 
an expedited manner as any other serious adverse events.  
Certain adverse events are considered to be Adverse Events of Special Interest and should be 
reported as serious adverse events. These include:

Suspected toxic effect on the bone marrow including severe thrombocytopenia (platelet 
count less than 50 x 109/L), severe neutropenia (white blood cell count less than 500/L), 
pancytopenia, aplastic anemia

Suspected severe hypersensitivity reaction (eg, anaphylaxis, angioedema, severe urticaria, 
bronchospasm, etc.)

Severe skin reactions such as Stevens-Johnson Syndrome

Suspected severe liver injury and concurrent elevations of ALT >5x ULN and total bilirubin 
>2x ULN 
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 (ie, Follow-Up Contact [phone contact]). 
Serious adverse events, including those spontaneously reported to the investigator within 30 days
after the last dose of study drug, must be reported via facsimile (fax) when applicable using the 
Serious Adverse Event page of the eCRF. The sponsor will evaluate any safety information that 
is spontaneously reported by an investigator beyond the time frame specified in the protocol.
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 


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respiratory infection"). Investigators must record in the eCRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (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.
For all studies with an outpatient phase, including open-label studies, parent/legally acceptable 
representative must be provided with a "wallet (study) card" and instructed to carry this card with 
them for the duration of the study indicating the following:

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event page of the eCRF, 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 transmitted electronically via facsimile (fax).
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


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
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:

For the purposes of this study, thrombotic events will not be reported as serious adverse 
events, refer to Section 12.3.1, All Adverse Events for details.

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, whether or not the event is expected or associated with 
the study drug, is considered a serious adverse event.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.


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13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)  
Rivaroxaban will be used as a 0.1% oral suspension (strength 1 mg/mL). It will be manufactured 
and provided under the responsibility of the sponsor. Refer to the Investigator's Brochure for a 
list of excipients.14
The active comparator ASA used in this study is 81-mg or 100-mg ASA tablet. It will be 
provided under the responsibility of the sponsor to the study sites according to local regulations.
14.2.
Packaging
Rivaroxaban will be provided in a glass bottle with a child-resistant screw cap. An adaptor and a 
dosing pipette will be provided to support drug administration.
Acetylsalicylic acid will be provided according to local approved product label in child-resistant 
packaging.
14.3.
Labeling
Study drug labels will contain information to meet the applicable local regulatory requirements.
14.4.
Preparation, Handling, and Storage 
Rivaroxaban and ASA must be stored at room temperatures 77°F (25°C); excursions from 59° -
86°F (15° - 30°C) are allowed.
Rivaroxaban oral suspension should be stored according to the label.
The ASA tablets should be stored according to the label.
Refer to the pharmacy manual/study site investigational product and procedures manual for 
additional guidance on study drug preparation, handling, and storage.


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14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. 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. Parents/legally acceptable representatives must be instructed to return all 
original containers, whether empty or containing study drug. The study drug administered to the 
subject must be documented on the drug accountability form. All study drug will be stored and 
disposed of according to the sponsor's instructions. Study-site personnel must not combine 
contents of the study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug, and study drug returned by the subject’s parents or 
legally acceptable representatives, 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.
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to parents/legally acceptable representatives of subjects participating in the study. Returned study 
drug must not be dispensed again, even to the same subject. Study drug may not be relabeled or 
reassigned for use by other subjects. The investigator agrees neither to dispense the study drug 
from, nor store it at, any site other than the study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator Brochure for rivaroxaban

Pharmacy manual/study site investigational product manual

Laboratory manual

IWRS manual 

Electronic data capture (eDC) Manual/eDC Completion Guidelines

Study booklet

Subject wallet card

Tablet splitter

60 mL BD™ syringes for reconstitution of rivaroxaban study medication

Process for submitting outcome information to CIAC

Transthoracic Echocardiogram Research Protocol and Core Laboratory Process


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
Sponsor-approved subject recruiting materials 

Other tools, as applicable including the use of an iPad® (Part A only) to keep key subject
information material easily available for the subject’s parents or legally acceptable 
representatives for their use and reference. The subject study booklet will be available on the 
iPad.
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
The primary ethical consideration in this study is the use of young pediatric subjects who have 
recently completed the Fontan procedure with a high thrombotic risk and for whom there is scant 
evidence-based information regarding thromboprophylaxis. There is limited data on the optimal 
use of thromboprophylaxis for these children and the data are primarily extrapolated from 
clinical studies in adults. None of the current standards of care (ASA or warfarin) appear to have 
been very successful at mitigating the risk and incidence of post-Fontan thrombosis according to 
the small amount of data from few clinical studies and the cumulative years of 
practice.12,11,23,20,18 Using ASA as the comparator in this study will allow a descriptive
comparison of results across 2 different drug classes: antiplatelet (ASA) versus anticoagulant 
(rivaroxaban, which has demonstrated effectiveness in the adult population as a 
thromboprophylaxis agent). In combination with extrapolation from adult efficacy data, this 
study could support an alternative treatment in this population by providing PK, PD, safety, and 
supportive efficacy data.
Therefore, this study aims to assess the safety and efficacy of a novel oral anticoagulant that has 
been extensively studied and has demonstrated safety and efficacy for the prevention and 
treatment of multiple thrombosis-mediated conditions in adults, and thus far has been well 
tolerated in pediatric subjects. The study is designed with sufficient scientific rigor to meet its 
objectives while having close oversight of an IDMC, in addition to the sponsor, to protect 
subjects from experiencing unacceptably high levels of risk of harm or suffering. Further, the 
study risk/benefit consideration will be addressed, and reviewed, by an independent ethics 
review board before the conduct of the study. Due to the limited availability of subjects in this 
study population and the expected low event rate, formal hypothesis testing of the primary 
efficacy endpoint is not feasible.
Parents/legally acceptable representatives of potential subjects will be fully informed of the risks 
and requirements of the study, and during the study they will be given any new information that 
may affect their decision to continue participation. Parents/legally acceptable representatives and 
subjects 7 to 8 years of age will be told that their consent/assent 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. 
When referring to the signing of the ICF, the term legally acceptable representative refers to the 
legally appointed guardian of the child with authority to authorize participation in research. For 
each subject, his or her parent(s) (preferably both parents, if available) or a legally acceptable 
representative(s), as required by local regulations, must give written consent (permission) 


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according to local requirements after the nature of the study has been fully explained and before 
the performance of any study-related assessments. Assent must be obtained from children (minors) 
capable of understanding the nature of the study, typically subjects 7 years of age and older, 
depending on the institutional policies. For the purposes of this study, all references to subjects 
who have provided consent (and assent as applicable) refer to the subjects and his or her parent(s) 
or the subject's legally acceptable representative(s) who have provided consent/assent according to 
this process. Minors who assent to a study and later withdraw that assent should not be maintained 
in the study against their will, even if their parents/legally acceptable representatives still want 
them to participate. 
Clinical Study with a New Study Drug 
Thorough scientific evaluation of any promising treatment before market 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 before public exposure. 
Full investigation and study of a new product must always include the study of pediatric subjects 
if there is any reasonable belief that the treatment will benefit the pediatric population.
Rivaroxaban has been proven to have a positive benefit-risk profile in multiple 
thrombosis-mediated conditions. This study is being conducted in pediatric subjects 2 to 8 years 
of age with single ventricle physiology who have completed the Fontan procedure within 
4 months prior to enrollment. The results of this study are expected to provide useful information 
on the PK, PK/PD, safety, and efficacy of rivaroxaban as well as the dosing guidelines for this 
pediatric patient population. 
The daily, cumulative, and total blood volume to be collected from each subject in this study is 
within the range of maximum allowances for pediatric research set by hospitals routinely 
participating in pediatric clinical studies.13 The total blood volume to be collected will be 
approximately 32.7 mL in Part A and 25 ml in Part B over a 12 month period (Attachment 1: 
Blood Volume). These estimates do not include any blood discarded due to blood drawing from 
peripheral or central lines, as these volumes may vary according to each site’s practice.
Safety of Dose 
This is the first clinical study with rivaroxaban in pediatric subjects after the Fontan procedure; a 
potential risk will be the actual exposure to study drug at the planned dose in the studied 
population being inconsistent with the estimated exposure based on PBPK modeling, which can 
lead to adverse events including bleeding events, or lack of efficacy. 
To ensure appropriate exposure to study drug, a staggered approach was chosen. In Part A of the 
study, in a small number of subjects, the single- and multiple-dose rivaroxaban PK will be 
evaluated as well as the initial safety and tolerability. The DRC will review the subject’s PK, PD,
and safety data obtained from the Initial PK, PD, and Safety Assessment Period prior to allowing 
the subject to continue on rivaroxaban therapy to complete the 12-month period. 


