Conditions: Thromboembolism
Keywords: Pediatric
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out whether rivaroxaban is safe and effective to use in children age newborn to less than 6 months and how long it stays in the body and how it is used in the body. Safety will be assessed by looking at the incidence and types of bleeding events. There will also be a check for worsening of blood clots.

Detailed description:
Neonates and infants aged less than 6 months who pass the screen of in- and exclusion criteria, who have been treated for at least five days with heparin and /or vitamin K antagonist (VKA) for confirmed symptomatic or asymptomatic arterial or venous thrombosis are eligible for the study. Study treatment consists of a 7-day treatment with an age- and body weight-adjusted three times daily, approximately 8 hours apart oral rivaroxaban dosing to achieve a similar exposure as that observed in adults treated for venous thromboembolism (VTE) with 20 mg rivaroxaban once daily. Rivaroxaban will be provided as granules for preparation of an oral suspension (1 mg/mL after re-suspension) using a t.i.d. regimen with 8-hour intervals. An ultrasound will be performed before starting rivaroxaban at treatment day 1 and after the end of rivaroxaban treatment at day 8. The last dose of rivaroxaban treatment will be followed by a 30-day post study treatment period, regardless of the duration of study drug administration. After cessation of rivaroxaban, it is at the investigator's discretion to continue with anticoagulants. The principal safety outcome is the combination of major and clinically relevant non-major bleeding. The efficacy outcome is the composite of all symptomatic recurrent thromboembolism and asymptomatic deterioration in thrombotic burden on repeat imaging. All suspected recurrent thromboembolism, asymptomatic deterioration in thrombotic burden on repeat imaging, deaths, as well as all episodes of bleeding will be evaluated by a central independent adjudication committee (CIAC). Adjudication results will be the basis for the final analyses.

For all children, visits are scheduled at regular time points (see Table 1). Enrolled children who are not treated or those with premature discontinuation of rivaroxaban will at least be seen at the end of the study treatment period. During all contacts, the treatment and clinical course of the child will be evaluated. Children with suspected efficacy or safety outcomes will undergo confirmatory testing as per standard of care. Blood samples for pharmacokinetic (PK)/pharmacodynamics (PD) will be taken at defined time points (see Table 2).

An Independent Data Monitoring Committee (DMC) will monitor the children's safety during the study and give recommendations to the steering committee.

Arms:
arm 1: Rivaroxaban oral suspension from granules will be dosed according to body weight as oral 0.1% suspension (1 mg/mL)

Interventions: intervention 1: Rivaroxaban (Xarelto, BAY59-7939)
Intervention descriptions: intervention 1: Body weight adjusted dosing of rivaroxaban to achieve a similar exposure in the range as that observed in adults treated for venous thromboembolism (VTE) with 20 mg once daily.

Protocol document:
Prot_001.pdf: 
 
Document Type: Study Protocol 
Official Title: 
7-day study of the safety, efficacy and the pharmacokinetic and 
pharmacodynamic properties of oral rivaroxaban in children from 
birth to less than 6 months with arterial or venous thrombosis 
NCT Number: 
NCT02564718 
Document Date: 
15 Nov 2016 
 


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Cover page of the integrated protocol
7-day study of the safety, efficacy and the pharmacokinetic and pharmacodynamic properties 
of oral rivaroxaban in children from birth to less than 6 months with arterial or venous 
thrombosis 
EINSTEIN Junior Phase I/II in children from birth to less than 6 months
This protocol version is an integration of the following documents / sections:

Original protocol, Version 1.0, dated 11 Nov 2014

Amendment 1 (described in Section 16.1)
forming integrated protocol Version 2.0, dated 21 Jul 2015

Amendment 2 applicable to Canada only, dated 22 Sep 2015

Amendment 3 applicable to Turkey only, dated 22 Mar 2016

Amendment 4 (described in Section 16.2)
forming integrated protocol Version 3.0, dated 10 May 2016

Amendment 5 (described in Section 16.3)
forming integrated protocol Version 4.0, dated 15 Nov 2016

Amendment 6 applicable to Turkey only, dated 15 Nov 2016 
This document integrates the original protocol and all global amendments.


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Title page - amended
Study title
7-day study of the safety, efficacy and the pharmacokinetic and pharmacodynamic properties 
of oral rivaroxaban in children from birth to less than 6 months with arterial or venous 
thrombosis 1
EINSTEIN Junior Phase I/II in children from birth to less than 6 months
Test drug:
BAY 59-7939/ Rivaroxaban
Clinical study phase:
I/II
Date:
15 Nov 2016
Registration:
2014-002385-74
Version no.:
4.0
Sponsor’s study no.:
17618
Sponsor:
Non-US territory: Bayer AG, D-51368 Leverkusen, Germany
US territory: Bayer Healthcare Pharmaceuticals Inc.,
100 Bayer Boulevard, P.O. Box 915,
Whippany NJ 07981-0915, USA 2
 
 
  
Telephone: 
Email:  
 
24-hour medical 
emergency contact:
Telephone: 
Email:
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation. Reproduction or disclosure of this document
whether in part or in full to parties not associated with the clinical investigation, or its use for 
any other purpose, without the prior written consent of the sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
                                                
1 The study population was modified via Amendment 4 (see Section 16.2.2.1)
2 The sponsor information was changed via Amendment 5 (see Section 16.3.2.1)
3 The medical expert was changed via Amendments 4 and 5 (see Section 16.2.2.1 and 16.3.2.1)
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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ov 2016 
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Signature of Bayer's medically responsible person 
The signatory agrees to the content ofthe final clinical study protocol as presented. 
Name:
Role: 
Date: IJol.>frt)ln 
')_01 { 
Signature 
PPD
PPD
PPD


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Signature of the investigator 
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
Affiliation:
Date:
Signature:
Signed copies of this signature page are stored in the sponsor’s study file and in the respective 
center’s investigator site file.


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Synopsis - amended
Title
7-day study of the safety, efficacy and the pharmacokinetic and 
pharmacodynamic properties of oral rivaroxaban in children from birth to 
less than 6 months with arterial or venous thrombosis 4
Short title
EINSTEIN Junior Phase I/II in children from birth to less than 6 months
Clinical study phase
I/II
Study objectives
The primary objective is:

to characterize the pharmacokinetic/pharmacodynamic profile of a 
7-day treatment with oral rivaroxaban
The secondary objectives are:

to assess the incidence of major bleeding and clinically relevant 
non-major bleeding,

to assess the incidence of symptomatic recurrent thromboembolism 
and

to assess asymptomatic deterioration in the thrombotic burden on 
repeat imaging
Test drug/ active ingredient
Rivaroxaban
Dose(s)
Age- and body weight-adjusted three times daily dosing of rivaroxaban to 
achieve a similar exposure as that observed in adults treated for venous 
thromboembolism (VTE) with 20 mg rivaroxaban once daily5
Route of administration
Oral suspension
Duration of treatment
7 days
Indication
Children from birth to less than 6 months with documented symptomatic or 
asymptomatic arterial or venous thrombosis 6
Diagnosis and main criteria for 
inclusion /exclusion
Children from birth to less than 6 months with documented symptomatic or 
asymptomatic arterial or venous thrombosis who have been treated with 
anticoagulant therapy for at least five days. 7
Inclusion
1.
Children from birth to less than 6 months with documented 
symptomatic or asymptomatic venous or arterial thrombosis 
who have been treated with anticoagulant therapy for at least 
5 days. 8
2.
Gestational age at birth of at least 37 weeks.
3.
Hemoglobin, platelets, creatinine, alanine aminotransferase 
(ALT) and total and direct bilirubin assessed within 10 days 
prior to enrollment.
                                                
4 The study population was modified via Amendment 4 (see Section 16.2.2.2)
5 The dosing was changed from b.i.d. to t.i.d. via Amendment 5 (see Section 16.3.2.2)
6 The study population was modified via Amendment 4 (see Section 16.2.2.2)
7 This section was modified via Amendment 4 (see Section 16.2.2.2)
8 Inclusion criterion 1 was changed via Amendment 4 (see Section 16.2.2.2)


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4.
Oral feeding/nasogastric/gastric feeding for at least 10 days.
5.
Informed consent provided.
6.
Body weight >2600 g. 9
Exclusion
1.
Active bleeding or high risk for bleeding contraindicating 
anticoagulant therapy, including history of intra-ventricular 
bleeding
2.
Symptomatic progression of thrombosis during preceding 
anticoagulant treatment
3.
Planned invasive procedures, including lumbar puncture and 
removal of non-peripherally placed central lines during study 
treatment
4.
Hepatic disease which is associated with either: coagulopathy 
leading to a clinically relevant bleeding risk, or alanine 
aminotransferase (ALT) > 5x upper level of normal (ULN) or 
total bilirubin (TB) > 2x ULN with direct bilirubin > 20% of 
the total
5.
Creatinine > 1.5 times of normal 
6.
Uncontrolled hypertension defined as > 95th percentilea  10
7.
History of gastrointestinal disease or surgery associated with 
impaired absorption
8.
Platelet count <100 x 109/L
9.
Concomitant use of strong inhibitors of both cytochrome 
P450 isoenzyme 3A4 (CYP3A4) and P-glycoprotein (P-gp), 
e.g. all human immunodeficiency virus protease inhibitors 
and the following azole-antimycotics agents: ketoconazole, 
itraconazole, voriconazole, posaconazole, if used systemically 
(fluconazole is allowed) 11
10.
Concomitant use of strong inducers of CYP3A4, e.g.
rifampicin, rifabutin, phenobarbital, phenytoin and 
carbamazepine 12
11.
Indication for anticoagulant therapy other than current 
thrombosis
12.
An indication for continued antiplatelet therapy or non-steroid 
anti-inflammatory drug (NSAID) therapy. Incidental use is 
allowed.13
13.
Hypersensitivity to rivaroxaban or its excipients
14.
Participation in a study with an investigational drug or 
medical device within 30 days prior to enrollment.
a See Appendix 17.1.2
Study design
Non-randomized, open label, multicenter, combined single and multiple 
dose study
                                                
9 Inclusion criterion 6 was added via Amendment 1 (see Section 16.1.2.1)
10 Exclusion criterion 6 was modified via Amendment 4 (see Section 16.2.2.2)
11 Exclusion criterion 9 was modified via Amendment 1 (see Section 16.1.2.1)
12 Exclusion criterion 10 was modified via Amendment 1 (see Section 16.1.2.1)
13 Exclusion criterion 12 was modified via Amendment 4 (see Section16.2.2.2)


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Methodology
Children with confirmed arterial or venous thrombosis who have been 
treated with anticoagulant therapy for at least five days.14
Children will receive an age- and body weight-adjusted rivaroxaban 
regimen using an oral suspension (1 mg/mL) for a total of 7 days followed 
by an observational period of another 30 days. Rivaroxaban will be 
administered three times daily.15
An ultrasound will be performed at day 1 and 8 of rivaroxaban treatment to 
document asymptomatic changes. In addition, children will be monitored 
for the occurrence of symptomatic recurrent thrombosis and bleedings.
All suspected clinical study outcomes and baseline and repeat ultrasound 
imaging tests will be assessed by a Central Independent Adjudication
Committee (CIAC).
An independent data monitoring committee (DMC) will monitor the 
children’s safety and give recommendations to the steering committee.
Number of subjects
At least 8 children will be included.
Primary outcome
Results of pharmacokinetics (PK) / pharmacodynamics (PD) (prothrombin 
time, activated partial thromboplastin time and anti-factor Xa activity)
Secondary outcomes
Composite of major and clinically relevant non-major bleeding. Composite 
of all symptomatic recurrent thromboembolism and asymptomatic 
deterioration in thrombotic burden on repeat imaging.
Plan for statistical analysis
The incidence of the composite of major and clinically relevant non-major 
bleeding and the incidence of symptomatic recurrent thromboembolism, 
and asymptomatic deterioration in thrombotic burden on repeat imaging 
will be summarized. Quantitative data will be described by summary 
statistics. Results of PK/PD analyses will be provided. 
                                                
14 This section was changed via Amendment 4 (see Section 16.2.2.2)
15 The dosing was changed from b.i.d. to t.i.d. via Amendment 5 (see Section 16.3.2.2)


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Table 1: Flow chart: study visits 16
Screen a
Treatment period
30 day post study 
treatment contact
Visit
1
2
3
4
5
Days
Day -10 to Day 1
Day 1
Day 3
Day 8
Day 37+ 7 days 
Obtain informed consent
●
Check in-/exclusion criteria
●
Obtain demographic data
●
Check medical history
●
●
Record anticoagulant medication
●
●
Obtain blood pressure
●
Obtain body weight
●
●
●
Check Hb, platelets, creatinine, ALT, 
total and direct bilirubin
●b
Obtain ALT, total and direct bilirubin
●
Re-confirm in-/exclusion criteria
●
Obtain INR, if receiving VKA f
●
Enroll patient 
●
Dispense study medication
Instruct how to administer the study 
medication 
Provide study booklet
Provide rivaroxaban oral suspension 
handling guidelines
●c
Record all concomitant medication
●
●
●
●
Collect baseline imaging d
●
Repeat ultrasound imaging d
●
●e
Check for study outcomes d
●
●
●
Check adverse events
●
●
●
●
Check drug accountability and 
compliance
●
Check if anticoagulant treatment 
continued after Visit 4
●
Complete eCRF
●
●
●
●
●
ALT = alanine aminotransferase, eCRF = electronic case report form, Hb = hemoglobin; INR= international normalized ratio, 
VKA= vitamin K antagonist
a
The screening visit can be performed up to 10 days prior to inclusion into the study.
b
Hb, platelets, creatinine, ALT, total and direct bilirubin results should be available within 10 days prior to inclusion into the 
study. If results are not available, obtain blood sample.
c
If child discharged from the hospital.
d
Compile adjudication package and send it to the adjudication office.
e  Repeat ultrasound can be obtained on Day 8 ± 1.
f
INR should be below 2.5 before starting rivaroxaban (see Section 5.1.1.3).
                                                
16 The study flow chart was modified via Amendment 1 (see Section 16.1.2.1)


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Table 2: Flow chart: pharmacokinetics and pharmacodynamics 17
PK and PDa
Visit 1
Visit 2
Visit 3
Visit 4
Rivaroxaban 
treatment days
Screen
day -10 
to day 1
Treatment 
day 1
Treatment day 2
Treatment
day 3
Treatment
day 4 to 7
Day 8
Rivaroxaban 
administration
1st
dose
2nd
dose
3rd 
dose
1st
dose
2nd
dose
3rd
dose
1st
dose
2nd
do
se
3rd 
do
se
1st
dose
2nd
dose
3rd dose
PK/PD time 
points
0.5 to 3 
hr post 
dose
7 to 
8hr
post 
dose
0.5 to 
3 hr 
post 
dose
7 to 
8hr
post 
dose
10-16 hr 
after last 
dose at 
day 7
Obtain blood 
sample for PK b
●
●
●
●
Obtain blood 
sample for PD c
●
●
●d
hr = hour(s), PD = pharmacodynamics, PK = pharmacokinetics
a The approximate total blood volume taken per child for PK/PD is 6.6 mL. Always draw the PD sample as the last sample.
b Blood volume per PK sample is approximately 0.6 mL; total blood volume for all PK samples is 2.4 mL.
c Blood volume per PD sample is approximately 1.4 mL; total blood volume for all PD samples is 4.2 mL.
d If continued treatment with anticoagulants is necessary, administer the anticoagulant after last sample is taken for rivaroxaban.
                                                
17 The PK/PD flow chart was changed via Amendment 5 (see Section 16.3.2.2)


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Table of contents
Cover page of the integrated protocol.................................................................................... 1
Title page - amended................................................................................................................ 2
Signature of Bayer’s medically responsible person .............................................................. 3
Signature of the investigator ................................................................................................... 4
Synopsis - amended .................................................................................................................. 5
Table of contents..................................................................................................................... 10
Table of tables......................................................................................................................... 12
List of abbreviations............................................................................................................... 13
1.
Introduction - amended .................................................................................................. 14
1.1
Rivaroxaban................................................................................................................... 15
1.2
Venous or arterial thrombosis - amended ..................................................................... 15
1.3
Rationale of the study and risk-benefit assessment - amended...................................... 15
2.
Study objectives............................................................................................................... 16
3.
Study design - amended.................................................................................................. 16
3.1
Study description - amended.......................................................................................... 17
4.
Study population ............................................................................................................. 18
4.1
Planned number of children........................................................................................... 18
4.2
Inclusion criteria - amended........................................................................................... 18
4.3
Exclusion criteria - amended ......................................................................................... 18
4.4
Concomitant medication - amended .............................................................................. 19
5.
Treatment groups and regimens.................................................................................... 19
5.1
Method of treatment allocation...................................................................................... 19
5.1.1
Rivaroxaban regimen - amended................................................................................ 19
5.2
Subject identification ..................................................................................................... 21
5.3
Duration of study treatment ........................................................................................... 21
5.4
Formulation and dose..................................................................................................... 21
5.4.1
Rivaroxaban - amended.............................................................................................. 21
5.5
Packaging, labeling, and storage - amended.................................................................. 22
5.6
Treatment assignment.................................................................................................... 22
5.7
Dose and administration ................................................................................................ 22
6.
Study procedures............................................................................................................. 22
6.1
Study visits - amended................................................................................................... 22
6.2
Visit 1 – Screening visit at 1 to 10 days before Visit 2 - amended................................ 23
6.3
Visit 2 – Treatment visit at Day 1 - amended................................................................ 23
6.4
Visit 3 – Treatment visit at Day 3 - amended................................................................ 24
6.5
Visit 4 – Day 8 - amended ............................................................................................. 26
6.6
Visit 5 – 30 day post treatment contact at Day 37 (+ 7 days)........................................ 27
6.7
Unscheduled visits ......................................................................................................... 27


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6.8
Safety outcomes............................................................................................................. 27
6.9
Recommendations before and after invasive procedures and surgical intervention...... 28
6.10
Management of bleeding in children ............................................................................. 28
6.11
Efficacy outcome ........................................................................................................... 28
6.12
PK/PD assessment ......................................................................................................... 29
6.13
Study booklet ................................................................................................................. 29
6.14
Study committees........................................................................................................... 30
6.14.1
Steering committee..................................................................................................... 30
6.14.2
Central independent adjudication committee (CIAC)................................................ 30
6.14.3
Data monitoring committee (DMC) ........................................................................... 30
7.
Statistical and analytical methods ................................................................................. 30
7.1
General considerations................................................................................................... 30
7.2
Analysis sets .................................................................................................................. 31
7.3
Demographic and other baseline characteristics............................................................ 31
7.4
Safety analysis ............................................................................................................... 31
7.5
Efficacy analysis............................................................................................................ 31
7.6
PK/PD analysis .............................................................................................................. 31
7.7
Interim analyses ............................................................................................................. 31
7.8
Determination of sample size......................................................................................... 32
7.9
Adverse events............................................................................................................... 32
7.9.1
Definitions .................................................................................................................. 32
7.9.2
Relationship of AE to the study drug ......................................................................... 33
7.9.3
Causal relationship to protocol-required procedures.................................................. 33
7.9.4
Intensity of an AE, action taken and outcome............................................................ 33
7.9.5
Assessments and documentation of adverse events ................................................... 34
7.9.6
Reporting of serious adverse events........................................................................... 34
7.9.7
Study specific exceptions to the (S)AE reporting ...................................................... 34
7.9.8
Expected AEs ............................................................................................................. 35
7.9.9
Adverse events of special safety interest.................................................................... 35
7.10
Premature discontinuation of study medication ............................................................. 35
7.11
Appropriateness of procedures / measurements ............................................................ 35
8.
Data handling and quality assurance............................................................................ 36
8.1
Data processing.............................................................................................................. 36
8.2
Audit and inspection ...................................................................................................... 36
8.3
Archiving ....................................................................................................................... 36
8.4
Missing data................................................................................................................... 37
9.
Premature termination of the study .............................................................................. 37
10. Ethical and legal aspects................................................................................................. 37
10.1
Ethical and legal conduct of the study........................................................................... 37
10.2
Consent .......................................................................................................................... 38
11. Investigators and other study personnel....................................................................... 38
12. Publication policy and use of data................................................................................. 39


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13. Insurance for children .................................................................................................... 39
14. Confidentiality................................................................................................................. 39
15. Reference list.................................................................................................................... 40
16. Protocol amendments...................................................................................................... 41
16.1
Amendment 1................................................................................................................. 41
16.1.1
Overview of changes .................................................................................................. 41
16.1.2
Changes to the protocol text....................................................................................... 43
16.2
Amendment 4................................................................................................................. 52
16.2.1
Overview of changes .................................................................................................. 52
16.2.2
Changes to the protocol text....................................................................................... 55
16.3
Amendment 5................................................................................................................. 69
16.3.1
Overview of changes .................................................................................................. 69
16.3.2
Changes to the protocol text....................................................................................... 72
17. Appendices....................................................................................................................... 82
17.1.1
Bioanalytics and pharmacokinetics ............................................................................ 82
17.1.2
Age percentiles for blood pressure in children........................................................... 82
Table of tables
Table 1: Flow chart: study visits ............................................................................................... 8
Table 2: Flow chart: pharmacokinetics and pharmacodynamics .............................................. 9
Table 3: Rivaroxaban dosing schedule..................................................................................... 20


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List of abbreviations
AE
adverse event
IEC
independent ethics committee 
ALT
alanine aminotransferase
INR
international normalized ratio 
aPTT
activated partial 
thromboplastin time
IRB
Institutional Review Board 
anti-Xa
anti-factor Xa activity
LMWH
low molecular weight heparin
AUC
area under the curve
MedDRA
Medical Dictionary for 
Regulatory Activities 
b.i.d.
twice daily
mmHg
millimeters of mercury
CCDS
company core data sheet
NSAID
non-steroid anti-inflammatory 
drug
CIAC
central independent 
adjudication committee
PD
pharmacodynamics
CNS
central nervous system
PE
pulmonary embolism
CRO
contract research 
organization
P-gp
P-glycoprotein
CV
coefficient of variation
PK
pharmacokinetic
CYP3A4
cytochrome P450 
isoenzyme 3A4 
SAE
serious adverse event 
dL
deciliter
SAP
statistical analysis plan
DMC
data monitoring committee
SID
subject identification number
DVT
deep vein thrombosis
SUSAR
Suspected Unexpected Serious 
Adverse Reaction 
eCRF
electronic case report form 
TB
total bilirubin
t.i.d.
three times daily
EudraCT
European Union Drug 
Regulating Authorities 
Clinical Trial
TOSCA
Tool for Syntactic Corpus 
Analysis
GCP
good clinical practice
U
units
GMP
good manufacturing 
practice
UFH
unfractionated heparin 
Hb
hemoglobin
ULN
upper limit of normal
IB
investigator’s brochure
VKA
vitamin K antagonist
ICH
International Conference on 
Harmonization
VTE
venous thromboembolism


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1.
Introduction - amended
The classical management of venous thromboembolism (VTE) in adults consists of an initial 
treatment with adjusted-dose intravenous unfractionated heparin (UFH), body weight-adjusted 
subcutaneous low molecular weight heparin (LMWH), or body weight-adjusted subcutaneous 
fondaparinux followed by long-term treatment with a vitamin K antagonist (VKA).(1) VKA 
therapy should be continued for at least three months. The dose of VKA needs to be adjusted 
to maintain the international normalized ratio (INR) in the therapeutic range (target 2.5, range 
2.0-3.0). This therapeutic approach has also been adopted for VTE treatment in children.
Treatment with heparins and VKA has several unsatisfying aspects. For heparins, these
include the requirement for intravenous or subcutaneous injection and monitoring of the 
activated partial thromboplastin time (aPTT). For VKA, these include a slow onset and offset 
of action, a narrow therapeutic window requiring frequent INR monitoring, and subsequent 
dose adjustments, caused by food and drug interactions.(2) An oral anticoagulant drug that 
requires no monitoring of its effect, with a rapid onset of action and a high benefit-risk ratio is 
of considerable interest not only for adults, but especially for the pediatric population.
Rivaroxaban has been extensively studied in the adult population with symptomatic deep vein 
thrombosis (DVT) and pulmonary embolism (PE). In two dose finding studies,(3,4) various 
rivaroxaban dosages were evaluated and compared to standard of care: LMWH and VKA. As 
a result of these dose finding studies, a rivaroxaban regimen was selected that consisted of
15 mg twice daily treatment for the initial 3 week acute treatment, followed by 20 mg once 
daily for long-term treatment. Subsequently, this fixed dose rivaroxaban regimen was 
evaluated in a large phase III study and was compared to body weight-adjusted LMWH and 
INR titrated VKA in patients with symptomatic deep vein thrombosis. The results 
demonstrated clear non-inferiority for the primary efficacy outcome and a similar safety
profile in terms of the occurrence of major bleeding and clinically relevant non-major 
bleeding.(5)
The goal of the rivaroxaban pediatric program is to make rivaroxaban available to children for 
treatment and secondary prevention of VTE. To accomplish this goal, an age- and body
weight adjusted dosing regimen has been developed and is being evaluated in a phase III 
program in children from 6 months to less than 18 years. 
Children between birth and less than 6 months will be evaluated within separate studies
because of distinct differences in the coagulation system, presentation of venous thrombosis 
and treatment requirements.
In this phase I/II study, children with confirmed symptomatic or asymptomatic arterial or 
venous thrombosis will be treated for 7 days with the age- and body weight-adjusted 
rivaroxaban three times daily dosing regimen to achieve a similar exposure as that observed in 
adults treated for VTE with 20 mg rivaroxaban once daily. 18
                                                
18 This section was modified via Amendment 4 and 5 (see Sections 16.2.2.3 and 16.3.2.3)


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1.1
Rivaroxaban
Rivaroxaban is an oral, highly selective direct factor Xa inhibitor. Inhibition of factor Xa 
interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both 
thrombin formation and development of thrombi. Rivaroxaban is widely approved for the 
prevention of VTE following elective hip or knee replacement surgery, for treatment and 
secondary prevention of DVT and PE, for the primary and secondary prevention of stroke and 
systemic non-central nervous system (CNS) embolism in non-valvular atrial fibrillation, and 
for the prevention of atherothrombotic events after an acute coronary syndrome.
1.2
Venous or arterial thrombosis - amended 19
Compared with adults, thrombosis is rare in children and often is a secondary complication of 
primary underlying medical conditions or of the use of central lines.(6)
In neonates who have a central line, a high risk of thrombotic events has been observed. 
Canadian prospective registries estimated an incidence of thrombosis of 24 per 10,000 
neonatal admissions, whereas for older children (>1 month old), the incidence is about 5.3 per 
10,000 hospital admissions.(7,8)
A Canadian registry published in 1994 in children aged 1 month to 18 years reported that 
thrombosis was associated with the use of central venous lines in 33%, with cancer in 23%, 
with congenital heart disease in 15%, with trauma in 15%, with inherited thrombophilia in 
9%, and with infection in 7.5%.(8) Multiple co-existing risk factors were often present and 
39.4% and 35% of children had 2 or 3 concomitant risk factors, respectively..(8)
In 1995, another Canadian registry reported that, except for spontaneous renal vein 
thrombosis, 89% of thromboses in neonates were associated with the use of central venous or 
arterial lines. Most of the cases involved the superior caval vein, inferior caval vein, right 
atrium or femoral veins. Less commonly affected were the brachiocephalic, subclavian, 
jugular and iliac veins. Arterial thrombosis typically affected the aorta or the iliac and femoral 
arteries. (7)
1.3
Rationale of the study and risk-benefit assessment - amended
Treatment options are limited to heparins and VKA, which are cumbersome to manage due to
the requirement for daily subcutaneous or intravenous injections and regular blood sampling 
for laboratory monitoring followed by dose adaptations. In children, the availability of an oral 
anticoagulant treatment that does not require subcutaneous or intravenous injections and 
regular blood sampling for laboratory monitoring, as is the case in adults, would be desirable.
In adults, rivaroxaban is administered orally and is characterized by stable and predictable 
pharmacokinetics and, therefore, does not require laboratory monitoring with subsequent dose 
adjustments. In the Phase III EINSTEIN DVT and PE studies in adults,(9) rivaroxaban was 
non-inferior to standard of care with enoxaparin followed by VKA treatment. In the pooled 
analysis, the incidence of the primary efficacy outcome (the composite of symptomatic 
                                                
19 The heading was modified via Amendment 4 (see Section 16.2.2.4)


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recurrent DVT, non-fatal and fatal PE) was lower on rivaroxaban than on enoxaparin/VKA 
treatment, with a similar incidence of clinically relevant bleeding. The comparison against 
placebo in patients studied for extended treatment of VTE (EINSTEIN extension study) 
demonstrated clear superiority for rivaroxaban against placebo in all efficacy analyses and 
across all subgroups. Rivaroxaban was well tolerated and the safety profile, including adverse 
events and observed laboratory abnormalities, was comparable to enoxaparin/VKA treatment.
As a consequence, the expectation is that the selected rivaroxaban age- and body-weight 
adjusted dose regimen in children will be safe and efficacious without the need for frequent 
blood sampling to monitor the anticoagulant activity.
To carefully allow for the evaluation of rivaroxaban in neonates and children younger than 
6 months with confirmed symptomatic or asymptomatic arterial or venous thrombosis, we 
elected to evaluate the selected rivaroxaban dose regimen first in children that have been 
treated with anticoagulant therapy for at least five days. If this study reveals that the selected 
rivaroxaban dose regimen results in a similar exposure as that observed with 20 mg 
rivaroxaban in adults, and safety and efficacy is confirmed, a subsequent study will evaluate 
the selected rivaroxaban dose regimen for the acute and continued treatment of VTE. 20
2.
Study objectives
The primary objective is:

to characterize the pharmacokinetic/pharmacodynamic profile of a 7-day treatment 
with oral rivaroxaban
The secondary objectives are:

to assess the incidence of major bleeding and clinically relevant non-major bleeding

to assess the incidence of symptomatic recurrent thromboembolism and 

to assess asymptomatic deterioration in the thrombotic burden on repeat imaging
3.
Study design - amended
This is a non-randomized, open label, multicenter study evaluating the safety, efficacy and 
PK/PD profile of a 7-day treatment with age- and body weight-adjusted oral rivaroxaban in 
neonates and infants younger than 6 months with symptomatic or asymptomatic arterial or 
venous thrombosis. 21
                                                