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Enrollment and randomization into Part B of this study will only begin once the PK and safety 
results in the Initial PK, PD, and Safety Assessment Period for subjects in Part A are deemed 
acceptable by the IDMC.
Capacity to Provide Informed Consent
Only parent(s) (preferably both parents if available) or legally acceptable representative(s) who 
are fully able to understand the risks, benefits, potential adverse events, and alternatives to 
participation, will provide their consent voluntarily. Subjects 7 to 8 years of age may be asked 
for their voluntary assent; the investigator will determine each subject’s capacity to provide 
informed assent. 
Subjects of 7 to 8 years of age or their parents or legally acceptable representatives may 
withdraw their assent or consent, respectively at any time without having to give a reason. 
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects


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
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), the ICF, applicable recruiting materials, and 
subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study. The 
reapproval should be documented in writing (excluding the ones that are purely administrative, 
with no consequences for subjects, data, or study conduct).


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At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
16.2.3.
Informed Consent/Assent
Parents/legally acceptable representatives and subjects must give written consent/assent
according to local requirements after the nature of the study has been fully explained. The ICF(s) 
must be signed before performance of any study-related activity. The ICF(s) and assent form 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/assent 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 parents/legally acceptable representatives of potential subjects and 
subjects the aims, methods, reasonably anticipated benefits, and potential hazards of the study,
and any discomfort participation in the study may entail. Subjects and parents/legally acceptable
representatives will be informed that their participation is voluntary and that they may withdraw 
consent/assent to participate at any time. They will be informed that choosing not to participate 
will not affect the care the subject will receive.  Finally, they will be told that the investigator 
will maintain a subject identification register for the purposes of long-term follow up if needed 
and that their records may be accessed by health authorities and authorized sponsor personnel
without violating the confidentiality of the subject, to the extent permitted by the applicable 
law(s) or regulations. By signing the ICF the parent/legally acceptable representative and 
subjects are authorizing such access, and agrees to allow his or her study physician to recontact 
the subject for the purpose of obtaining consent/assent for additional safety evaluations, if 
needed.
The parent/legally acceptable representative and subjects 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/assent should be appropriately recorded by means of the subject's parent/legally 
acceptable representative’s personally dated signature. After having obtained the consent/assent, 
a copy of the ICF must be given to the parent/legally acceptable representative of the subject.
If the subject or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent/assent process (which includes reading and 
explaining all written information) and should personally date and sign the ICF after the oral 
consent/assent of the subject or legally acceptable representative is obtained.
Children (minors) or subjects who are unable to comprehend the information provided can be 
enrolled only after obtaining consent/assent of a legally acceptable representative. Assent must 
be obtained from children (minors) capable of understanding the nature of the study, typically 
subjects 7 years of age and older, depending on the institutional policies. Written assent should 
be obtained from subjects who are able to write. After having obtained the assent, a copy of the 


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assent form must be given to the subject, and to the subject's parent and/or legally acceptable 
representative.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent/assent
obtained from the subject’s
parents/legally acceptable
representatives includes explicit consent/assent 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/assent also addresses the transfer of the data to other entities and to other countries.
The subject’s parents/legally acceptable representatives have 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.
16.2.5.
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, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.


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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 (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the eCRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical study agreement, which includes the financial agreement

Any other documentation required by local regulations


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The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
and date of birth. In cases where the subject is not enrolled into the study, the date seen and date 
of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentations 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/assent; dates of visits; results of safety and efficacy parameters 
as required by the protocol; record of all adverse events and follow-up of adverse events; 
concomitant medication; drug receipt/dispensing/return records; study drug administration 
information; and date of study completion and reason for early discontinuation of study drug or 
withdrawal from the study, if applicable. 
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by parent/legally acceptable representative interview or other protocol required 
assessment (eg, physical examination, laboratory assessment) and documented in the source 
documents.


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An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as 
the clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the sponsor. If the electronic source system is utilized, references made to 
the eCRF in the protocol include the electronic source system but information collected through 
the electronic source system may not be limited to that found in the eCRF. Data in this system 
may be considered source documentation.
17.5.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format.
All 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.
Electronic data capture will be used for this study. The study data will be transcribed by study-
site personnel from the source documents onto an electronic 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 documentation. All data relating to the 
study must be recorded in eCRFs prepared by the sponsor. Data must be entered into eCRFs 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.
The investigator must verify that all data entries in the eCRFs are accurate and correct.
All eCRF entries, corrections, and alterations must be made by the investigator or other 
authorized study-site personnel. If necessary, queries will be generated in the eDC tool. 
If necessary, queries will be generated in the eDC tool. If corrections to a eCRF are needed after 
the initial entry into the eCRF, this can be done 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.


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17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor, and direct 
transmission of 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. 
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study.
The sponsor will review eCRFs 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. 
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
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.


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17.8.
Monitoring
The sponsor will use a combination of monitoring techniques, central, remote, or on-site 
monitoring, to monitor this study.  The sponsor will perform on-site monitoring visits as 
frequently as necessary. The monitor will record dates of the visits in a study site visit log that 
will be kept at the study site. The first post-initiation visit will be made as soon as possible after 
enrollment has begun. At these visits, the monitor will compare data entered into the eCRFs 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.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The study is considered completed with the last scheduled study contact shown in the Time and 
Events Schedule for the last subject participating in the study. The final data from the study site 
will be sent to the sponsor (or designee) after completion of the final subject study contact at that 
study site, in the time frame specified in the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.


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The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Subject privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and 
available for consultation during routinely scheduled study-site audit visits conducted by the 
sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding rivaroxaban 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 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 rivaroxaban, 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 Clinical Study Report 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. Results of analyses performed after 


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the Clinical Study Report has been issued will be reported in a separate report and will not 
require a revision of the Clinical Study Report. Study subject identifiers will not be used in 
publication of results. Any work created in connection with performance of the study and 
contained in the data that can benefit from copyright protection (except any publication by the 
investigator as provided for below) shall be the property of the sponsor as author and owner of 
copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
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 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law.


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19.
McCrindle BW, Li JS, Manlhiot C, et al .  Challenges and priorities for research: a report from the National 
Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH) Working Group on thrombosis 
in pediatric cardiology and congenital heart disease.  Circ. 2014 Sep 30;130(14):1192-1203. 
20.
Monagle P, Cochrane A, Roberts R, Manlhiot C, Weintraub R, Szechtman B, et al; Fontan Anticoagulation 
Study Group. A multicenter, randomized trial comparing heparin/warfarin and acetylsalicylic acid as primary 
thromboprophylaxis for 2 years after the Fontan procedure in children. J Am Coll Cardiol. 2011 Aug 
2;58(6):645-651. 


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21.
Monagle P, Cochrane A, McCrindle B, Benson L, Williams W, Andrew M. Thromboembolic complications 
after Fontan procedures- the role of prophylactic anticoagulation. J Thorac Cardiovasc Surg. 1998 Mar; 
115(3):493-498.
22.
Monagle P, Karl TR. Thromboembolic problems after the Fontan operation. Semin Thora Cardiovasc Surg 
Pediatr Card Surg Annu. 2002;5: 36-47.
23.
Potter BJ, Leong-Sit P, Fernandez SM, Feifer A, Mayer JE, Triedman JK, et al. Effect of aspirin and warfarin 
on thromboembolic events in patients with univentricular hearts and Fontan palliation. Int J Cardiol 
2013;168:3040-3043.
24.
Rychik J, Veldtman G, Rand E, Russo P, Rome JJ, Krok K, et al. The precarious state of the liver after a 
Fontan operation: summary of a multidisciplinary symposium. Pediatr Cardiol. 2012;33:1001-1012.
25.
Samama M, et al . Evaluation of the anti-factor chromogenic assay for the measurement of rivaroxaban plasma 
concentrations using calibrators and controls. Thromb Haemost. 2012;107.
26.
Schnizler, K. PH-38483: Physiology-based prediction of rivaroxaban pharmacokinetics in children with 
congenital heart disease after Fontan procedure, Bayer Pharma AG, 2015 .
27.
Schulman S, Kearnon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal 
products in non-surgical patients. J Thromb Haemost. 2005;3:692- 694. 
28.
Schwartz GJ, Haycock GB, Edelmann CM, Jr., Spitzer A. A simple estimate of glomerular filtration rate in 
children derived from body length and plasma creatinine. Pediatr. 1976 Aug;58(2):259-263.
29.
Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New equations to estimate GFR 
in children with CKD. J Am Soc Nephrol. 2009 Mar;20(3):629-637. 
30.
Stümper O, Sutherland GR, Geuskens R, Roelandt JR, Bos E, Hess J. Transesophageal echocardiography in 
evaluation and management after a Fontan procedure. J Am Coll Cardiol. 1991;17(5):1152-1160. 
31.
The Society of Thoracic Surgeons (STS) National Database. http://www.sts.org/nationaldatabase. Accessed on 
30 June 2015
32.
Turpie AGG, Lassen MR, Eriksson BI, et al . Rivaroxaban for the prevention of venous thromboembolism 
after hip or knee arthroplasty: pooled analysis of four studies. Thromb Haemost. 2011;105:444-453.


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Attachment 1: Volume of Blood to be Collected 
Volume of Blood to be Collected From Each Subject  
Type of Sample
Volume per 
Sample 
(mL)
No. of Samples 
per Subject
Part A/Part B
Total Volume of 
Blood (mL)a
Part A/Part B
Safety Labs
- Hematologyb
1.2
  2/2
  2.4/2.4
- Serum chemistryc
1.1
  3/2
  3.3/2.2
- Baseline PT, aPTT 
1.4
  1/0 
  1.4/0 
Pharmacokinetic samples
0.6
10/6
  6.0/3.6
PD-1: PD samples (PT and aPTT tests)
1.4
10/7 
  14/9.8 
PD-2: PD samples (anti-FXa assay)
1.4
  4/5
  5.6/7.0
Approximate Total
32.7/25
ALT= alanine aminotransferase; aPTT= activated partial thromboplastin time; AST= aspartate aminotransferase; CBC= 
complete blood count; FXa=Factor Xa; No.= number; PD= pharmacodynamics; PT= prothrombin time.
.
a.
Calculated as number of samples multiplied by amount of blood per sample.
b.
CBC with differential, platelet count; 
c. Liver function tests (ALT, AST, total and direct bilirubin, alkaline phosphatase) and creatinine.
Notes: 
Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples.
An indwelling intravenous cannula is recommended for blood sample collection.
Blood discarded due to blood drawing from peripheral or central lines are not included in this table.


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Attachment 2: Post-Fontan Echocardiographic Examination protocol
Boston Children’s Hospital: Echocardiographic Examination Protocol (Please see Technical Reference 
Manual for further details)
Status Post Fontan Operation
Inclusion: Patient having undergone a Fontan operation. This operation has been performed with various 
surgical modifications including: 1) direct anastomosis of the right atrium to the pulmonary artery; 2) 
valved or non-valved conduit from right atrium to right ventricle; 3) classic Glenn shunt (superior vena 
cava to transected right pulmonary artery) and conduit from inferior vena cava to left pulmonary artery; 4) 
bidirectional Glenn shunt plus intra-atrial conduit connection from the inferior vena cava to the right 
pulmonary artery; 5) bidirectional Glenn shunt plus extracardiac conduit connection from the  inferior 
vena cava to the main pulmonary artery. Optimal evaluation of the Fontan is achieved by knowledge 
of the specific type of connection that was performed. The individual performing the examination 
must find out the details of the operation before the examination.
Blood pressure in arm and leg if status post Norwood or arch reconstruction.
Full examination of anatomy using 2D, color and spectral Doppler and 3-D evaluation when indicated. 
Particular attention should be given to the following:
Subcostal

The inferior vena cava (IVC) and intracardiac portion of Fontan with 2D, color, and pulsed Doppler. 
Visualization of Fontan fenestration and if present, pulsed Doppler with mean gradient measured

Baffle leak

Atrial septal defect (ASD) (pulmonary vein to atrioventricular [AV] valve pathway), rule out
obstruction or restriction along entire pathway including pulmonary veins. If 2D or Doppler evidence 
of restriction, obtain mean gradient

Rule out thrombus
Apical

Fontan fenestration with pulsed Doppler and mean gradient

Baffle leak

Atrial Septal Defect (pulmonary vein to AV valve pathway) to exclude restriction.  If 2D or Doppler 
evidence of restriction, obtain mean gradient.

Atrioventricular valve regurgitation

Aortic and/or pulmonary valve if present, including pulsed wave and continuous wave Doppler of
outflow and assessment of regurgitation jet

Rule out thrombus 


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Parasternal

Aortic and/or pulmonary valve for regurgitation

Aortic, neoaortic and ascending aorta measurements

Assess for main pulmonary artery stump and any thrombus

Assess a hypoplastic aortic root for flow, rule out thrombus

Branch pulmonary arteries with 2D measurements, color, and pulsed Doppler 

Baffle in parasternal short axis, and long axis. Assess for thrombus

Assess for pulmonary vein obstruction 
Suprasternal 

Glenn shunt (superior vena cava down to cavopulmonary anastomosis if possible) with 2D and with 
color (color compare) and pulsed Doppler  

Branch pulmonary arteries with 2D measurements, color and pulsed Doppler 

Aortic arch
Full function protocol (systolic and diastolic) regardless of ventricular morphology


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Attachment 3: Estimated glomerular filtration rate (eGFR)

The original Schwartz formula: If serum creatinine (SCr) is measured with routine methods 
that have not been recalibrated to be traceable to isotope dilution mass spectrometry (IDMS) 
(eg, the traditional Jaffé reaction), the estimated glomerular filtration rate (eGFR) should be 
obtained from the original Schwartz formula:28
eGFR (mL/min/1.73 m2) = k * height (cm) / SCr g/dL) where k is proportionality constant:
k = 0.55 in children up to 13 years

The updated Schwartz formula: If SCr is measured by an enzymatic creatinine method that 
has been calibrated to be traceable to IDMS, the updated Schwartz formula should be used 
to obtain the eGFR:29
eGFR (mL/min/1.73 m2) = 0.413 * height (cm) / SCr mg/dL
The National Kidney Disease Education Program website
(http://www.nkdep.nih.gov/professionals/gfr_calculators/index.htm) offers electronic calculators 
of eGFR in the pediatric population based on the updated Schwartz formula. Serum creatinine in 
micromoles per liter, the value should be multiplied by 88.4 (1 mg/dL = 88.4 umol/L).