20 This section was modified via Amendment 4 (see Section 16.2.2.5)
21 This section was modified via Amendment 4 (see Section 16.2.2.6)


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3.1
Study description - amended
Neonates and infants aged less than 6 months who pass the screen of in- and exclusion 
criteria, who have been treated for at least five days with heparin and /or VKA for confirmed 
symptomatic or asymptomatic arterial or venous thrombosis are eligible for the study. Study 
treatment consists of a 7-day treatment with an age- and body weight-adjusted three times
daily oral rivaroxaban dosing to achieve a similar exposure as that observed in adults treated 
for venous thromboembolism (VTE) with 20 mg rivaroxaban once daily. Rivaroxaban will be 
provided as granules for preparation of an oral suspension (1 mg/mL after re-suspension) 
using a t.i.d. regimen with 8-hour intervals. 22
An ultrasound will be performed before starting rivaroxaban at treatment day 1 and after the 
end of rivaroxaban treatment at day 8. The last dose of rivaroxaban treatment will be followed 
by a 30-day post study treatment period, regardless of the duration of study drug 
administration. After cessation of rivaroxaban, it is at the investigator’s discretion to continue 
with anticoagulants. The principal safety outcome is the combination of major and clinically 
relevant non-major bleeding. The efficacy outcome is the composite of all symptomatic 
recurrent thromboembolism and asymptomatic deterioration in thrombotic burden on repeat 
imaging. All suspected recurrent thromboembolism, asymptomatic deterioration in thrombotic 
burden on repeat imaging, deaths, as well as all episodes of bleeding will be evaluated by a 
CIAC. Adjudication results will be the basis for the final analyses. 23
For all children, visits are scheduled at regular time points (see Table 1). Enrolled children 
who are not treated or those with premature discontinuation of rivaroxaban will at least be 
seen at the end of the study treatment period. During all contacts, the treatment and clinical 
course of the child will be evaluated. Children with suspected efficacy or safety outcomes will 
undergo confirmatory testing as per standard of care. Blood samples for PK/PD will be taken 
at defined time points (see Table 2).
An Independent Data Monitoring Committee (DMC) will monitor the children’s safety during 
the study and give recommendations to the steering committee.
                                                
22 The dosing was changed to t.i.d. via Amendment 5 (see Section 16.3.2.4)
23 This section was modified via Amendment 4 (see Section 16.2.2.7)


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4.
Study population
4.1
Planned number of children
At least eight children are planned to be enrolled in the study. 
4.2
Inclusion criteria - amended
1. Children from birth to less than 6 months with documented symptomatic or 
asymptomatic venous or arterial thrombosis who have been treated with anticoagulant 
therapy for at least 5 days. 24
2. Gestational age at birth of at least 37 weeks.
3. Hemoglobin, platelets, creatinine, ALT and total and direct bilirubin assessed within 
10 days prior to enrollment.
4. Oral feeding/nasogastric/gastric feeding for at least 10 days.
5. Informed consent provided.
6. Body weight >2600 g. 25
4.3
Exclusion criteria - amended
1. Active bleeding or high risk for bleeding contraindicating anticoagulant therapy, 
including history of intra-ventricular bleeding.
2. Symptomatic progression of thrombosis during preceding anticoagulant treatment.
3. Planned invasive procedures, including lumbar puncture and removal of non-
peripherally placed central lines during study treatment.
4. Hepatic disease which is associated with either: coagulopathy leading to a clinically 
relevant bleeding risk, or alanine aminotransferase (ALT) > 5x upper level of normal 
(ULN) or total bilirubin (TB) > 2x ULN with direct bilirubin > 20% of the total.
5. Creatinine >1.5 times of normal.
6. Uncontrolled hypertension defined as >95th percentile. 26
7. History of gastrointestinal disease or surgery associated with impaired absorption.
8. Platelet count <100 x 109/L.
9. Concomitant use of strong inhibitors of both cytochrome P450 isoenzyme 3A4
(CYP3A4) and P-glycoprotein (P-gp), e.g. all human immunodeficiency virus protease 
                                                
24 Inclusion criterion 1 was modified via Amendment 4 (see Section 16.2.2.8)
25 Inclusion criterion 6 was added via Amendment 1 (see Section 16.1.2.2)
26 Exclusion criterion 6 was modified via Amendment 4 (see Section 16.2.2.9)


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inhibitors and the following azole-antimycotics agents: ketoconazole, itraconazole, 
voriconazole, posaconazole, if used systemically (fluconazole is allowed). 27
10. Concomitant use of strong inducers of CYP3A4, e.g. rifampicin, rifabutin, 
phenobarbital, phenytoin and carbamazepine.28
11. Indication for anticoagulant therapy other than current thrombosis.
12. An indication for continued antiplatelet therapy or non-steroid anti-inflammatory 
drug (NSAID) therapy. Incidental use is allowed. 29
13. Hypersensitivity to rivaroxaban or its excipients.
14. Participation in a study with an investigational drug or medical device within 30 days 
prior to enrollment
4.4
Concomitant medication - amended
Concomitant medications include either continuation of a treatment started before study 
enrollment, or addition of a new treatment during the study. An indication for the continued
use of NSAIDs or antiplatelet agents is an exclusion criterion since they increase the risk for 
bleeding in patients treated with anticoagulants. However, incidental use is allowed. 30
Concomitant use of strong inhibitors of both CYP3A4 and P-gp is not allowed, as well as 
concomitant use of strong inducers of CYP3A4.
Any anticoagulant medication taken for the current thrombosis prior to study entry will be 
documented. Anticoagulant use after the study treatment period will also be documented.
5.
Treatment groups and regimens
5.1
Method of treatment allocation
5.1.1
Rivaroxaban regimen - amended
Age- and body weight-adjusted rivaroxaban will be administered three times daily 
approximately 8 hours apart as oral suspension. The oral suspension will be administered 
immediately before or (early) during feeding. 31
Originally, the study started with a b.i.d. regimen. Rivaroxaban was well tolerated in the 5 
children treated according to the b.i.d. regimen and there were no bleeding events. 
Furthermore, no symptomatic recurrent venous thromboembolic complications occurred. 
Repeat imaging of the thrombosis in two children with a persistent thrombosis at the start of 
                                                
27 Exclusion criterion 9 was modified via Amendment 1 (see Section 16.1.2.3)
28 Exclusion criterion 10 was modified via Amendment 1 (see Section 16.1.2.3)
29 Exclusion criterion 12 was modified via Amendment 4 (see Section 16.2.2.9)
30 This section was modified via Amendment 4 (see Section 16.2.2.10)
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rivaroxaban treatment showed normalization and substantial regression of the thrombosis, 
respectively, after the 7-day treatment with rivaroxaban. 
However, PK results of the first 5 children enrolled with the b.i.d. regiment indicate lower 
rivaroxaban exposure (AUCss,24h) and Ctrough concentrations than initially expected by the PK 
model. Based on these observations, the Data Monitoring Committee recommended to change 
the dosing regimen from a b.i.d. (approx. 12-hour intervals) to a t.i.d. (approx. 8-hour 
intervals) schedule applying the same individual doses previously administered twice daily. 
This recommendation was endorsed by the steering committee. 
Following implementation of Amendment 5, children will be dosed according to the t.i.d. 
schedule (according to Table 3). The 50% increase of the total daily dose will increase the 
exposure, and the shortening of the dosing interval from 12 to 8 hours (t.i.d. schedule) aims to 
increase the Ctrough concentrations. 
If a rivaroxaban individual dose was missed, the t.i.d. administration schedule with approx. 8-
hour intervals should be resumed without compensating for the missed dose.
Instructions on how to handle rivaroxaban oral suspension are provided in the oral suspension 
handling guidelines, which will be issued separately from the protocol. Parents will be 
instructed and trained to prepare the suspension according to the guidelines, if applicable. The 
training will be documented.
The body weight-adjusted rivaroxaban dosing schedule is provided in Table 3. 32
Table 3: Rivaroxaban dosing schedule 
Body weight [kg]
Oral suspension dose (t.i.d.)*
Total daily dose
Min
Max
[mg]
[mg]
2.6
<3
0.5
1.5
3
<4
0.6
1.8
4
<5
0.9
2.7
5
<6
1.2
3.6
6
<7
1.6
4.8
7
<8
1.9
5.7
8
<9
2.5
7.5
9
<10
2.7
8.1
10
<12
2.9
8.7
* to be administered every 8 hours
Switching from heparin to rivaroxaban
5.1.1.1
If the child received heparin treatment before enrollment, enrollment should be planned 4 
hours after stopping the infusion of UFH, 6 - 12 hours after the last injection of LMWH with 
a twice-daily regimen, 12 - 24 hours after the last injection of LMWH with a once-daily 
                                                
32 The dosing table was added via Amendment 1 (see Section 16.1.2.4)


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regimen. Heparin treatment cannot be continued after the start of rivaroxaban treatment in 
these children.
Switching from rivaroxaban to heparin
5.1.1.2
Children who switch from rivaroxaban to heparin can switch at the time the next rivaroxaban 
dose would have been scheduled.
Switching from VKA to rivaroxaban - amended
5.1.1.3
If a child is on VKA therapy and has a supra-therapeutic INR (> 3.0), enrollment into the 
study should be delayed. In case of an INR between 2.5 to 3.0, enrollment can be done and 
the first rivaroxaban dose should be delayed to the next day. If the INR is below 2.5, 
enrollment can be done and the first rivaroxaban dose can be taken on the day of enrollment. 
VKA therapy cannot be continued after enrollment.
Children who switch from VKA to rivaroxaban should avoid using both drugs at therapeutic 
doses simultaneously. Rivaroxaban can be started only if the INR is < 2.5. 33
Switching from rivaroxaban to VKA
5.1.1.4
Children who switch from rivaroxaban to VKA need to switch to heparin and VKA at the 
time the next rivaroxaban dose would have been scheduled. Thereafter, heparin needs to be 
co-administered with VKA until the INR is ≥ 2.0. 
5.2
Subject identification
After the parents/ legal representative sign the informed consent form, each child will be 
assigned by the site staff a unique 9-digit subject identification (SID) number for 
unambiguous identification. The first 2 digits represent the country number, the next 3 digits 
represent the center number, and the last 4 digits represent a sequential number assigned to 
each child. SID numbers will have to be used in sequence and no number should be skipped 
or substituted. All enrolled subjects must be listed on the site enrollment log.
5.3
Duration of study treatment
Children will receive study treatment for a period of 7 days.
5.4
Formulation and dose
5.4.1
Rivaroxaban - amended
Rivaroxaban will be provided as granules for preparation of a 0.1% oral suspension 
(1 mg/mL). Rivaroxaban will be dosed according to body weight. Since children with renal 
impairment will be excluded from the study, a dose adaptation is not indicated. 34
                                                
33 Text was modified via Amendment 1 (see Section 16.1.2.5)
34 This section was modified via Amendment 4 (see Section 16.2.2.12)


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5.5
Packaging, labeling, and storage - amended
Rivaroxaban will be provided by Bayer and labeled according to local law and regulations.
A system of numbering in accordance with Good Manufacturing Practice (GMP) will be used, 
ensuring that each dose of study medication can be traced back to the respective bulk ware of 
the ingredients. A complete record of batch numbers and expiry dates of all study medication
provided by Bayer, as well as the labels, will be maintained in the study file. Rivaroxaban
granules for oral suspension need to be stored at the investigational site according to the 
labeled storage advice and in accordance with Good Clinical Practice (GCP) and GMP
requirements. Rivaroxaban granules for oral suspension should not be frozen and should be 
stored at a temperature not exceeding 25°C and kept in a secure area (e.g. locked cabinet). 
Complete records of batch numbers and expiry dates can be found in the Bayer study file. The 
responsible site personnel will confirm receipt of rivaroxaban as described in the study drug 
guidance document and will use rivaroxaban only for this study and in accordance with this 
protocol. Receipt, distribution, return and destruction (if any) of rivaroxaban must be properly 
documented according to specified procedures. 35
5.6
Treatment assignment
All subjects will receive an age- and body weight-adjusted rivaroxaban dosing.
5.7
Dose and administration
Rivaroxaban will be dosed according to body weight as oral 0.1% suspension (1 mg/mL).
Instruction will be given to return all unused study drug including packaging, if applicable, at 
visit 3, visit 4, and, if applicable, at the premature discontinuation visit. Compliance will be 
evaluated by measuring remaining suspension. All non-used rivaroxaban should be kept 
securely in the original containers in a designated locked storage area until retrieved or 
dispensed.
6.
Study procedures
6.1
Study visits - amended
The study has 5 planned visits (see Table 1).
Visit 1 is a screening visit and will be a hospital visit. This visit is to identify potential 
eligibility of children who are treated with anticoagulants for confirmed symptomatic or 
asymptomatic arterial or venous thrombosis. This visit will take place 1 to 10 days before 
inclusion into the study. Visit 2 is the first treatment visit and will be a hospital visit. Eligible 
children will start 7 days of anticoagulation with rivaroxaban (day 1). 36
                                                
35 This section was modified via Amendment 4 (see Section 16.2.2.13)
36 This section was modified via Amendment 4 (see Section 16.2.2.14)


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Visit 3 and visit 4 are treatment and end of treatment visits, respectively. These visits will be 
hospital visits which will take place at day 3 and day 8, respectively. 
PK/PD blood sampling will be done at visit 2, 3 and 4. ALT, total and direct bilirubin will be 
measured at visit 4.
Rivaroxaban will be stopped at day 7. After cessation of study treatment with rivaroxaban, it 
is at the investigator’s discretion to continue with anticoagulation, as needed. Repeat imaging 
will be obtained, if applicable.
Visit 5 is the 30-day post treatment contact visit and will be a hospital visit or a telephone 
contact. It will take place at day 37 + 7 days. This visit will be the last study visit.
6.2
Visit 1 – Screening visit at 1 to 10 days before Visit 2 - amended
The parents/legal representative will be given explanation about the study and will be given 
sufficient time to consider participation of their child in the study. Parents/legal representative
who are willing to have their child participate in the study will be asked to sign an informed 
consent form.
Screening will only be performed after having received informed consent. Children who pass 
the screen of inclusion and exclusion criteria can be enrolled into the study.
Then demographic data, medical history, weight, blood pressure and anticoagulant medication 
will be collected. 37
Children are not eligible for enrollment into the study, if the mother is treated with strong 
inhibitors of both cytochrome P450 isoenzyme 3A4 (CYP3A4) and P-glycoprotein (P-gp), or 
with strong inducers of CYP3A4, and is breastfeeding the child.
The images of the index thrombotic event need to be collected and the adjudication package 
needs to be completed and sent to the central adjudication office for their assessment. 38
Adverse events will not be collected between visit 1 and visit 2. Since hemoglobin, platelet 
count, creatinine, ALT, total and direct bilirubin tests are performed as part of routine clinical 
practice in children treated with anticoagulants, recent results will be available and, therefore, 
a blood sample is not required as part of the study screening assessments. Availability of 
results for hemoglobin, platelets, creatinine, ALT, total and direct bilirubin within 10 days 
prior to enrollment is an inclusion criterion for this study.
6.3
Visit 2 – Treatment visit at Day 1 - amended
If the child still meets the inclusion criteria and does not meet any of the exclusion criteria, 
the child can be enrolled. If results for hemoglobin, platelets, creatinine, ALT and total and 
direct bilirubin were not available within 10 days prior to enrollment, obtain a blood sample.
                                                
37 The blood pressure measurement was added via Amendment 1 (see Section 16.1.2.6)
38 This section was modified via Amendment 4 (see Section 16.2.2.15)


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For children receiving VKA, the INR should be obtained. INR should be below 2.5 before 
starting rivaroxaban. 39
The following assessments and procedures have to be performed on visit 2:

Collect body weight.