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Attachment 4: Amendment 1 changes
Amendment 1 (7 April 2016)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.  
The overall reason for the amendment: The overall reason for the amendment is to address the feedback 
received from Investigators.
Applicable Section(s)
Description of Change(s)
Rationale:  Clarification of study design, simplification of study conduct, to enhance enrollment and data collection 
and also to avoid scheduling difficulties (in response to comments from investigators in attendance.
Synopsis Overview Of Study Design; 
Time And Events Schedule, Part A 
and Part B 
The window of administering rivaroxaban for subjects in Part A and Part B 
for 12 days was increased from 6 days to 9 days, to allow for sufficient 
time to complete this visit/phone call.
Synopsis, Subject Population; 
Section 4.2 Exclusion Criteria
Exclusion criterion #1: Clarified that the screening transthoracic 
echocardiogram to rule out thrombosis needs to be post-Fontan.  
Exclusion criterion #4: Current chest-tube placement was deleted as an 
example of high risk for bleeding qualifying for exclusion.
Exclusion criterion #6: Deleted ‘Indication’.
Exclusion criterion #7: To align with global practices, study participation 
exclusion limit of platelet counts at screening was changed from less than 
100 x 109/L to less than 50 x 109/L.
Time And Events Schedule, Part A 
and B, Screening Period
Footnote regarding the screening period was added to also allow for local 
reading of the subjects’ transthoracic echocardiogram to rule out 
thrombosis. In addition, if subject is enrolled, instruction was added to send 
the transthoracic echocardiogram also to the core laboratory. 
Clarification was provided that adverse event assessment includes a review 
of all ongoing and new adverse events.
For Hematology, serum chemistry, PT, and aPTT testing at screening, 
clarification was added that either hospital laboratory, local laboratory 
results or central laboratory results are acceptable.
Section 1.1.5, Efficacy and Safety 
Profile Based on Pediatric Clinical 
Studies
The section was updated with a more current cut-off date on the status of 
enrollment and overall safety assessment.
Section 1.2, Comparator Agent
References to the PI and SmPC for ASA were replaced with reference to 
the local approved product label.
Synopsis, Section 6, Dosage and 
Administration
Minor edits for ASA tablet. 
Instructions were added regarding handling a missed morning and evening 
dose of rivaroxaban and ASA.
Section 9.1.2 Screening Period
Clarification was added that the screening visit will take place after the 
Fontan procedure.


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Applicable Section(s)
Description of Change(s)
Synopsis, Overview Of Study 
Design, Early Study Medication 
Discontinuation; 
Section3.1.Overview of Study 
Design; Section 9.1.5. Posttreatment 
Period (Follow-Up Contact); Section 
10.2.2. Permanent Discontinuation of 
Study Drug; Section 10.3. 
Withdrawal From the Study
Instructions were added regarding the follow-up of subjects who were 
reported by the core laboratory to have an event on the Screening 
transthoracic echocardiogram.
Section 9.1.6, Transthoracic 
Echocardiograms
For the Screening post-Fontan transthoracic echocardiogram, instructions 
were added to allow local reading to meet the inclusion criteria for 
enrollment and additional evaluation by the core laboratory if subject is 
enrolled.
Section 9.2. 
Pharmacokinetics/Pharmacodynamics 
Evaluations Part A
Procedure of sending blood samples to the central laboratory was 
simplified by limiting it to after the collection of the last sample on Day 4 
only.
Section 9.3.2, Approach to the 
Subject with a Bleeding Event
Clarified that it is the treating physician who could consider the measures 
provided to treat a serious bleed.
Clarifications for parents/ legally acceptable representatives were added if 
the subject has signs and symptoms of clinically significant bleeding.
Section 9.4. Efficacy 
Evaluations/Outcomes
Further clarification was added regarding the adjudication procedure by the 
CIAC and responsibility of sites to compile the adjudication package.
Section 9.6. Study Booklet
More information was added related to the packaging and storage of 
rivaroxaban and comparator ASA.  
Section 10.2.2. Permanent 
Discontinuation of Study Drug
Persistent noncompliance was added as an example of safety reasons for 
study treatment discontinuation.
Section 10.3. Withdrawal From the 
Study
Additional reasons for withdrawing a subject from the study were added.
Section 11.5 Efficacy Analysis
To clarify the analysis set in which the efficacy analyses will be performed.
Section 12.3.2. Serious Adverse 
Events
To clarify the current company-wide clinical study conduct processes to 
transmit initial and follow-up reports of a serious adverse event.
Section 14.1. Physical Description of 
Study Drug(s)  
Minor edits for ASA tablet.
Section 14.2, Packaging
Minor edits were made.
Section 14.4. Preparation, Handling, 
and Storage
Minor edits were made.
Section 15. Study-Specific Materials
Recruiting tools were edited to ‘Sponsor-approved subject recruiting 
materials’. 
Use of an iPAD was added to study management tools provided to the 
investigator.
Section 16.1 Study-Specific Design 
Considerations; Attachment 1, 
Volume of Blood to be Collected
Clarified that the blood volume estimates do not include any blood 
discarded, as these volumes may differ from site to site.


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Applicable Section(s)
Description of Change(s)
Section 17.4. Source Documentation; 
Section 17.5. Case Report Form 
Completion; Section 17.9.1.Study 
Completion/End of Study
Changes were made to align wording with current company-wide clinical 
study conduct processes (use of electronic source system and CRFs).
Rationale: The collection of blood samples was further clarified and heparin flushes are to be allowed. Heparin 
flushes can be used except before PK/PD samples are drawn. These have to be performed with saline to avoid 
interference with PK/PD results.
Section 9.2. 
Pharmacokinetics/Pharmacodynamics 
Evaluations; 9.5 Sample Collection 
and Handling
Explained procedure for blood sample collection via an indwelling cannula 
and central line in more detail and heparin flush was allowed, except before 
collecting PK/PD samples.
Throughout the
protocol
Minor, consistency and logical clarifications were made throughout the 
document, which do not affect the overall study concept.
References
Addition of 2 references


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INVESTIGATOR AGREEMENT
PPD

SAP_001.pdf: 
1
Approved, Date: 16 May 2019
Janssen Research & Development *
Statistical Analysis Plan
A Prospective, Open-Label, Active-Controlled Study to Evaluate the Pharmacokinetics, 
Pharmacodynamics, Safety and Efficacy of Rivaroxaban for Thromboprophylaxis in 
Pediatric Subjects 2 to 8 Years of Age after the Fontan Procedure (UNIVERSE Study)
Protocol 39039039CHD3001; Phase 3
JNJ-39039039; BAY 59-7939 (rivaroxaban)
Amendment 1
Status:
Approved
Date:
16 May 2019
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-ERI-133843356, 2.0
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.
NCT02846532


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT FIGURES ........................................................................................................................ 2
ABBREVIATIONS ........................................................................................................................................ 3
SAP AMENDMENT ...................................................................................................................................... 4
1.
INTRODUCTION.................................................................................................................................. 4
1.1
Trial Objectives ................................................................................................................................ 4
1.2 
Trial Design ...................................................................................................................................... 5
1.3
Statistical Hypotheses for Trial Objectives....................................................................................... 6
1.4
Sample Size Justification ................................................................................................................. 6
1.5
Randomization and Blinding ............................................................................................................ 6
1.6
Interim Analysis and Committees .................................................................................................... 6
1.6.1
Data Review Committee (DRC).................................................................................................... 7
1.6.2
Independent Data Monitoring Committee (IDMC) ........................................................................ 7
1.6.3
Central Independent Adjudication Committee (CIAC).................................................................. 7
1.6.4
Executive Committee (EC) ........................................................................................................... 8
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 8
2.1
Definition of Trial Dates.................................................................................................................... 9
2.2
Analysis Sets.................................................................................................................................. 10
2.3
Analysis Periods............................................................................................................................. 11
2.4
Definition of Subgroups.................................................................................................................. 11
3.
SUBJECT INFORMATION................................................................................................................ 11
3.1
Enrollment and Medical History ..................................................................................................... 12
3.2
Demographics and Baseline Characteristics ................................................................................. 12
3.3
Disposition Information................................................................................................................... 12
3.4
Treatment Compliance................................................................................................................... 12
3.5
Duration of Exposure ..................................................................................................................... 13
3.6
Protocol Deviations ........................................................................................................................ 13
3.7
Prior and Concomitant Medications ............................................................................................... 14
4.
SAFETY............................................................................................................................................. 14
4.1
Bleeding Events ............................................................................................................................. 15
4.2
Adverse Events .............................................................................................................................. 16
4.3
Clinical Laboratory Tests................................................................................................................ 16
4.4
Vital Signs and Physical Examination Findings ............................................................................. 16
5.
EFFICACY ......................................................................................................................................... 17
6.
PHARMACOKINETICS ..................................................................................................................... 18
7.
HEALTH ECONOMICS ..................................................................................................................... 19
8.
REFERENCES................................................................................................................................... 21
LIST OF IN-TEXT FIGURES
Figure 1:
Schematic Overview of Study 39039039CHD3001.................................................................... 5
Figure 2:
Pharmacokinetic Decision Tree................................................................................................ 20


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ABBREVIATIONS
ASA
aPTT
AXA
Acetyl Salicylic Acid 
Activated Partial Thromboplastin Time
Anti-FXa Activity
CI
Confidence Interval
CIAC
Central Independent Adjudication Committee
CrCl
DPS
Creatinine Clearance
Data Presentation Specifications
DRC 
Data Review Committee
EC 
Executive Committee
eCRF
Electronic Case Report Form
ESMD
IDMC
ISTH
Early Study Medication Discontinuation
Independent Data Monitoring Committee
International Society on Thrombosis and Haemostasis
IWRS
Interactive Web Response System
KM
Kaplan-Meier
PBPK
Physiologically-based Pharmacokinetic
PD
PT
Pharmacodynamics
Prothrombin Time
PK
Pharmacokinetics
SAP
Statistical Analysis Plan
SC
Sponsor Committee
TE
Treatment-Emergent
TEAE
Treatment-Emergent Adverse Events 


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SAP AMENDMENT 
SAP Version
Issue Date
  
Original SAP
November 15th, 2016
Amendment 1
May 16th, 2019
The principal rational for the SAP Amendment 1 is to clarify the definition of the categories and 
terms of key protocol deviations considered for the Per protocol Set. Also, PK/PD analysis plan 
in Section 6 was updated to include Part B data, and Attachment 1 was removed because a full 
PK/PD data analysis plan will be provided separately. 
1.
INTRODUCTION
This Statistical Analysis Plan (SAP) specifies definitions of analysis sets, key derived variables,
and statistical methods for analysis of safety and efficacy data, as well as statistical summaries of 
PK and PD findings for the Phase 3 study 39039039CHD3001 (also known as UNIVERSE).
This SAP is based on the Protocol 39039039CHD3001, Amendments INT-1 and INT-2, which 
were finalized on April 7th, 2016 and July 28th, 2017, respectively. Titles, mock-ups and 
programming instructions for all statistical outputs (tables, figures, and listings) are provided in a 
separate document entitled Data Presentation Specifications (DPS).
1.1
Trial Objectives
The primary objective of Part A of the study is to characterize the single- and multiple-dose 
pharmacokinetics (PK) and pharmacodynamics (PD) profiles after oral rivaroxaban therapy 
administered to pediatric subjects 2 to 8 years of age with single ventricle physiology who have 
completed the Fontan surgery within 4 months prior to enrollment. The secondary objective of 
Part A is to assess the safety and tolerability of rivaroxaban treatment.
The primary objective of Part B is to evaluate the safety and efficacy of rivaroxaban, 
administered twice daily (total daily exposure matched to rivaroxaban 10 mg once daily in 
adults) compared to acetylsalicylic acid (ASA), given once daily (approximately 5 mg/kg) for 
thromboprophylaxis in pediatric subjects 2 to 8 years of age with single ventricle physiology 
who have completed the Fontan surgery within 4 months prior to enrollment. The secondary 
objective in Part B is to further characterize the PK and PD profiles of rivaroxaban.


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1.2 
Trial Design
This is a prospective, open-label, active-controlled, multicenter study designed to evaluate the 
PK and PD profiles, safety and efficacy of rivaroxaban for thromboprophylaxis in pediatric 
subjects 2 to 8 years of age with single ventricle physiology who have completed the Fontan 
surgery within 4 months prior to enrollment.
The two parts of the study are as follows:
-
Part A: This is the 12-month, non-randomized, open-label, part of the study which 
includes an Initial PK, PD and Safety Assessment Period. The Data Review Committee 
(DRC) will assess by Day 12 the single- and multiple-dose rivaroxaban PK, PD and the 
initial safety and tolerability data available from each subject, prior to the subject 
continuing in the study to complete the planned 12 months of open-label rivaroxaban 
therapy of Part A. Subjects in Part A will not participate in Part B.
-
Part B: This is the randomized, open-label, active-controlled part of the study that will 
evaluate the safety and efficacy of rivaroxaban compared to ASA for thromboprophylaxis 
for 12 months. Subjects randomized to rivaroxaban will also have PK and PD 
assessments.
A diagram of the study design is provided below in Figure 1.
Figure 1:
Schematic Overview of Study 39039039CHD3001
Note: An internal DRC will assess before the Day 12 Visit, the PK, PD, and safety data from each subject, prior to 
the subject continuing in the study to complete the planned 12 months of open-label rivaroxaban therapy.
Enrollment in Part A will end, and enrollment in Part B will start, once the cumulative data from all subjects in 
the Initial PK, PD, and Safety Assessment Period of Part A are deemed acceptable by the IDMC.


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1.3
Statistical Hypotheses for Trial Objectives
There is no formal hypothesis testing for this study.
1.4
Sample Size Justification
A total of at least 100 pediatric subjects overall are planned to be enrolled in this study. Due to 
the limited availability of the study population and the expected low event rates, this study is not 
powered to test formal hypothesis for efficacy. The total sample size is based on regulatory 
feedback to obtain sufficient safety data in this pediatric population.
The sample size of approximately 10 subjects for Part A is considered adequate for the initial PK 
assessment of rivaroxaban in the studied pediatric subjects. Approximately 90 subjects will be 
enrolled into Part B of the study. 
1.5
Randomization and Blinding
Subjects in Part A will not be randomized.
Randomization in Part B of this study will begin once the cumulative subjects’ data from initial 
PK and Safety Assessment in Part A are deemed acceptable by the IDMC.
Central randomization will be implemented in this study for Part B: approximately 90 subjects 
will be randomly assigned to 1 of 2 treatment groups based on a computer-generated 
randomization schedule prepared before the study by or under the supervision of the sponsor; the 
assignment to treatment groups will be 2 to 1 (rivaroxaban to ASA).
The interactive web response system (IWRS) will assign a unique treatment code, which will 
dictate the
treatment assignment for the subject. The requestor of the treatment 
code/randomization must use his or her own user identification and personal identification 
number when contacting the IWRS to receive the relevant subject details to uniquely identify the 
subject. The study drug number will be assigned and recorded in the IWRS.
As this is an open-label study, blinding procedures are not applicable. Open-label treatment will 
be used to allow for further evaluation of the PK and PD profiles of rivaroxaban throughout the 
study.
1.6
Interim Analysis and Committees
No interim analysis is planned to be conducted in this study (PK evaluation in Part A is not 
considered interim analysis.)