Provide instructions on how to administer the study drug and give the study booklet 
and the rivaroxaban oral suspension handling guidelines to parents, if applicable.

Administer the first rivaroxaban dose according to the oral suspension handling 
guidelines. 40

Document the exact time of rivaroxaban intake and the type (e.g., breast milk, formula, 
porridge, or pureed food) and estimated volume of fluid (e.g. breast milk and formula) 
or food (e.g. porridge or pureed food) rivaroxaban was administered with. 41

In case rivaroxaban is administered together with porridge or pureed food, encourage 
the child to drink a typical serving of liquid thereafter (e.g., breast milk, formula, water, 
juice) and document the type of liquid and the estimated volume.

At 0.5-3 hr after rivaroxaban, collect only a PK blood sample.

At 7-8 hr after rivaroxaban intake, collect a PK blood sample followed by the PD 
sample.

Document the exact time of each blood sampling for PK/PD.

Obtain ultrasound and prepare an adjudication package to be sent to the adjudication 
office. In case other diagnostic tests were performed to visualize the clot, these should 
be sent as well.

Check for adverse events.

Record all concomitant medication including anticoagulant medication for the current 
thrombosis.

Update eCRF.
6.4
Visit 3 – Treatment visit at Day 3 - amended
The following assessments and procedures have to be performed on visit 3:42

Check for potential study outcomes. If a suspected study outcome occurred, an 
adjudication package needs to be compiled and sent to the adjudication office.

Check for adverse events.
                                                
39 This section was modified via Amendment 1 and 5 (see Section 16.1.2.7 and 16.3.2.6)
40 Bullet was modified via Amendment 4 (see Section 16.2.2.16)
41 Bullet was modified via Amendment 1 (see Section 16.1.2.7)
42 This section was modified via Amendment 4 (see Section 16.2.2.17)


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
Collect body weight and if needed adjust the dosage of rivaroxaban.

Administer the next dose of rivaroxaban according to the oral suspension handling 
guidelines. 43

Document the exact time of rivaroxaban intake and the type (e.g. breast milk, formula, 
porridge, or pureed food) and estimated volume of food rivaroxaban was administered 
with.

In case rivaroxaban is administered together with porridge or pureed food, encourage 
the child to drink a typical serving of liquid thereafter (e.g., breast milk, formula, water, 
juice) and document the type of liquid and the estimated volume.

At 0.5-3 hr after rivaroxaban, collect a PK blood sample followed by the PD blood
sample.

At 7-8 hr after rivaroxaban intake, collect only a PK blood sample.

Document the exact time of blood sampling for PK/PD.

Check changes in concomitant medications.

Instruct to document in the study booklet
o the exact time of the last dose of rivaroxaban on the day prior to visit 4,
o the type (e.g. breast milk, formula, porridge, or pureed food) and estimated 
volume of fluid (e.g. breast milk and formula) or food (e.g. porridge or pureed 
food) rivaroxaban was administered with, 44
o In case rivaroxaban is administered together with porridge or pureed food, 
parents should document the type and estimated volume of liquid (e.g., breast 
milk, formula, water, juice) that the child took thereafter.

Update eCRF.
                                                
43 Bullet was modified via Amendment 4 (see Section 16.2.2.17)
44 Bullet was modified via Amendment 1 (see Section 16.1.2.8)


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If a child discontinues rivaroxaban permanently before visit 3, visit 3 will still need to take 
place:

Check for potential study outcomes. If a suspected study outcome occurred, an 
adjudication package needs to be compiled and sent to the adjudication office.

Check for adverse events. If an adverse event occurred, update the eCRF.

Perform drug accountability and assess compliance.

Check changes in (concomitant) medications.

No blood sampling for PK/PD is required.
6.5
Visit 4 – Day 8 - amended
The following assessments and procedures have to be performed on visit 4: 45

Rivaroxaban should not be taken anymore.

Check for potential study outcomes. If a suspected study outcome occurred, an 
adjudication package needs to be compiled and sent to the adjudication office.

Check for adverse events.

Document 
o the exact time of the last dose of rivaroxaban on the day prior to visit 4,
o the type (e.g. breast milk, formula, porridge, or pureed food) and estimated 
volume of fluid (e.g. breast milk and formula) or food (e.g. porridge or pureed 
food) rivaroxaban was administered with. 46
o In case rivaroxaban was administered together with porridge or pureed food, 
parents should document the type and estimated volume of liquid (e.g., breast 
milk, formula, water, juice) that the child took thereafter.

At 10-16 hr after last rivaroxaban intake, collect ALT, total and direct bilirubin sample, 
followed by the PD blood sample. If continued treatment with anticoagulants is 
necessary, administer the anticoagulant after this sample is taken.

Document the exact time of blood sampling for PD.

Repeat ultrasound and prepare an adjudication package to be sent to the adjudication 
office. The repeat ultrasound can be performed on day 8 ± 1. In case other diagnostic 
tests were performed to visualize the clot, these should be sent as well.

Perform drug accountability and assess compliance.

Check changes in concomitant medications.
                                                
45 This section was modified via Amendment 4 and 5 (see Section 16.2.2.18 and 16.3.2.8)
46 Bullet was modified via Amendment 1 (see Section 16.1.2.9)


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
Update eCRF
If a child discontinues study treatment permanently before visit 4, visit 4 will still need to 
take place:

Check for potential study outcomes. If a suspected study outcome occurred, an 
adjudication package needs to be compiled and sent to the adjudication office.

Check for adverse events. If an adverse event occurred, update the eCRF.

Perform drug accountability and assess compliance.

Check changes in (concomitant) medications.

No blood sampling for PK/PD is required.
6.6
Visit 5 – 30 day post treatment contact at Day 37 (+ 7 days)
This visit or telephone contact is to document what happens to children during the 30-day
post study treatment period. Therefore, this visit or telephone contact will take place at day 37 
+ 7 days in children who completed the study treatment. 
The following assessments and procedures have to be performed on visit 5:

Check for potential study outcomes. If a suspected study outcome occurred, an 
adjudication package needs to be compiled and sent to the adjudication office.

Check for adverse events. If an adverse event occurred, update the eCRF.

Check for changes in (concomitant) medications.

Document if anticoagulant treatment was continued or stopped after visit 4.

Update eCRF.
6.7
Unscheduled visits
If deemed necessary, it is at the investigator’s discretion to arrange additional visits.
6.8
Safety outcomes
The principal safety outcome is the composite of major bleeding and clinically relevant non-
major bleeding. Other safety outcomes include all deaths and other vascular events 
(myocardial infarction, cerebrovascular accident, non-CNS systemic embolism).
The CIAC will classify bleeding as:
Major bleeding which 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


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
occurring in a critical site, e.g. 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 child such as pain 
All other overt bleeding episodes not meeting the criteria for clinically relevant bleeding will 
be classified as trivial bleed.
6.9
Recommendations before and after invasive procedures and surgical 
intervention
If an invasive procedure or surgical intervention is required, rivaroxaban should be stopped at 
least 24 hours before the intervention, if possible and based on the clinical judgment of the 
physician. If the procedure cannot be delayed, the increased risk of bleeding should be 
assessed against the urgency of the intervention. Rivaroxaban should be restarted after the 
invasive procedure or surgical intervention within 24 hours, provided the clinical situation 
allows and adequate hemostasis has been established. 
6.10
Management of bleeding in children
If a child has a serious bleed during study treatment, the following routine measures could be 
considered:

Consider usual treatment for bleeding, including blood transfusion, and/or fresh frozen 
plasma.

Obtain PK/PD blood sample.

If bleeding cannot be controlled, consider administration of one of the following 
procoagulants:
- 4-factor prothrombin complex concentrate
- recombinant factor VIIa (NovoSeven®)

Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of 
rivaroxaban.
6.11
Efficacy outcome
The efficacy outcome will be the composite of all symptomatic recurrent thromboembolism 
and asymptomatic deterioration in thrombotic burden on repeat imaging.


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6.12
PK/PD assessment - amended
Blood samples will be taken for PK/PD measurements. The number and volume of PK/PD 
blood samples represents the minimum amount of blood needed for adequate analysis (sparse 
sampling approach). The following blood samples will be taken: 47

two post-dose PK samples at visit 2 

one post-dose PD sample at visit 2

two post-dose PK sample at visit 3

one post-dose PD sample at visit 3

one post-dose PD sample at visit 4
The exact time of rivaroxaban dosing and PK/PD blood sampling will be documented in the 
eCRF. If, for any reason, PK/PD samples are taken outside of the pre-specified time window, 
the exact time that the sample was taken should be recorded and not the time of the time 
window.
The use of low dose heparin and tissue plasminogen activator to maintain catheter patency is 
acceptable. However before collecting PK/PD samples, the catheters need to be flushed with 
saline. In addition, if PK/PD samples are drawn through a central line, a small amount of 
blood needs to be drawn and discarded, before collecting the PK/PD sample in order to avoid 
dilution of the PK/PD sample with saline that remains in the central line. 
The prothrombin time, activated partial thromboplastin time and anti-factor Xa activity 
(anti Xa) will be used to assess the pharmacodynamic effects after administration of the study 
drug.
Detailed information about the handling and labeling of the samples will be provided in the 
laboratory manual.
The data obtained from the blood samples taken will be analyzed.
6.13
Study booklet
Parents will receive a booklet with the following information:

The local medical contact person and emergency telephone number

The visit schedule, including dates of telephone and/or hospital visits

Instructions to keep empty, partially used, and unused bottles of study medication

Instructions on signs and symptoms of bleeding

How to take rivaroxaban
                                                
47 This section was modified via Amendment  5 (see Section 16.3.2.9)


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6.14
Study committees
6.14.1
Steering committee
The steering committee has the overall scientific responsibility of the study. Its tasks and 
responsibilities are:

To facilitate and approve the final protocol

To help select the investigators network

To support and organize the national logistics in the initiation and conduct of the study

To ensure a scientifically sound and safe conduct of the study

To decide on the DMC recommendations

To guarantee the integrity of data collection and analyses

To monitor progress of study enrollment

To assist in the analysis and presentation of the results

To decide on the publication and presentation policy of final results
6.14.2
Central independent adjudication committee (CIAC)
All index venous or arterial thrombotic events, and all suspected recurrent thromboembolic 
events, asymptomatic deterioration in the thrombotic burden on repeat imaging, bleeding, 
other vascular events and deaths that occur after visit 2 including the 30-day post treatment 
period will be evaluated by a CIAC, which will be provided with all relevant documentation 
related to the events. The procedures followed by the CIAC will be described in an 
adjudication manual. Adjudication results will be the basis for the final analyses.
6.14.3
Data monitoring committee (DMC)
This committee has the responsibility to provide the steering committee with 
recommendations related to the protection of the children’s safety, including stopping 
recruitment and study treatment. For that purpose, the DMC will regularly review all 
incidences of serious adverse events, recurrent venous or arterial thromboembolic events and 
bleeding. Organizational aspects, responsibilities, and processes will be described in the DMC 
charter.
7.
Statistical and analytical methods
7.1
General considerations
The plan described in the following sections will be detailed in a statistical analysis plan 
(SAP). The SAP will accommodate protocol amendments or unexpected issues in study 
execution or data that affect planned analyses. Any revision will be clearly identified in the 
final SAP, issued prior to data base lock. If not stated otherwise, the following statistical 
specifications will apply.


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7.2
Analysis sets
Full analysis set: 
This analysis set will include all children from whom 
informed consent was obtained.
Safety analysis set:
This analysis set will include all children who received at 
least one dose of rivaroxaban.
Per protocol analysis set:
This population includes all children who completed the 
7-day treatment period or had an efficacy or bleeding 
outcome before. This analysis set may exclude major 
protocol deviations.
Listing only set: 
This population includes all screening failures.
7.3
Demographic and other baseline characteristics
Summary statistics (arithmetic mean, standard deviation, median, minimum and maximum for 
quantitative variables) will be presented. Frequency tables for qualitative data will be 
provided. Medical history findings will be summarized using Medical Dictionary for 
Regulatory Activities (MedDRA) terms.
7.4
Safety analysis
All safety analyses will be performed on the safety population. The analysis will primarily 
focus on bleeding that occurred during or within 2 days after stop of rivaroxaban. Bleeding 
events observed later will be described separately. Individual listings of major and clinically 
relevant non-major bleeding will be provided. The incidence of bleeding will be summarized. 
If a sufficient number of bleeding events is observed, factors which potentially influence the 
occurrence of bleeding will be assessed by appropriate statistical procedures. Quantitative
data will be described by the summary statistics and will be presented for the original data as 
well as for the difference to baseline. Frequency tables will be provided for qualitative data.
7.5
Efficacy analysis
All efficacy analyses will be performed on the full analysis set population. The incidence of 
symptomatic recurrent venous thromboembolism and asymptomatic deterioration in 
thrombotic burden on repeat imaging will be summarized.
7.6
PK/PD analysis
PK/PD modeling, using population approaches will be used to describe the pharmacokinetics 
of rivaroxaban, and to relate anticoagulant parameters of rivaroxaban with plasma 
concentrations.
7.7
Interim analyses
No interim analysis will be performed.