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1.6.1 Data Review Committee (DRC)
The DRC consists of members from the sponsor not directly involved in the conduct of the 
study, who will evaluate the PK and safety of each subject in Part A, and who will evaluate that 
information relative to the physiologically-based pharmacokinetic (PBPK) model predictions.
The DRC will assess the PK, PD, and the safety data available from each subject, prior to the 
subject continuing in the study to complete the planned 12 months of open-label rivaroxaban 
therapy. The DRC will only operate during the initial PK, PD, and safety assessment period of 
Part A.
The DRC review package for individual subjects may include the following 3 parts (details are 
provided in a separate DRC Charter document that details the process of DRC review):

PK data: rivaroxaban AUC0-24, Cmax and Cmin on Days 1 and 4.

PD data: PT and aPTT values at baseline and Days 1 and 4; time-matched PT and aPTT 
versus rivaroxaban plasma concentration plots on Days 1 and 4.

Safety data: all available subject information including but not limited to demographic 
information, medical history, baseline lab values, dosing information, adverse events and 
outcome events (including best available bleeding and thrombotic events).
1.6.2 Independent Data Monitoring Committee (IDMC)
The IDMC will evaluate PK, PD, safety and efficacy data to ensure subject safety throughout the 
study. The IDMC will be an independent expert advisory group external to the sponsor and 
study. For Part A only, the IDMC will review the cumulative data from the Initial PK, PD, and 
Safety Assessment Period and will provide the recommendation to the EC and sponsor
committee to cease enrollment in Part A and to start enrollment directly into Part B. The IDMC 
will operate for both Part A and Part B. The acceptability criteria will be described in the IDMC 
charter.
1.6.3 Central Independent Adjudication Committee (CIAC)
The CIAC is comprised of specialist physicians as appropriate and necessary. Committee 
members do not directly enroll subjects in the study, are not involved in the study monitoring, 
and do not have direct operational responsibilities for the conduct of the study. Members will 
review all safety and efficacy outcomes that occur post- enrollment as they become available and 


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adjudicate and classify the following events in a consistent and unbiased manner according to 
definitions in the CIAC charter while blinded to treatment assignment: 
Safety and efficacy outcomes include bleeding events, any thrombotic event (venous or arterial), 
other vascular events, and deaths that occur during the study and the 30-day post-study treatment 
period. 
Sites will be required to complete a worksheet, compile an adjudication package, and to send it 
to the adjudication office within 6 weeks from occurrence of the event. The CIAC procedures 
will be described in the CIAC charter. Adjudication results will be the basis for the final 
analyses.
The best available data will be used for DRC and IDMC reviews. The CIAC-adjudicated results 
will be used in the final analysis for all subjects.
1.6.4 Executive Committee (EC)
The EC will provide overall academic leadership for the study and will oversee the conduct and 
the publications of the results. In addition, the EC will receive recommendations from the IDMC 
regarding modification to the study and will decide whether to accept the recommendations. The 
EC will have 2 co-chairs and will consist of members of academic institutions and 1 member 
from the sponsor.
2.
GENERAL ANALYSIS DEFINITIONS
Statistical analysis of the overall study data will be done by the sponsor.
Description of the statistical methods to be used to analyze the efficacy and safety data is 
outlined in this document, including imputation rules for missing or partially missing dates. 
Summaries by treatment group using appropriate descriptive statistics will be provided for study 
variables. Descriptive statistics such as mean, median, standard deviation, 95% CIs (when 
applicable), minimum, and maximum will be used to summarize continuous variables; Counts 
and percentages will be used to summarize categorical variables. The Kaplan-Meier (KM) 
method will be used to summarize time-to-event data. Graphical data displays may also be used 
to summarize the data.
For analysis purposes, the data from subjects receiving rivaroxaban in Part A of the study will be 
combined with the data from subjects in Part B of the study randomized to rivaroxaban. The data 


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will also be summarized separately for subjects randomized in Part B only (rivaroxaban vs. 
ASA), and for subjects participating in Part A only.
All CIAC adjudicated efficacy and bleeding outcomes will be used in the final analyses.
The statistical evaluation will be performed by using the software package SAS release 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA).
2.1
Definition of Trial Dates
Trial reference start date is defined as the date on which the first dose of study drug is taken by 
the subject.
Trial reference end date is defined as the date of the last trial-related procedure for the subject; 
specifically it is equal to the maximum of the following dates:

Date of the last study-related visit or phone contact (including scheduled or unscheduled 
visits)

Date of the last study-related procedure, finding or event, including, but not limited to, 
safety and efficacy endpoint events, adverse events, concomitant medications, 
disposition, and death
First dose date is defined as the date on which the first dose of study drug is taken by the subject. 
Due to the nature of Part A, the first dose date for Part A subjects will not be allowed to be 
missing. For Part B randomized subjects, if this date is missing or incomplete for a subject who 
takes study drug, the first dose date is set to the earliest logically possible date. More 
specifically, the first dose date is defined as the maximum of the randomization date and the first 
day of the month if only day is missing; it is defined as the randomization date if day and month 
are missing.
Last dose date is defined as the date on which the last dose of study drug is taken by the subject. 
If this date is missing or incomplete for a subject who takes study drug, the last dose date will be 
set to the latest logically possible date. It will be capped by (that is, taking the minimum with) 
Day 353 date, death date, trial reference end date, and the upper bound of the logically possible 
range if partial date is available, and further bounded below by (that is, taking the maximum 
with) the (imputed) first dose date, any complete temporary drug stop and re-start date, or the 
lower bound of the logically possible range.


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Last efficacy-evaluation date is defined as the date of the last study visit at which the outcome 
status of efficacy endpoints is evaluated – Month 12 or ESMD visit.
Planned treatment end date: 12 months since randomization or enrollment for each subject. The
planned treatment end date varies for subjects depending on their randomization or enrollment 
date.
2.2
Analysis Sets
Full Analysis Set: This analysis set consists of all subjects in Part A who receive at least 1 dose 
of study drug and all subjects in Part B who are randomized and receive at least 1 dose of study 
drug.
Safety Analysis Set: This is the same as Full Analysis Set. 
Per-protocol Set: The per-protocol set will exclude subjects with key protocol deviations from 
full analysis set. These deviations will include the following:

Not meeting the following key inclusion or exclusion criteria:
o
INT-1: inclusion criteria 1, exclusion criteria 1, 4, 6 (> 90 consecutive days), 7, 8, 13, 
14, 15, 18
o
INT-2: inclusion criteria 1, exclusion criteria 1, 4, 6 (> 90 consecutive days), 7, 8.1, 13, 
14, 15, 18

Taking incorrect study drug

Not discontinuing study drug permanently according to the protocol 

Having been taking prohibited concomitant therapies as specified in the protocol
PK Analysis Set: All subjects who receive at least 1 dose of study drug and have quantifiable 
rivaroxaban plasma concentrations will be included in the descriptive PK analysis. 
PD Analysis Set: All subjects who receive at least 1 dose of study drug and have quantifiable and 
time-matched PT, aPTT, and/or anti-FXa activity values will be included in the descriptive PD 
analysis. 