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7.8
Determination of sample size
At least 8 children are planned to be enrolled in the study. For the area under the curve 
(AUC), a geometric coefficient of variation (geom. CV) of about 40% was observed in adults, 
and was also observed in study 12892 in the age group 12 to 18 years (n=9). In the age cohort 
6 to <12 years, an even smaller geometric coefficient of variation was observed. Although it 
is expected from the model that the variability will be higher in neonates and infants, the exact 
numbers remain unclear. The sample size of 8 subjects will yield an exploratory 90% 
confidence interval for the geometric mean AUC-estimate between 50% and 200% of the 
estimate, provided the geometric coefficient of variation does not exceed 138%, which would 
be more than a tripling of the variability observed in adolescents. If the geometric coefficient 
of variation will be 80%, the exploratory 90% confidence interval for the geometric mean 
AUC-estimate would be located between 62% and 161% of the estimate.
7.9
Adverse events
Individual listings of adverse events (including age, gender, adverse event as reported, time to 
adverse event after study drug intake, duration, intensity, relation to study drug, action taken
and outcome) will be provided.
7.9.1
Definitions
Adverse event (AE)
7.9.1.1
An AE is any untoward medical occurrence in a subject administered with a pharmaceutical 
product and does not necessarily have to have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, whether or not 
considered related to the drug. AE associated with the use of a drug, whether or not 
considered drug related, includes AE occurring in the course of the use of a drug, from an
overdose whether accidental or intentional, from drug abuse, from drug withdrawal, or if there 
is a reasonable possibility that the event occurred purely as a result of participation in the 
study, even if it is not related to the drug.
The clinical manifestation of any failure of expected pharmacological action is not recorded 
as an AE, if it is already reflected as an outcome captured in the eCRF, except if the event 
fulfills the criteria for a “serious” AE.
A surgical procedure or intervention that was planned prior to visit 2 should not be recorded 
as an AE. Conditions, including abnormal physical examination findings, symptoms, and 
diseases will be recorded as medical history if they started before visit 2 and no symptoms or 
treatment are present until visit 2, or symptoms or treatment are present after visit 2 at 
unchanged intensity.
If the condition started or deteriorated after administration of study drug at visit 2, it will be 
documented as adverse event.


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Serious adverse event (SAE)
7.9.1.2
An SAE is any untoward medical occurrence that at any dose is resulting in death, is life-
threatening (i.e. the patient was at risk of death at the time of the event), requires 
hospitalization or prolongation of existing hospitalization unless the admission results in a 
hospital stay of less than 12 hours, is pre-planned, or is not associated with an AE (i.e. social 
hospitalization for purposes of respite care), results in persistent or significant 
disability/incapacity. In addition, SAE is a congenital anomaly or a birth defect or an 
important medical event, including associated invasive treatment, as judged by the 
investigator. For reporting of a SAE, local regulations take precedence if more stringent 
definitions are applicable.
Unexpected AEs
7.9.1.3
An unexpected AE is any adverse drug event whose specificity or severity is not consistent 
with the investigator brochure (or package inserts for marketed products). Also, reports which 
add significant information on specificity or severity of an already documented AE constitute 
unexpected AEs. For example, an event more specific or more severe than described in the 
investigator brochure would be considered “unexpected”. 
Specific examples: 1) acute renal failure as a labeled adverse event with a subsequent new 
report of interstitial nephritis and 2) hepatitis with a first report of fulminant hepatitis.
7.9.2
Relationship of AE to the study drug
The assessment of the causal relationship between an AE and the use of medication is a 
clinical decision based on all available information at the time of the completion of the eCRF 
and is based on whether there was a "reasonable causal relationship" to the medication.
An assessment of "no" would include the existence of a clear alternative explanation, e.g. 
mechanical bleeding at surgical site, or non-plausibility. An assessment of "yes" indicates that 
there is a reasonable suspicion that the AE is associated with the use of the drug. Factors in 
assessing the relationship of the AE to study treatment include the temporal sequence from 
drug administration (the event should occur after the drug is given) and the length of time 
from drug exposure, recovery on drug discontinuation (de-challenge), and recurrence on drug 
re-introduction (re-challenge), underlying, concomitant, or intercurrent diseases should be 
evaluated in the context of the natural history and course of any disease the child may have, 
concomitant medication or treatment and, finally, the pharmacology and pharmacokinetics of 
study treatment.
7.9.3
Causal relationship to protocol-required procedures
The assessment of a possible causal relationship between the AE and protocol-required 
procedures is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s). Possible answers are “yes” or “no”.
7.9.4
Intensity of an AE, action taken and outcome
The intensity of an AE is assessed as mild (usually transient in nature and generally not 
interfering with normal activities), moderate (sufficiently discomforting to interfere with 
normal activities), or severe (prevents normal activities).


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Any action on study treatment to resolve the AE is to be documented as either: study drug 
withdrawn, interrupted, dose not changed, not applicable or unknown. Other specific 
treatment(s) of AEs will be documented as: none, remedial drug therapy or other. The 
outcome of the AE is to be documented as: recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, not recovered/not resolved, fatal or unknown.
7.9.5
Assessments and documentation of adverse events
Complications that occur during the screening period between visit 1 and visit 2 will not be 
reported as AEs, because no study medication or study related procedures are required during 
this period, but may be documented in the medical history, if applicable.
After study drug intake at visit 2, documentation of AEs must be supported by an entry in the 
subject’s file. A laboratory test abnormality considered clinically relevant, e.g. causing the 
subject to withdraw from the study, requiring treatment or causing apparent clinical 
manifestations, or judged relevant by the investigator, should be reported as an AE. Each 
event should be described in detail along with start and stop dates, severity, relationship to 
study drug, action taken and outcome.
When assigning the cause of death, "death" should not be recorded as an AE on the AE page. 
Instead, "death" is the outcome of underlying AE(s).
7.9.6
Reporting of serious adverse events
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
reporting obligations for SAEs. This information, including all relevant contact details, is 
summarized in the investigator site file and will be updated as needed.
SAEs occurring after study drug intake at visit 2 until 1 month after the last dose must be 
reported within 24 hours of the investigator’s awareness. Reports should be as complete as 
possible, and must be followed up until resolution or stabilization. When required, and 
according to local law and regulations, SAEs must be reported to the ethics committee and 
regulatory authorities.
If reported, SAEs occurring after the protocol-defined observation period will be processed by
Bayer according to all applicable regulations.
Bayer will inform all investigational sites about the occurrence of suspected unexpected 
serious adverse reactions (SUSARs) according to all applicable regulations.
7.9.7
Study specific exceptions to the (S)AE reporting
AEs between visit 1 and visit 2 will not need to be reported. The efficacy outcomes 
(symptomatic recurrent thromboembolism and asymptomatic deterioration in thrombotic 
burden on repeat imaging) will not be reported as (S)AE. Transfer of children to a 
rehabilitation unit as a standard practice will not be considered as a prolonged hospitalization 
and should not be reported as a SAE. However, if this transfer is part of treatment of a 
medical complication, it should be considered as prolonged hospitalization and the event 
should be reported as a SAE. To collect additional information about clinically important 
laboratory abnormalities, any laboratory abnormality that required cessation of the study drug 
will be captured as a SAE.


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7.9.8
Expected AEs
The applicable reference document is the most current version of the investigator’s brochure 
(IB) / Company Core Data Sheet (CCDS). Overview listings of frequent events that have 
occurred so far in the clinical development are shown in the current IB. If relevant new safety 
information is identified, it will be integrated into an update of the IB and distributed. The 
expectedness of AEs will be determined by Bayer according to the applicable reference 
document and according to all local regulations.
7.9.9
Adverse events of special safety interest
The following AEs are considered as AEs of special safety interest:

Concurrent elevations of alanine aminotransferase (ALT) > 5x ULN and total bilirubin 
> 2x ULN with direct bilirubin > 20% of the total.

A platelet count below 100 x 109/L.

Allergic skin reactions, allergic systemic reactions
7.10
Premature discontinuation of study medication
Children prematurely discontinue study medication

at the request of parents/legal representative without the need to provide a reason.

if, in the investigator's opinion, study medication should be stopped for any reason.

In case of symptomatic efficacy outcome for which anticoagulant or fibrinolytic 
therapy is indicated.

at the (exceptional) request of Bayer.
If study medication is temporarily discontinued, it can be restarted as long as the total 
treatment duration does not exceed the intended 7-day treatment period. If study medication is 
permanently discontinued, further treatment is at the investigator’s discretion.
If parents/legal representative indicate to stop study medication, the investigator will ask to 
continue with study visits as planned, only with the aim to collect potential study outcomes 
and AEs. If parents/legal representative indicate that they no longer authorize the investigator 
to continue to obtain outcome data, this will be respected and documented in the source 
records.
In all children who prematurely discontinue study treatment for other reasons than withdrawal 
of the informed consent, study visits will take place as planned only with the reason to collect 
potential study outcomes and AEs. A special effort will be made to collect data from children 
who did not complete all study visits. 
7.11
Appropriateness of procedures / measurements
The diagnostic methods to document safety and efficacy outcomes are standard methods in 
clinical practice and are used and generally recognized as reliable, accurate and relevant.


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8.
Data handling and quality assurance
For all data entered into the eCRF, source documentation should be available at the site. A 
source document checklist will be used to identify the source data for all data points collected.
In accordance with GCP and Bayer’s procedures, monitors will review the protocol, study 
requirements, and responsibilities with the site staff, including identification and 
documentation of source data items. Bayer personnel will monitor the site to verify that data 
are authentic, accurate, complete and that the safety and rights of participating children are 
being protected. In addition, they will assess if the study is conducted in accordance with the 
latest version of the protocol and study agreements. The investigator and the head of the 
medical institution (where applicable) agrees to allow the monitor direct access to all relevant 
documents.
8.1
Data processing
The data collection tool for this study will be a validated electronic system called RAVE and 
data will be entered into a validated database or data system (Tools for Syntactic Corpus 
Analysis [TOSCA]). Study data management will be performed in accordance with applicable 
Bayer’s standards. This is applicable for data recorded on eCRF as well as for data from other 
study sources. Internationally recognized and accepted dictionaries will be used for data 
coding.
8.2
Audit and inspection
Bayer’s (or a designated contract research organization’s [CRO's]) quality assurance unit may 
conduct an audit to ensure compliance with GCP and regulatory requirements. The 
investigator/institution will be informed verbally at the closing meeting of the audit outcome. 
In addition, inspections by regulatory health authority representatives, ethic committees, 
and/or institutional review boards might occur and the site will notify Bayer immediately.
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate time to the auditor/inspector to discuss any findings. Audits and 
inspections may occur at any time during or after completion of the study.
8.3
Archiving
Study documents will be archived safely and securely in such a way that they are readily 
available upon authorities' request. Patient and related hospital files will be archived 
according to local regulations and in accordance with the maximum period of time permitted 
by the hospital, institution or private practice. If the archiving procedures do not meet the 
minimum timelines required by Bayer, alternative arrangements will be made to ensure the 
availability of the source documents for the required period. The investigator/institution will 
notify Bayer if a change in archival arrangements occurs. The investigator site file will not be 
destroyed without Bayer’s approval. The investigator's contract will contain all regulations 
relevant for the study center.


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8.4
Missing data
Counts and proportion of missing data of baseline and post-baseline measurements will be 
displayed.
9.
Premature termination of the study
The investigator has the right to stop participating in the study at any time.
Bayer has the right to close this study or study sites at any time, which may be due but not 
limited to the following reasons: 1) The risk-benefit ratio becomes unacceptable due to, for 
example, safety or efficacy findings from this study or results of parallel clinical studies. 2) 
Study conduct (e.g. recruitment rate; dropout rate; data quality; protocol compliance) does not 
suggest a proper completion of the trial within a reasonable time frame. For any of the above 
closures, the following applies: 1) closures should occur only after consultation between 
involved parties, 2) all affected institutions must be informed, as applicable, according to 
local law.
All study materials will be returned to Bayer, except documentation that has to remain stored 
at the site. This documentation can only be destroyed with approval from Bayer.
10.
Ethical and legal aspects
10.1
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that Bayer and the investigator abide by
GCP guidelines and under the guiding principles detailed in the Declaration of Helsinki. The 
study will also be carried out in keeping with applicable local law(s) and regulation(s).
Documented approval from appropriate Independent Ethics Committees (IECs)/Institutional 
Review Boards (IRBs) will be obtained for all participating centers/countries before start of 
the study, according to GCP, local laws, regulations and organizations. When necessary, an 
extension, amendment or renewal of the IEC/IRB approval must be obtained and also 
forwarded to Bayer. The responsible unit (e.g. IEC/IRB, head of the study center/medical 
institution) must supply Bayer, upon request, a list of the IEC/IRB members involved in the 
vote and a statement to confirm that the IEC/IRB is organized and operates according to GCP 
and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.
Modifications to the study protocol will not be implemented by either Bayer or the 
investigator without agreement by both parties. However, the investigator or Bayer may 
implement a deviation from, or a change of the protocol to eliminate an immediate hazard to 
the trial children without prior IEC/IRB/Bayer approval/favorable opinion. As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 


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institution/Bayer. Any deviations from the protocol must be explained and documented by the 
investigator.
For each participating EU country, the end of the study according to the EU Clinical Trial 
Directive will be reached when the last visit of the last subject for all centers in the respective 
country has occurred.
The end of the study as a whole will be reached as soon as the end of the study according to 
the above definition has been reached in all participating countries (EU and non-EU).
10.2
Consent
All relevant study information will be summarized in an integrated informed consent form 
provided by Bayer or the study center. A sample informed consent form is provided as a 
document separate to this protocol. Consent will be asked from the parents or legal 
representative.
The investigator or designee will explain all relevant aspects of the study to the parents/legal 
representative prior to entry into the study (i.e. before any examinations and procedures 
associated with the selection for the study are performed or any study-specific data is 
recorded on study-specific forms).
The parents/legal representative will have ample time and opportunity to ask questions and 
will be informed about the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for their decision.
The child can only enter the study if the parents/legal representative agree to sign and date the 
informed consent and have done so. Then the investigator or designee will sign and date the 
form. The parents/legal representative will receive a copy of the signed and dated form(s).
The signed informed consent will remain in the investigator site file or, if locally required, in 
the patient's note/file of the medical institution. If informed consent is obtained on the date 
that study specific procedures are performed, the study record or child's clinical record must 
clearly show that informed consent was obtained prior to these procedures.
The informed consent form and any other written information provided to the parents/legal 
representative will be revised whenever important new information becomes available that 
may be relevant to the consent, or if there is an amendment to the protocol that necessitates a 
change to the written informed consent form. The investigator will inform the parents/legal 
representative of changes in a timely manner and will ask the parents/legal representative to 
confirm participation in the study by signing the revised informed consent form. Revised 
informed consent must receive the IEC's/IRB's approval before implementation.
11.
Investigators and other study personnel
The principal investigator of each site must sign the protocol signature sheet before 
recruitment may start at the respective center. Likewise, all protocol amendments/integrated 
protocols must be signed and dated by the principal investigator before coming into effect at 
the respective center. A complete list of all participating centers and their investigators, as 
well as all required signature documents, will be maintained in the Bayer study file.