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2.3
Analysis Periods
On-Treatment Period: This analysis period includes all data from the first dose of study drug to 
2 days after the last dose of the study drug administration (inclusive). 
Up-to-End-of-Treatment Period: This analysis period includes all data from first dose to end of 
treatment visit (i.e., last efficacy-evaluation date - Month 12 or ESMD visit) 
Up-to-Last-FU (last contact): This analysis period includes all data from first dose to trial 
reference end date.
2.4
Definition of Subgroups
Descriptive summaries of efficacy and safety may be done by considering the following 
subgroups:

Age groups

Sex 

Race 

Ethnicity

Geographic region

Baseline Creatinine Clearance (CrCl)

Weight groups

Type of antiplatelet/anticoagulant therapy prior to enrollment 

Others (e.g., use of central venous lines for > x days, and other parameters related to 
baseline characteristics of Fontan population – to be specified in the DPS)
3.
SUBJECT INFORMATION
Summary statistics (arithmetic mean, standard deviation, median, minimum and maximum for 
quantitative variables) will be presented by treatment. Frequency tables for qualitative data will 
be provided. No statistical tests will be performed to compare these characteristics across 
treatment groups. Unless stated otherwise, all subject information summaries will be based on 
safety analysis set and will be presented for rivaroxaban combined from Parts A and B, ASA and 
rivaroxaban from Part B, and rivaroxaban from Part A.


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3.1
Enrollment and Medical History
Enrollment, screen failures, and inclusion/exclusion criteria will be summarized for all screened
subjects. 
Medical history findings will be summarized using Medical Dictionary for Regulatory Activities 
(MedDRA) by Primary System Organ Class / High Level Term.
Type and other relevant information of the Fontan procedure performed will be summarized
(details specified in the DPS).
3.2
Demographics and Baseline Characteristics
Descriptive statistics by treatment group will be provided for the baseline demographics and 
disease characteristics.
3.3
Disposition Information
The number of subjects and the reasons for premature discontinuation of study treatment will be 
summarized by treatment group as recorded on the eCRF.
The distribution of time from enrollment into the study to early discontinuation will be shown by 
KM plot.
A subject will be considered to have completed the study if the subject completes:

The Follow-Up Contact 30 days after the last dose of study drug taken for subjects who
complete the 12 month treatment

The ESMD Month 12 Follow-Up for subjects who discontinue the study drug 
prematurely
Available vital status at the planned treatment end period (Month 12) will be summarized for 
subjects who prematurely discontinued the study or were lost to follow up. 
3.4
Treatment Compliance
Rivaroxaban will be administered twice daily in an open-label fashion. Rivaroxaban will be 
taken in the morning and in the evening (approximately 12 hours apart) as described in study 
booklet. 


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Subjects randomized to ASA will receive approximately 5 mg/kg as a single dose. ASA will be 
provided as tablets according to the local practices.
Dose adjustments due to increased body weight will be made at Month 6 for subjects in Parts A 
and B for both rivaroxaban and ASA.
IWRS will keep track of study drug dispensed to subjects in both Part A and Part B. Study drug 
accountability will be performed at each visit.
For each subject, the treatment compliance rate is estimated as follows
Compliance rate (%) = 100 * actual treatment duration / intended treatment duration
More specifically, the actual treatment duration will be calculated by minimum of [Day 353 date, 
last dose date, death date, and the first primary efficacy outcome date] - first dose date + 1 - dose 
interruption days. The intended treatment duration will be calculated by minimum of [Day 353
date, death date, and the first primary efficacy outcome date] - first dose date + 1 - dose 
interruption days due to the reasons specified in protocol 10.2.1 (for example, bleeding, and 
other AEs).
Compliance rate will be summarized by treatment group. 
3.5
Duration of Exposure
Duration of treatment exposure is defined as the duration between the first dose date and last 
dose date, inclusive. Note that temporary study drug interruption is not excluded from this 
definition. Duration of treatment exposure will be summarized by treatment group.
Number of patients who had interruptions and total interruption days will be summarized by 
treatment group.
3.6
Protocol Deviations
Major protocol deviations will be summarized by treatment group. The categories of protocol 
deviations may include, but are not limited to the following: 

Not meeting key inclusion or exclusion criteria

Taking incorrect study drug

Not discontinuing study drug permanently according to the protocol 

Having been taking prohibited concomitant therapies as specified in the protocol


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3.7
Prior and Concomitant Medications
Medications received prior to the first dose of study drug are considered prior medications, even 
if the subject continued on the medication concomitantly with the study drug. 

The number and percentage of subjects who received prior medications will be 
summarized.

The number and percentage of subjects who received any anticoagulant/antiplatelet 
medication taken after the Fontan procedure and prior to first dose of study drug will be 
summarized. 
Concomitant medications include all other medications received between the first dose and the 
last dose of study drug.

The number and percentage of subjects who received concomitant medications will be 
summarized.
Separately, anticoagulant/antiplatelet use after the study treatment period (i.e., after stopping 
study treatment) will be summarized.
All prior and concomitant medications will be summarized using the WHO-DD.
4.
SAFETY
No formal hypothesis testing will be performed.
If the date of an outcome event is missing or partially missing, the earliest logically possible date 
after enrollment will be used as the event date. The date of an outcome event is defined as the 
maximum of date of enrollment and the first day of the month if only day is missing and is 
defined as maximum of date of enrollment and the first day of the year if both day and month are 
missing. Maximum efforts will be undertaken to avoid missing event data.
All missing or partial data will be presented in the subject data listing as they are recorded on the 
eCRF.
Unless otherwise stated, all safety summaries and analyses will be performed based on the Safety 
Analysis Set (which is equivalent to Full Analysis Set).


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4.1
Bleeding Events
The primary safety outcome is the major bleeding events, as defined below. Clinically relevant 
non-major bleeding events and trivial (minimal) bleeding will be secondary safety outcomes.
Bleeding events will be adjudicated by the CIAC using the International Society on Thrombosis 
and Hemostasis (ISTH) recommendations (Buller 2007, Schulman 2005).
Major bleeding is defined as overt bleeding and:

Associated with a fall in hemoglobin of 2 g/dL or more; or

Leading to a transfusion of the equivalent of 2 or more units of packed red blood cells or 
whole blood in adults; or

Occurring in a critical site: intracranial, intraspinal, intraocular, pericardial, intra-
articular, intramuscular with compartment syndrome, retroperitoneal; or

Contributing to death.
Clinically relevant non-major bleeding is defined as overt bleeding not meeting the criteria for 
major bleeding but associated with: 

Medical intervention, or

Unscheduled contact (visit or telephone call) with a physician, or

(Temporary) cessation of study treatment, or 

Discomfort for the subject such as pain, or 

Impairment of activities of daily life (such as loss of school days or hospitalization).
Trivial (minimal) bleeding is defined as any other overt bleeding event that does not meet criteria 
for clinically relevant non major bleeding.
The main description will be based on Safety Analysis Set during the On-treatment period   
(bleeding events confirmed by the CIAC).
Incidence rates (number of subjects with bleeding event during the period divided by the number 
of subjects at risk at the beginning of the period) and the respective 95% CIs will be calculated 
for the major and clinically relevant non major bleedings by treatment group. Cumulative 


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incidence rates (time to first event; Kaplan-Meier) will be calculated for the major bleeding and 
clinically relevant non-major bleeding. 
In addition, listing for all bleedings will be provided, including those that are reported more than 
2 days after stop of study medication.
Baseline demographics and disease characteristics relationship to bleeding risk may be explored.
4.2
Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as those adverse events that occur from
the first day of study drug to the last day of study drug + 2 days inclusive. Summary of the
incidence of the following adverse events will be done:

Treatment-emergent adverse events

Treatment-emergent serious adverse events

Serious adverse events with onset > 2 days from the stop of study drug 

Adverse events leading to permanent study drug discontinuation
In addition, incidences of adverse events by system organ class and dictionary-derived 
(preferred) term will be provided.
Listings will be done for all Adverse Events, and for all Serious Adverse Events.
Additional summaries, listings, or subject narratives may be provided, as appropriate.
For subjects who are not in Safety Analysis Set, AEs will be listed separately. 
The ICF is signed at screening, prior to any study related procedure is done. Any AE that a 
subject develops after the ICF is signed but before the first dose is administered will be reported 
separately.
4.3
Clinical Laboratory Tests
The study will collect laboratory data at baseline, Month 3 (limited laboratory data at Month 3), 
and Month 12. Laboratory data will be summarized by treatment group and time point by 
descriptive statistics.
4.4
Vital Signs and Physical Examination Findings
Vital signs and physical examination findings will be summarized by treatment group and time 
point. 