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If required by local law, local co-sponsors will be nominated; they will be identified on the 
respective country-specific signature pages.
12.
Publication policy and use of data
Bayer is committed to publication of the results of every study it performs. The steering 
committee will be responsible for the publication and presentation strategy. All publications 
will be based on data released or agreed by Bayer, verified by the steering committee. The 
study protocol has been made publicly available on the internet at www.clinicaltrials.gov.
13.
Insurance for children
Bayer maintains clinical trial insurance coverage for this study in accordance with the laws 
and regulations of the countries in which the study is performed.
14.
Confidentiality
All records identifying the child will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Children’s names will not be supplied to Bayer. Only the child’s subject identification (SID)
number will be recorded in the eCRF. If the child’s name appears on any other document, it 
will be anonymized. Study data stored in a computer will be handled in accordance with local 
data protection laws. As part of the informed consent process, parents/legal representative will 
be informed in writing that representatives of Bayer, IEC/IRB, or regulatory authorities may 
inspect their medical records to verify collected information and that all personal information 
made available for inspection will be handled in strictest confidence and in accordance with 
local data protection laws. If the results of the study are published, the child’s identity will 
remain confidential. The investigator will maintain a list to enable children to be identified.


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15.
Reference list 
1. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. 
Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of 
Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical 
Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e419S-494S.
2. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G; American 
College of Chest Physicians. Oral anticoagulant therapy: Antithrombotic Therapy and 
Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-
Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e44S-88S.
3. Agnelli G, Gallus A, Goldhaber SZ, Hass S, Huisman MV, Hull RD, et al. Treatment of 
proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY
59-7039): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients 
With Acute Symptomatic Deep-Vein Thrombosis) study. Circulation 2007 Jul 10; 
116(2):180-7.
4. Buller HR, Lensing AW, Prins MH, Agnelli G, Cohen A, Gallus AS, et al. A dose ranging 
study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in 
the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT 
Dose-Ranging Study. Blood 2008 Sep 15; 112(6):2242-7.
5. The EINSTEIN investigators. Oral Rivaroxaban for Symptomatic Venous 
Thromboembolism. N Engl J Med 2010; 363: 2499-2510.
6. Chalmers EA. Epidemiology of venous thromboembolism in neonates and children. 
Thromb Res 2006;118(1):3-12.
7. Schmidt B, Andrew M. Neonatal thrombosis: report of a prospective Canadian and 
international registry. Pediatrics. 1995;96(5 pt 1): 939-943
8. Andrew M, David M, Adams M, Ali K, Anderson R, Barnard D, et al. Venous 
thromboembolic complications (VTE) in children: first analyses of the Canadian Registry
of VTE. Blood 1994;83 (5):1251-1257.
9. Report of the Second Task Force on Blood Pressure Control in Children. Pediatrics 1987; 
79(1):1-25.


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16.
Protocol amendments
16.1
Amendment 1
16.1.1
Overview of changes
Amendment 1 is the first global amendment dated 21 Jul 2015.
Change 1: Addition of minimum body weight for inclusion
16.1.1.1
A minimum body weight for inclusion to the study was added to inclusion criterion 6.
Rationale:
The minimum body weight of 2600 g was added as inclusion criterion based on a Steering 
Committee recommendation. This will ensure that the total volume of blood collected in the 
course of the study does not exceed the total volume allowed by respective guidelines.
Affected sections: Synopsis, Section 4.2  Inclusion criteria
Change 2: Addition of examples for concomitant medication 
16.1.1.2
excluding study participation
Examples for concomitant medication were added to exclusion criteria 9 and 10.
Rationale:
Examples were added for consistency with other rivaroxaban pediatric studies. It is now 
specified that fluconazole is an allowed antimycotic drug.
Affected sections: Synopsis, Section 4.3  Exclusion criteria
Change 3: Addition of blood pressure measurement at screening
16.1.1.3
The blood pressure measurement was added at Visit 1 in the study flow chart and the visit 
description at screening.
Rationale:
The addition of the blood pressure measurement to the flow chart highlights the requirement 
to check for exclusion criterion 6 and ensures consistency with the inclusion/exclusion criteria 
and description of the screening visit.
Affected section: Synopsis, Section 6.2  Visit 1 – Screening visit at 1 to 10 days before Visit 2


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Change 4: Minor clarifications for consistency
16.1.1.4
Minor, consistency and logical clarifications were made throughout the document.
Rationale:
Changes were made to ensure consistency throughout the document. These changes do not 
affect the overall study concept.
Affected sections: Synopsis, Section 5.1.1  Rivaroxaban regimen
Change 5: Addition of INR measurement at Visit 2
16.1.1.5
The INR measurement was added at Visit 2 in the study flow charts and the visit description 
at screening.
Rationale:
Children who switch from VKA to rivaroxaban should avoid using both drugs at therapeutic 
doses simultaneously. Rivaroxaban can be started only if the INR is below 2.5. Therefore, the 
INR has to be collected before rivaroxaban is started. 
Affected section: Synopsis, Section 5.1.1.3  Switching from VKA to rivaroxaban
Change 6: Addition of body-weight adjusted dosing table 
16.1.1.6
A body weight-adjusted dosing Table for rivaroxaban oral suspension was added.
Rationale:
After confirmation of the age- and body weight-adjusted dosing regimen for the age group 
between 6 months and less than 2 years in the phase I study 12892 and approval by the data 
monitoring committee and steering committee, the dosing schedule/regimen for the present 
study 17618 was added. 
Affected section: Section 5.1.1  Rivaroxaban regimen
Change 7: Replacement of CIAC confirmation for enrollment
16.1.1.7
The text of visit 2 was change in order to enroll children without prior CIAC confirmation if 
they meet the inclusion criteria and do not meet any of the exclusion criteria.
Rationale:
It was decided that a CIAC evaluation to confirm enrollment of a child to the study is not 
required. If children meet the inclusion criteria and do not meet any of the exclusion criteria, 
they can be enrolled without further CIAC confirmation. This is in line with other studies in 
the rivaroxaban pediatric program.
Affected section: Section 6.3  Visit 2 – Treatment visit at Day 1


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Change 8: Clarification of recording food and fluid intake together 
16.1.1.8
with rivaroxaban
The recording of estimated food and fluid volumes that are given together with rivaroxaban
was further specified.
Rationale:
The new wording considers liquid meals but also solid meals, which should be accompanied 
by fluid intake.
Affected section: Section 6.3  Visit 2 – Treatment visit at Day 1, Section 6.4  Visit 3 –
Treatment visit at Day 3, Section 6.5  Visit 4 – Day 8
16.1.2
Changes to the protocol text
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. In the display of modifications, the “old text” refers to 
the protocol version preceding this amendment. Deletions are crossed out in the “old text”. 
Additions are underlined in the “new text”. Corrections of typing errors or omissions are not 
highlighted in this amendment.
Synopsis
16.1.2.1
This section was modified via Changes 1, 2, 3, 4 and 5.
Old text:
[…]
[…]
Diagnosis and main criteria for 
inclusion /exclusion
Inclusion
[…] 
5.
Informed consent provided.
[…]
Exclusion
[…]
9.
Concomitant use of strong inhibitors of both cytochrome P450 
isoenzyme 3A4 (CYP3A4) and P-glycoprotein (P-gp)
10.
Concomitant use of strong inducers of CYP3A4
[…]
[…]
[…]


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New text:
[…]
[…]
Diagnosis and main criteria for 
inclusion /exclusion
Inclusion
[…] 
5.
Informed consent provided.
6. 
Body weight >2600 g.
[…]
Exclusion
[…]
9.
Concomitant use of strong inhibitors of both cytochrome P450 
isoenzyme 3A4 (CYP3A4) and P-glycoprotein (P-gp), e.g. all 
human immunodeficiency virus protease inhibitors and the 
following azole-antimycotics agents: ketoconazole, 
itraconazole, voriconazole, posaconazole, if used systemically 
(fluconazole is allowed)
10.
Concomitant use of strong inducers of CYP3A4, e.g. 
rifampicin, rifabutin, phenobarbital, phenytoin and 
carbamazepine
[…]
[…]
[…]


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Old text:
[…]
Table 1: Flow chart: study visits 
Screen a
Treatment period
30 day post study 
treatment contact
Visit
1
2
3
4
5
Days
Day -10 to Day 1
Day 1
Day 3
Day 8
Day 37+ 7 days 
[…]
Record anticoagulant medication
●
●
Obtain body weight
●
●
●
Check Hb, platelets, creatinine, ALT, 
total and direct bilirubin
●b
Obtain ALT, total and direct bilirubin
●
Re-confirm in-/exclusion criteria
●
[…]
ALT = alanine aminotransferase, eCRF = electronic case report form, Hb = hemoglobin
a
The screening visit can be performed up to 10 days prior to inclusion into the study.
b
Hb, platelets, creatinine, ALT, total and direct bilirubin results should be available within 10 days prior to inclusion into the 
study. If results are not available, obtain blood sample.
c 
If child discharged from the hospital.
d
Compile adjudication package and send it to the adjudication office.
e
Repeat ultrasound can be obtained on Day 8 ± 1.
[…]


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New text:
[…]
Table 1: Flow chart: study visits 
Screen a
Treatment period
30 day post study 
treatment contact
Visit
1
2
3
4
5
Days
Day -10 to Day 1
Day 1
Day 3
Day 8
Day 37+ 7 days 
[…]
Record anticoagulant medication
●
●
Obtain blood pressure
●
Obtain body weight
●
●
●
Check Hb, platelets, creatinine, ALT, 
total and direct bilirubin
●b
Obtain ALT, total and direct bilirubin
●
Re-confirm in-/exclusion criteria
●
Obtain INR, if receiving VKA f
●
[…]
ALT = alanine aminotransferase, eCRF = electronic case report form, Hb = hemoglobin, INR= international normalized ratio, 
VKA= vitamin K antagonist
a
The screening visit can be performed up to 10 days prior to inclusion into the study.
b
Hb, platelets, creatinine, ALT, total and direct bilirubin results should be available within 10 days prior to inclusion into the 
study. If results are not available, obtain blood sample.
c 
If child discharged from the hospital.
d
Compile adjudication package and send it to the adjudication office.
e     Repeat ultrasound can be obtained on Day 8 ± 1.
f
INR should be below 2.5 before starting rivaroxaban (see Section 5.1.1.3). 
[…]


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Section 4.2  Inclusion criteria
16.1.2.2
This section was modified via Change 1.
Old text:
[…]
4.
Oral feeding/nasogastric/gastric feeding for at least 10 days. 
5.
Informed consent provided.
[…]
New text:
[…]
4.
Oral feeding/nasogastric/gastric feeding for at least 10 days. 
5.
Informed consent provided.
6. 
Body weight >2600 g.
[…]
Section 4.3  Exclusion criteria
16.1.2.3
This section was modified via Change 2.
Old text:
[…]
9.
Concomitant use of strong inhibitors of both cytochrome P450 isoenzyme 3A4 
(CYP3A4) and P-glycoprotein (P-gp).  
10.
Concomitant use of strong inducers of CYP3A4.
[…]
New text:
[…]
9.
Concomitant use of strong inhibitors of both cytochrome P450 isoenzyme 3A4 
(CYP3A4) and P-glycoprotein (P-gp), e.g. all human immunodeficiency virus protease 
inhibitors and the following azole-antimycotics agents: ketoconazole, itraconazole, 
voriconazole, posaconazole, if used systemically (fluconazole is allowed).  
10.
Concomitant use of strong inducers of CYP3A4, e.g. rifampicin, rifabutin, 
phenobarbital, phenytoin and carbamazepine.
[…]


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Section 5.1.1  Rivaroxaban regimen
16.1.2.4
This section was modified via Change 4 and 6.
Old text:
[…]
If a rivaroxaban dose was missed, the child should take rivaroxaban immediately to ensure intake 
of the maximum daily dose per day. In this case, two oral suspension doses may be taken at once. 
Thereafter, the child should continue with the regular b.i.d. rivaroxaban administrations.
Instructions on how to handle rivaroxaban oral suspension are provided in the oral suspension 
handling guidelines, which will be issued separately from the protocol. Parents will be instructed 
and trained to prepare the suspension according to the guidelines, if applicable. The training will 
be documented.
Once the age- and body weight-adjusted dosing regimen has been confirmed for the age group 
between 6 months and less than 2 years in the phase I study 12892 and approved by the data 
monitoring committee and steering committee, the dosing schedule/regimen for the present study 
17618 (age group birth to less than 6 months) will be made available through an administrative 
amendment. The investigators and ethics committees/IRBs will receive the administrative 
amendment well in advance with an opportunity for evaluation before permission will be given to 
start enrolling children in this age group.
[…]
New text:
[…]
If a rivaroxaban dose was missed, the child should take rivaroxaban immediately to ensure intake 
of the total daily dose per day. In this case, two oral suspension doses may be taken at once. 
Thereafter, the child should continue with the regular b.i.d. rivaroxaban administrations.
[…]
The body weight-adjusted rivaroxaban dosing schedule is provided in Table 5–1. 
Table 3: Rivaroxaban dosing schedule
Body weight [kg]
Oral suspension dose (b.i.d.)
Total daily dose
Min
Max
[mg]
[mg]
2.6
<3
0.5
1.0
3
<4
0.6
1.2
4
<5
0.9
1.8
5
<6
1.2
2.4
6
<7
1.6
3.2
7
<8
1.9
3.8
8
<9
2.5
5.0
9
<10
2.7
5.4
10
<12
2.9
5.8
12
<20
3.2
6.4
[…]


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Section 5.1.1.3  Switching from VKA to rivaroxaban
16.1.2.5
This section was modified via Change 5.
New text:
[…]
Children who switch from VKA to rivaroxaban should avoid using both drugs at therapeutic 
doses simultaneously. Rivaroxaban can be started only if the INR is < 2.5.
[…]
Section 6.2  Visit 1 – Screening visit at 1 to 10 days before Visit 2
16.1.2.6
This section was modified via Change 3.
Old text:
[…]
Then demographic data, medical history, weight and anticoagulant medication will be collected.
[…]
New text:
[…]
Then demographic data, medical history, weight, blood pressure and anticoagulant medication 
will be collected.  
[…]


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Section 6.3  Visit 2 – Treatment visit at Day 1
16.1.2.7
This section was modified via Changes 7 and 8.
Old text:
[…]
If the CIAC confirmed the qualifying thrombotic event, then reconfirm eligibility. If results for 
hemoglobin, platelets, creatinine, ALT and total and direct bilirubin were not available within 
10 days prior to enrollment, obtain a blood sample. If the child still meets the inclusion criteria 
and does not meet any of the exclusion criteria, the child can be enrolled.
The following assessments and procedures have to be performed on visit 2:
[…]

Document the exact time of rivaroxaban intake and the type (e.g., breast milk, formula, 
porridge, or pureed food) and estimated volume of food rivaroxaban was administered 
with.
[…]
New text:
[…]
If the child still meets the inclusion criteria and does not meet any of the exclusion criteria, the 
child can be enrolled. If results for hemoglobin, platelets, creatinine, ALT and total and direct 
bilirubin were not available within 10 days prior to enrollment, obtain a blood sample. For 
children receiving VKA, the INR should be obtained. INR should be below 2.5 before starting 
rivaroxaban. 
The following assessments and procedures have to be performed on visit 2:
[…]

Document the exact time of rivaroxaban intake and the type (e.g., breast milk, formula, 
porridge, or pureed food) and estimated volume of fluid (e.g. breast milk and formula) 
or food (e.g. porridge or pureed food) rivaroxaban was administered with.
[…]


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Section 6.4  Visit 3 – Treatment visit at Day 3
16.1.2.8
This section was modified via Change 8.
Old text:
[…]

Instruct to document in the study booklet 
o
the exact time of the last dose of rivaroxaban on the day prior to visit 4,
o
the volume and type of liquid (e.g., breast milk, formula, water, juice) used to 
predilute the rivaroxaban oral suspension,
o
the type (e.g. breast milk, formula, porridge, or pureed food) and estimated volume 
of food  rivaroxaban was administered with,
[…]
New text:
[…]

Instruct to document in the study booklet 
o
the exact time of the last dose of rivaroxaban on the day prior to visit 4,
o
the volume and type of liquid (e.g., breast milk, formula, water, juice) used to 
predilute the rivaroxaban oral suspension,
o
the type (e.g. breast milk, formula, porridge, or pureed food) and estimated volume 
of fluid (e.g. breast milk and formula) or food (e.g. porridge or pureed food)
rivaroxaban was administered with,
[…]


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Section 6.5  Visit 4 – Day 8
16.1.2.9
This section was modified via Change 8.
Old text:
[…]

Document 
o
the exact time of the last dose of rivaroxaban on the day prior to visit 4,
o
the volume and type of liquid (e.g., breast milk, formula, water, juice) used to 
predilute the rivaroxaban oral suspension,
o
the type (e.g. breast milk, formula, porridge, or pureed food) and estimated volume 
of food rivaroxaban was administered with.
[…]
New text:
[…]

Document 
o
the exact time of the last dose of rivaroxaban on the day prior to visit 4,
o
the volume and type of liquid (e.g., breast milk, formula, water, juice) used to 
predilute the rivaroxaban oral suspension,
o
the type (e.g. breast milk, formula, porridge, or pureed food) and estimated volume 
of fluid (e.g. breast milk and formula) or food (e.g. porridge or pureed food) 
rivaroxaban was administered with.
[…]
16.2
Amendment 4
16.2.1
Overview of changes
Amendment 4 is the second global amendment dated 10 May 2016.
Change 1: Replacement of Medical Expert details
16.2.1.1
The Medical Expert and the contact details were updated on the Title page.
Rationale:
The responsible Medical Expert for this study has changed and details on the title page were 
updated accordingly.
Affected sections: Title page


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Change 2: Modification of study population
16.2.1.2
The study population was extended by removing the requirement of having a “catheter-
related” arterial or venous thrombosis.
Rationale: 
The original study protocol focused on children with catheter-related arterial or venous 
thrombosis, as this type of thrombosis – based on the limited amount of literature available -
was considered to be the most prevalent form of thrombosis in the age range birth to 
6 months. However, feedback from investigators indicates, that children with other forms of 
thrombosis requiring anticoagulant therapy should be included into the study as well. Through 
this change, the study will not only collect PK/PD, safety and efficacy data in catheter-related 
arterial or venous thrombosis, but in all kind of arterial of venous thrombosis requiring 
anticoagulant therapy. 
Affected sections: Title page; Synopsis; Section 1.  Introduction; Section 1.2 Venous or 
arterial thrombosis; Section 1.3  Rationale of the study and risk-benefit assessment; Section 3.  
Study design; Section 3.1  Study description; Section 4.2  Inclusion criteria; Section 6.1  
Study visits
Change 3: Modification of inclusion criterion 1
16.2.1.3
Inclusion criterion 1 was changed.
Rationale: 
Current guidelines recommend anticoagulant therapy for 6 weeks in case of catheter-related 
thrombosis. However, in current practice, many neonates and young infants are treated for a 
shorter period of time. Therefore, the minimum time of initial heparinization before start of 
rivaroxaban treatment is reduced from at least 2 weeks to at least 5 days in order to 
accommodate for shorter treatment durations.
Affected sections: Synopsis; Section 4.2  Inclusion criteria
Change 4: Clarification of exclusion criterion 6
16.2.1.4
In exclusion criterion 6, the word uncontrolled was added.
Rationale: 
Children with a antihypertensive therapy leading to normal blood pressure values (ie. < 95th
percentile) are allowed to be enrolled in the study. 
Affected sections: Synopsis; Section 4.3  Exclusion criteria


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Change 5: Clarification of exclusion criterion 12
16.2.1.5
In exclusion criterion 12, it was clarified that children should not have an indication for 
continued  antiplatelet or NSAID therapy. However, incidental use is allowed.
Rationale: 
Children should not have an indication requiring continued antiplatelet or NSAID therapy at 
the time rivaroxaban treatment is started. Incidental doses of an antiplatelet or NSAID 
treatment may be given during the 7-day treatment course with rivaroxaban.
Affected sections: Synopsis; Section 4.3  Exclusion criteria; Section 4.4  Concomitant 
medication
Change 6: Change of oral suspension formulation
16.2.1.6
The rivaroxaban formulation was changed from “ready-to-use” suspension to “granules for 
oral suspension”.
Rationale: 
The study started with the rivaroxaban “ready-to-use” oral suspension, which requires a 
dilution step during preparation of individual doses. As this dilution step is putting an 
additional burden on parents of sick children and may introduce a potential source of handling 
errors, the formulation in this study will be replaced by the “granules for oral suspension” 
formulation, which was recently developed, and is currently investigated in a phase I study in 
children aged 6 months to 12 years (# 17992), after the formulation had been tested in a 
relative bioavailability in adults. PK data obtained from 16 children (thereof, 5 children aged 
6 months to 2 years) after administration of the resuspended granules for oral suspension are 
in line with predictions by the pediatric physiologically-based PK (PBPK) model. The 
granules for oral suspension formulation does not require dilution of individual doses, and is 
the preferred formulation for the phase III program.
Affected sections: Synopsis; Section 3.1  Study description; Section 5.1.1  Rivaroxaban 
regimen; Section 5.5  Packaging, labeling, and storage; Section 6.3  Visit 2 – Treatment visit 
at Day 1; Section 6.4  Visit 3 – Treatment visit at Day 3; Section 6.5  Visit 4 – Day 8


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Change 7: Clarification of CIAC assessment
16.2.1.7
The process for assessment of the index event by the CIAC was clarified.
Rationale:
The CIAC will assess the index event; however, inclusion of child into the study does not 
depend on the outcome of the assessment.
Affected sections: Section 6.2  Visit 1 – Screening visit at 1 to 10 days before Visit 2
Change 8: Change of drug accountability and compliance assessment 
16.2.1.8
procedure
At visit 3 (day 3) drug accountability and compliance will be not be assessed.
Rationale:
Due to the small dose volumes and the limited accuracy of measuring the remaining volume 
after 3 days of dosing, it was decided to measure the volume only after completion of 
treatment. 
Affected sections: Synopsis; Section 6.4  Visit 3 – Treatment visit at Day 3
Change 9: Timing of rivaroxaban administration in relation to 
16.2.1.9
feeding
With the introduction of the granules for oral suspension formulation, rivaroxaban should be 
administered immediately before or (early) during feeding.
Rationale: 
The properties of the granules formulation allows for rivaroxaban administration immediately 
before or early during feeding. This timing is also more consistent with instructions in case of 
administrations through a gastric or nasogastric tube. This should be suitable to reduce the 
risk of children refusing drug intake. In addition, drug administration before or early during 
feeding should lower the risk that all or part of the suspensions is spit out (with the usual burp 
after feeding). 
Affected section: Section 5.1.1  Rivaroxaban regimen
16.2.2
Changes to the protocol text
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. In the display of modifications, the “old text” refers to 
the protocol version preceding this amendment. Deletions are crossed out in the “old text”. 
Additions are underlined in the “new text”. Corrections of typing errors or omissions are not 
highlighted in this amendment.


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Title page
16.2.2.1
This section was modified based on Changes 1 and 2. 
Old text:
[…]
7-day study of the safety, efficacy and the pharmacokinetic and pharmacodynamic properties 
of oral rivaroxaban in children from birth to less than 6 months with catheter-related arterial 
or venous thrombosis
[…]
 
 
 at Bayer
Bayer HealthCare Pharmaceuticals
Brazil
Telephone:
Email:
[…]
New text:
[…]
7-day study of the safety, efficacy and the pharmacokinetic and pharmacodynamic properties 
of oral rivaroxaban in children from birth to less than 6 months with arterial or venous 
thrombosis
[…]
 
 
  
Telephone: 
Email:  
[…]
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Synopsis
16.2.2.2
This section was modified based on Changes 2, 3, 4 and 5.
Old text:
[…]
Title
7-day study of the safety, efficacy and the pharmacokinetic and 
pharmacodynamic properties of oral rivaroxaban in children from birth to 
less than 6 months with catheter-related arterial or venous thrombosis
[…]
Indication
Children from birth to less than 6 months with documented symptomatic or 
asymptomatic catheter-related arterial or venous thrombosis
Diagnosis and main criteria for 
inclusion /exclusion
Children from birth to less than 6 months with documented symptomatic or 
asymptomatic catheter-related arterial or venous thrombosis who have been 
treated with anticoagulant therapy for at least two weeks.
Inclusion
1.
Children from birth to less than 6 months with documented 
symptomatic or asymptomatic catheter-related venous or 
arterial thrombosis who have been treated with anticoagulant 
therapy for at least two weeks. 
[…]
Exclusion
4.
[…]
5.
Creatinine > 1.5 times of normal 
6.
Hypertension defined as > 95th percentilea
[…]
11.
Indication for anticoagulant therapy other than current 
thrombosis
12.
Indication for antiplatelet therapy or non-steroid anti-
inflammatory drug (NSAID) therapy
13.
[…]
[…]
Methodology
Children with confirmed catheter-related arterial or venous thrombosis who 
have been treated with anticoagulant therapy for at least two weeks.
[…]
[…]
[…]


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New text:
[…]
Title
7-day study of the safety, efficacy and the pharmacokinetic and 
pharmacodynamic properties of oral rivaroxaban in children from birth to 
less than 6 months with arterial or venous thrombosis
[…]
Indication
Children from birth to less than 6 months with documented symptomatic or 
asymptomatic arterial or venous thrombosis
Diagnosis and main criteria for 
inclusion /exclusion
Children from birth to less than 6 months with documented symptomatic or 
asymptomatic arterial or venous thrombosis who have been treated with 
anticoagulant therapy for at least five days.
Inclusion
1.
Children from birth to less than 6 months with documented 
symptomatic or asymptomatic venous or arterial thrombosis 
who have been treated with anticoagulant therapy for at least 
five days.
[…]
Exclusion
4.
[…]
5.
Creatinine > 1.5 times of normal 
6.
Uncontrolled hypertension defined as > 95th percentilea 
[…]
11.
Indication for anticoagulant therapy other than current 
thrombosis
12.
An indication for continued antiplatelet therapy or non-steroid 
anti-inflammatory drug (NSAID) therapy. Incidental use is 
allowed.
13.
[…]
[…]
Methodology
Children with confirmed arterial or venous thrombosis who have been 
treated with anticoagulant therapy for at least five days.
[…]
[…]
[…]


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Section 1.  Introduction
16.2.2.3
This section was modified based on Change 2.
Old text:
[…]
In this phase I/II study, children with confirmed symptomatic or asymptomatic catheter 
related arterial or venous thrombosis will be treated for 7 days with the age- and body weight-
adjusted rivaroxaban twice daily dosing regimen to achieve a similar exposure as that 
observed in adults treated for VTE with 20 mg rivaroxaban once daily.
[…]
New text:
[…]
In this phase I/II study, children with confirmed symptomatic or asymptomatic arterial or 
venous thrombosis will be treated for 7 days with the age- and body weight-adjusted 
rivaroxaban twice daily dosing regimen to achieve a similar exposure as that observed in 
adults treated for VTE with 20 mg rivaroxaban once daily.
[…]
Section 1.2 Venous or arterial thrombosis
16.2.2.4
This section was modified based on Change 2.
Old text:
[…]
1.2  Catheter related venous or arterial thrombosis
[…]
New text:
[…]
1.2
Venous or arterial thrombosis
[…]


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Section 1.3  Rationale of the study and risk-benefit assessment
16.2.2.5
This section was modified based on Change 2.
Old text:
[…]
To carefully allow for the evaluation of rivaroxaban in neonates and children younger than 
6 months with confirmed symptomatic or asymptomatic catheter related arterial or venous 
thrombosis, we elected to evaluate the selected rivaroxaban dose regimen first in children that 
have been treated with anticoagulant therapy for at least two weeks. If this study reveals that 
the selected rivaroxaban dose regimen results in a similar exposure as that observed with 20 
mg rivaroxaban in adults, and safety and efficacy is confirmed, a subsequent study will 
evaluate the selected rivaroxaban dose regimen for the acute and continued treatment of VTE.
[…]
New text:
[…]
To carefully allow for the evaluation of rivaroxaban in neonates and children younger than 
6 months with confirmed symptomatic or asymptomatic arterial or venous thrombosis, we 
elected to evaluate the selected rivaroxaban dose regimen first in children that have been 
treated with anticoagulant therapy for at least five days. If this study reveals that the selected 
rivaroxaban dose regimen results in a similar exposure as that observed with 20 mg 
rivaroxaban in adults, and safety and efficacy is confirmed, a subsequent study will evaluate 
the selected rivaroxaban dose regimen for the acute and continued treatment of VTE.
[…]
Section 3.  Study design
16.2.2.6
This section was modified based on Change 2.
Old text:
[…]
This is a non-randomized, open label, multicenter study evaluating the safety, efficacy and 
PK/PD profile of a 7-day treatment with age- and body weight-adjusted oral rivaroxaban in 
neonates and infants younger than 6 months with symptomatic or asymptomatic catheter-
related arterial or venous thrombosis.
[…]


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New text:
[…]
This is a non-randomized, open label, multicenter study evaluating the safety, efficacy and 
PK/PD profile of a 7-day treatment with age- and body weight-adjusted oral rivaroxaban in 
neonates and infants younger than 6 months with symptomatic or asymptomatic arterial or 
venous thrombosis.
[…]
Section 3.1  Study description
16.2.2.7
This section was modified based on Changes 2 and 6.
Old text:
[…]
Neonates and infants aged less than 6 months who pass the screen of in- and exclusion criteria
and who have been treated for at least 2 weeks with heparin and /or VKA for confirmed 
symptomatic or asymptomatic catheter related arterial or venous thrombosis are eligible for 
the study. Study treatment consists of a 7-day treatment with an age- and body weight-
adjusted twice daily oral rivaroxaban dosing to achieve a similar exposure as that observed in 
adults treated for venous thromboembolism (VTE) with 20 mg rivaroxaban once daily. 
Rivaroxaban will be provided as an oral suspension (1 mg/mL) using a b.i.d. regimen with 12-
hour intervals.
[…]
New text:
[…]
Neonates and infants aged less than 6 months who pass the screen of in- and exclusion 
criteria, who have been treated for at least five days with heparin and /or VKA for confirmed 
symptomatic or asymptomatic arterial or venous thrombosis are eligible for the study. Study 
treatment consists of a 7-day treatment with an age- and body weight-adjusted twice daily oral 
rivaroxaban dosing to achieve a similar exposure as that observed in adults treated for venous 
thromboembolism (VTE) with 20 mg rivaroxaban once daily. Rivaroxaban will be provided 
as granules for preparation of an oral suspension (1 mg/mL after re-suspension) using a b.i.d. 
regimen with 12-hour intervals.
[…]