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5.
EFFICACY
No formal hypothesis testing will be performed. The primary efficacy outcome will be any 
thrombotic event (venous or arterial), defined as: 

The appearance of a new thrombotic burden within the cardiovascular system on either 
routine surveillance or clinically indicated imaging, or

The occurrence of a clinical event known to be strongly associated with thrombus (such 
as cardioembolic stroke, pulmonary embolism).
Subjects who develop either a symptomatic or asymptomatic thrombotic event during the study 
must permanently discontinue study drug. After cessation of study treatment, it is at the 
investigator’s discretion to continue with other antithrombotic therapy. The investigator should 
document this therapy in the electronic case report form (eCRF). All available imaging results, 
e.g., transthoracic or transesophageal echocardiograms, or MRIs, relevant to a suspected 
thrombotic event should be sent to the CIAC for event adjudication. Thrombotic events will not 
be reported as adverse events or serious adverse events, as they will be reported as efficacy 
outcomes.
Transthoracic Echocardiograms will be obtained at screening, at Month 6 and Month 12 for the 
assessment of thrombotic events. For subjects who prematurely discontinue study drug for any 
reason (except when the child is enrolled because the local reader reviews the screening echo as 
without thrombosis and later on the central reviewer reports the presence of a thrombus), the 
final echocardiogram will be performed as soon as possible after discontinuation, at the ESMD 
visit. Investigators can image as often as medically necessary or as needed based on their 
institution’s standard of care; however, protocol-based imaging must be performed at screening, 
Month 6 and at the end of therapy. Echocardiograms will be sent to a core laboratory for blinded 
reading and to minimize inter-site variability and bias.
The main efficacy description will be based on Full Analysis Set, excluding subjects who start on 
study drug but are discontinued if central reading by the core laboratory reports thrombosis on 
the Screening transthoracic echocardiogram (these subjects will be included however in the 
safety analysis) based on up-to-the-end-of-treatment period (outcomes confirmed by the CIAC). 
Events that are reported after Month 12 or ESMD visit will be described in additional summaries 
or listings.


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Additionally, data may also be summarized based on Full Analysis Set and up-to-last-FU (last 
contact) period or Per-protocol Analysis Set and On-treatment period.
Incidences rates (number of subjects with efficacy event during the period divided by number of 
subjects at risk at the beginning of the period) and the respective 95% CIs will be calculated for 
the primary efficacy outcome by treatment group.
Cumulative incidences (time to first event; Kaplan-Meier) will also be calculated for the efficacy 
outcomes. 
In addition, listings of any efficacy outcomes will be provided. 
Baseline demographics and disease characteristics relationship to thrombotic risk may be 
explored.
The numbers and percentages of subjects with missing Follow-Up Contact (30-days after last 
dose or Month 12) will be summarized. 
All missing or partial data will be presented in the subject data listing as they are recorded on the 
eCRF.
6.
PHARMACOKINETICS
Part A
PK and PD blood samples will be collected on the first day of dosing (Visit 2/D1) between 0.5 to 
1.5 hours and again between 1.5 to 4.0 hours post-dose. Additional samples will be collected on 
Day 4 (Visit 2/D4), just prior to dose administration and again between 0.5 to 1.5 hours, 1.5 to 
4.0 hours and 6.0 to 8.0 hours post-dose. PK and PD samples will also be taken at Month 3 and
Month 12.
All PK and PD samples will be sent to a central laboratory for quantitative analysis.
The plasma PK parameters determined will be AUC0-24 and Cmax after a single dose and at 
steady-state AUC0-24ss, Cmaxss and Cminss. The PT and aPTT will be used to assess the PK/PD 
relationship after administration of the study drug. 
Part B
PK and PD blood samples will be collected on the first day of dosing (Visit 2/D1) up to 3 hours 
prior to the AM dose, between 0.5 to 1.5 hours and again between 2.5 to 4.0 hours post-dose. PK 
and PD samples will also be taken at Month 3 and Month 12.


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All PK and PD samples will be sent to a central laboratory for quantitative analysis.
The plasma PK parameters determined will be AUC0-24 and Cmax after a single dose and at 
steady-state AUC0-24ss, Cmaxss and Cminss. The PT, aPTT, and anti-FXa activity (AXA) will be 
used to assess the PK/PD relationship after administration of the study drug when data are 
available. 
Both Parts
Descriptive statistics will be used to summarize rivaroxaban PK data for each time interval and 
the concentration-time profile will also be described. PD measurements, including PT, aPTT, and 
AXA will be plotted against rivaroxaban plasma concentrations and will also be summarized by 
timepoint when data are available.
Rivaroxaban PK parameters including AUC0-24ss, Cmaxss, and Cminss at steady date will be derived 
by model-based methods.
The subject’s steady-state AUC0-24ss will also be evaluated if it matches with that of the reference 
AUC0-24ss after 10 mg total daily dose at steady-state (Refer to Figure 2, Pharmacokinetic 
Decision Tree). Cmaxss and Cminss at steady-state might also be compared numerically with those 
in adult patients. PK/PD relationship will be explored in pediatric subjects. 
PK and PD Analysis datasets will be respectively used for summaries of PK and PD parameters.
PK/PD data analysis plan (DAP) will be provided separately before database lock (DBL). 
Results from PK and PK/PD analyses will be reported separately from the Clinical Study Report.
7.
HEALTH ECONOMICS
There are no plans to collect health economics data.


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Figure 2:
Pharmacokinetic Decision Tree  
VTE = venous thromboembolism; ped = pediatric; post-op = post-operative; TKHR = total knee or hip replacement 
Rivaroxaban exposure (steady-state AUC0-24ss) in target (green) zone according DRC recommendations for 
individual subjects at steady-state; 
Target
Low
High
AUC0-24[g.h/L]
95th percentile of 
VTE Ped 20 mg 
(2000)
5th percentile of 
TKHR post-op adult 
10 mg (400)
Body Weight (kg)
10
20
30
40
Adult reference 10 mg 
exposure (1000)


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8. REFERENCES
1.
Protocol 39039039CHD3001: A Prospective, open-label, active-controlled study to evaluate the 
pharmacokinetics, pharmacodynamics, safety, and efficacy of rivaroxaban for thromboprophylaxis in pediatric 
subjects 2 to 8 years of age after the Fontan procedure.
2.
Bayer report no: PH-38851:  Exploratory population pharmacokinetic analysis of rivaroxaban (BAY 59-7939) 
in single-dose pilot study of oral rivaroxaban in pediatric subjects with venous thromboembolism.
3.
Clinical Study Report PH-38444: Single-dose pilot study of oral rivaroxaban in pediatric subjects with venous 
thromboembolism.
4.
Mueck W, Eriksson BI, Bauer KA, Borris L, Dahl OE, Fisher WD, Gent M, Haas S, Huisman MV, Kakkar 
AK, Kalebo P, Kwong LM, Misselwitz F and Turpie AG (2008) Population pharmacokinetics and 
pharmacodynamics of rivaroxaban--an oral, direct factor Xa inhibitor--in patients undergoing major 
orthopaedic surgery. Clinical Pharmacokinetics 47:203-216.
5.
Barrett YC, Wang Z, Frost C, Shenker A. (2010)  Clinical laboratory measurement of direct factor Xa 
inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost. 2010;104(6):1263–1271.