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Section 4.2  Inclusion criteria 
16.2.2.8
This section was modified based on Changes 2 and 3.
Old text:
[…]
1. Children from birth to less than 6 months with documented symptomatic or 
asymptomatic catheter-related venous or arterial thrombosis who have been treated 
with anticoagulant therapy for at least two weeks.
[…]
New text:
[…]
1. Children from birth to less than 6 months with documented symptomatic or 
asymptomatic venous or arterial thrombosis who have been treated with anticoagulant 
therapy for at least five days.
[…]
Section 4.3  Exclusion criteria
16.2.2.9
This section was modified based on Changes 4 and 5.
Old text:
[…]
6. Hypertension defined as >95th percentile.
[…]
12. Indication for antiplatelet therapy or non-steroid anti-inflammatory drug (NSAID) 
therapy.
[…]


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New text:
[…]
6. Uncontrolled hypertension defined as >95th percentile.
[…]
12. An indication for continued antiplatelet therapy or non-steroid anti-inflammatory 
drug (NSAID) therapy. Incidental use is allowed.
[…]
Section 4.4  Concomitant medication 
16.2.2.10
This section was modified based on Change 5.
Old text:
[…]
Concomitant medications include either continuation of a treatment started before study 
enrollment, or addition of a new treatment during the study. An indication for the use of 
NSAIDs or antiplatelet agents is an exclusion criterion since they increase the risk for 
bleeding in patients treated with anticoagulants. 
[…]
New text:
[…]
Concomitant medications include either continuation of a treatment started before study 
enrollment, or addition of a new treatment during the study. An indication for the continued
use of NSAIDs or antiplatelet agents is an exclusion criterion since they increase the risk for 
bleeding in patients treated with anticoagulants. However, incidental use is allowed.
[…]
Section 5.1.1  Rivaroxaban regimen
16.2.2.11
This section was modified based on Change 9.
Old text:
Age- and body weight-adjusted rivaroxaban will be administered twice daily (approximately 
12 hours apart) as oral suspension. Rivaroxaban will be taken in the morning and evening 
during or directly after feeding.
[…]


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New text:
[…]
Age- and body weight-adjusted rivaroxaban will be administered twice daily (approximately 
12 hours apart) as oral suspension. Rivaroxaban will be taken in the morning and evening 
immediately before or (early) during feeding.
Section 5.4.1  Rivaroxaban
16.2.2.12
This section was modified based on Change 6.
Old text:
[…]
Rivaroxaban will be provided as a 0.1% suspension (1 mg/mL). Rivaroxaban will be dosed 
according to body weight. Since children with renal impairment will be excluded from the 
study, a dose adaptation is not indicated.
[…]
New text:
[…]
Rivaroxaban will be provided as granules for preparation of a 0.1% oral suspension 
(1 mg/mL). Rivaroxaban will be dosed according to body weight. Since children with renal 
impairment will be excluded from the study, a dose adaptation is not indicated.
[…]
Section 5.5  Packaging, labeling, and storage
16.2.2.13
This section was modified based on Change 6.
Old text:
[…]
A system of numbering in accordance with Good Manufacturing Practice (GMP) will be used, 
ensuring that each dose of study medication can be traced back to the respective bulk ware of 
the ingredients. A complete record of batch numbers and expiry dates of all study medication
provided by Bayer, as well as the labels, will be maintained in the study file. Rivaroxaban
needs to be stored at the investigational site according to the labeled storage advice and in 
accordance with Good Clinical Practice (GCP) and GMP requirements. Rivaroxaban oral 


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suspension should not be frozen and should be stored at a temperature not exceeding 25°C 
and kept in a secure area (e.g. locked cabinet).
[…]
New text:
[…]
A system of numbering in accordance with Good Manufacturing Practice (GMP) will be used, 
ensuring that each dose of study medication can be traced back to the respective bulk ware of 
the ingredients. A complete record of batch numbers and expiry dates of all study medication
provided by Bayer, as well as the labels, will be maintained in the study file. Rivaroxaban
granules for oral suspension need to be stored at the investigational site according to the 
labeled storage advice and in accordance with Good Clinical Practice (GCP) and GMP
requirements. Rivaroxaban granules for oral suspension should not be frozen and should be 
stored at a temperature not exceeding 25°C and kept in a secure area (e.g. locked cabinet).
[…]
Section 6.1  Study visits
16.2.2.14
This section was modified based on Change 2.
Old text:
[…]
Visit 1 is a screening visit and will be a hospital visit. This visit is to identify potential 
eligibility of children who are treated with anticoagulants for confirmed symptomatic or 
asymptomatic catheter related arterial or venous thrombosis. This visit will take place 1 to 
10 days before inclusion into the study. Visit 2 is the first treatment visit and will be a hospital 
visit. Eligible children will start 7 days of anticoagulation with rivaroxaban (day 1).
[…]
New text:
[…]
Visit 1 is a screening visit and will be a hospital visit. This visit is to identify potential 
eligibility of children who are treated with anticoagulants for confirmed symptomatic or 
asymptomatic arterial or venous thrombosis. This visit will take place 1 to 10 days before 
inclusion into the study. Visit 2 is the first treatment visit and will be a hospital visit. Eligible 
children will start 7 days of anticoagulation with rivaroxaban (day 1).
[…]


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Section 6.2  Visit 1 – Screening visit at 1 to 10 days before Visit 2
16.2.2.15
This section was modified based on Change 7.
Old text:
[…]
The images of the index thrombotic event need to be collected and the adjudication package 
needs to be completed and sent to the central adjudication office. The CIAC will assess the 
images and will inform the investigator about their decision.
[…]
New text:
[…]
The images of the index thrombotic event need to be collected and the adjudication package 
needs to be completed and sent to the central adjudication office for their assessment.
[…]
Section 6.3  Visit 2 – Treatment visit at Day 1
16.2.2.16
This section was modified based on Change 6.
Old text:
[…]

Provide instructions on how to administer the study drug and give the study booklet 
and the rivaroxaban oral suspension handling guidelines to parents, if applicable.

Administer the first rivaroxaban dose according to the oral suspension handling 
guidelines and document the volume and type of liquid (e.g., breast milk, formula, 
water, or juice) used to predilute the rivaroxaban oral suspension. 

Document the exact time of rivaroxaban intake and the type (e.g., breast milk, formula, 
porridge, or pureed food) and estimated volume of fluid (e.g. breast milk and formula) 
or food (e.g. porridge or pureed food) rivaroxaban was administered with.
[…]


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New text:
[…]

Provide instructions on how to administer the study drug and give the study booklet 
and the rivaroxaban oral suspension handling guidelines to parents, if applicable.

Administer the first rivaroxaban dose according to the oral suspension handling 
guidelines.

Document the exact time of rivaroxaban intake and the type (e.g., breast milk, formula, 
porridge, or pureed food) and estimated volume of fluid (e.g. breast milk and formula) 
or food (e.g. porridge or pureed food) rivaroxaban was administered with.
[…]
Section 6.4  Visit 3 – Treatment visit at Day 3
16.2.2.17
This section was modified based on Change 6.
Old text:
[…]

Administer the next dose of rivaroxaban according to the oral suspension handling 
guidelines and document the volume and type of liquid (e.g., breast milk, formula, 
water, or juice) used to predilute the rivaroxaban oral suspension.

Document the exact time of rivaroxaban intake and the type (e.g. breast milk, formula, 
porridge, or pureed food) and estimated volume of food rivaroxaban was administered 
with.

In case rivaroxaban is administered together with porridge or pureed food, encourage 
the child to drink a typical serving of liquid thereafter (e.g., breast milk, formula, water, 
juice) and document the type of liquid and the estimated volume.

At 2–8 hr after rivaroxaban, collect a post-dose PK blood sample followed by the PD 
blood sample.

Document the exact time of blood sampling for PK/PD.

Perform drug accountability and assess compliance.

Check changes in concomitant medications.

Inform that on the day before visit 4, the evening dose of rivaroxaban should be taken 
as late as possible.


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
Instruct to document in the study booklet 
o the exact time of the last dose of rivaroxaban on the day prior to visit 4,
o the volume and type of liquid (e.g., breast milk, formula, water, juice) used to 
predilute the rivaroxaban oral suspension,
o the type (e.g. breast milk, formula, porridge, or pureed food) and estimated 
volume of fluid (e.g. breast milk and formula) or food (e.g. porridge or pureed 
food) rivaroxaban was administered with, 
[…]
New text:
[…]

Administer the next dose of rivaroxaban according to the oral suspension handling 
guidelines.

Document the exact time of rivaroxaban intake and the type (e.g. breast milk, formula, 
porridge, or pureed food) and estimated volume of food rivaroxaban was administered 
with.

In case rivaroxaban is administered together with porridge or pureed food, encourage 
the child to drink a typical serving of liquid thereafter (e.g., breast milk, formula, water, 
juice) and document the type of liquid and the estimated volume.

At 2–8 hr after rivaroxaban, collect a post-dose PK blood sample followed by the PD 
blood sample.

Document the exact time of blood sampling for PK/PD.

Check changes in concomitant medications.

Inform that on the day before visit 4, the evening dose of rivaroxaban should be taken 
as late as possible.

Instruct to document in the study booklet 
o the exact time of the last dose of rivaroxaban on the day prior to visit 4,
o the type (e.g. breast milk, formula, porridge, or pureed food) and estimated 
volume of fluid (e.g. breast milk and formula) or food (e.g. porridge or pureed 
food) rivaroxaban was administered with, 
[…]


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Section 6.5  Visit 4 – Day 8 
16.2.2.18
This section was modified based on Change 6.
Old text:
[…]

Document 
o the exact time of the last dose of rivaroxaban on the day prior to visit 4,
o the volume and type of liquid (e.g., breast milk, formula, water, juice) used to 
predilute the rivaroxaban oral suspension,
[…]
New text:
[…]

Document 
o the exact time of the last dose of rivaroxaban on the day prior to visit 4,
[…]
16.3
Amendment 5
16.3.1
Overview of changes
Amendment 5 is the third global amendment dated 15 Nov 2016.
Change 1: Change Medical Expert’s name
16.3.1.1
The surname of the sponsor’s Medical Expert we updated.
Rational:
The surname of the sponsor’s Medical Expert changed during the course of the study and was 
adjusted accordingly.
Affected sections: Title page
Change 2: Change of sponsorship information
16.3.1.2
The sponsor was changed from Bayer Healthcare AG to Bayer AG for non-US territory and
sponsor information for Bayer Healthcare Pharmaceuticals Inc. was added for US-territory.
Rational:
Bayer HealthCare AG merged with Bayer AG, an affiliated company within the Bayer Group,
effective as of 1st July 2016. Thereby, Bayer HealthCare AG ceased to exist and Bayer AG
became its legal successor and automatically took over all of the Bayer HealthCare AG’s


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rights, obligations and liabilities by law. As a result of the above mentioned merger, Bayer
AG assumes the role of the sponsor.
Affected sections: Title page


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Change 3: Modification of dosing regimen
16.3.1.3
The total daily dose will be increased by 50% for all body weight groups. This will be
achieved by three times daily administration of the same individual dose previously used with 
the b.i.d. schedule.
Rationale:
Rivaroxaban was well tolerated in the 5 children treated according to the b.i.d. regimen and 
there were no bleeding events. Furthermore, no symptomatic recurrent venous 
thromboembolic complications occurred. Repeat imaging of the thrombosis in two children 
with a persistent thrombosis at the start of rivaroxaban treatment showed normalization and
substantial regression of the thrombosis, respectively, after the 7-day treatment with 
rivaroxaban. 
However, PK results of the first 5 children enrolled with the b.i.d. regiment indicate lower 
rivaroxaban exposure (AUCss,24h) and Ctrough concentrations than initially expected by the PK 
model. 
Based on these observations the Data Monitoring Committee in its meeting on September 19, 
2016, identified an efficacy concern. The DMC clarified that “the efficacy concern the 
committee identified was related to the potential for the low levels to be associated with 
thrombotic events, not related to any observed events in the patients treated to date.” The 
DMC recommended to change the dosing regimen from a b.i.d. (approx. 12-hour intervals) to 
a t.i.d. (approx. 8-hour intervals) schedule, applying the same individual doses previously 
administered twice daily. This recommendation was endorsed by the steering committee. 
The 50% increase of the total daily dose aims to elevate the exposure to the lower end of the 
adult reference range. The shortening of the dosing interval from 12 hours (b.i.d. schedule) to 
8 hours (t.i.d. schedule) aims to increase the Ctrough concentrations to match the adult reference 
range which will allow to extrapolate safety and efficacy from the adult VTE treatment 
population. 
The change from b.i.d. to t.i.d. schedule requires an adaptation of PK/PD sampling timepoints 
and instructions for administration of rivaroxaban. 
The original protocol included dosing information for children with body weight of 12 to 
< 20 kg. This specific dosing information was deleted as this body weight group does not 
apply to children aged younger than 6 months.
Affected sections:sections: Synopsis, Section 1 Introduction, Section 3.1  Study description, 
Section 5.1.1  Rivaroxaban regimen, Section 6.3  Visit 2 – Treatment visit at Day 1, Section 
6.4  Visit 3 – Treatment visit at Day 3, Section 6.5  Visit 4 – Day 8, Section 6.12  PK/PD 
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Change 4: Provision of additional imaging tests for adjudication
16.3.1.4
Investigators are asked to also submit diagnostic tests other than ultrasound for evaluation of 
repeat imaging by the Central Independent Adjudication Committee, if available.
Rationale:
Repeat imaging will provide valuable efficacy information. The protocol requires repeat 
ultrasound imaging before start and after completion of the 7-day rivaroxaban treatment. If 
other imaging tests (e.g., CT, MRI) are planned and conducted independently of the study 
protocol, these imaging tests may support the evaluation of the status of the thrombosis and 
should therefore be submitted for adjudication, in addition to the ultrasound imaging required 
by the protocol.
Affected sections: Section 6.3  Visit 2 – Treatment visit at Day 1; Section 6.5  Visit 4 – Day 8
16.3.2
Changes to the protocol text
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. In the display of modifications, the “old text” refers to 
the protocol version preceding this amendment. Deletions are crossed out in the “old text”. 
Additions are underlined in the “new text”. Corrections of typing errors or omissions are not 
highlighted in this amendment.
Title page
16.3.2.1
This section was modified based on Changes 1 and 2.
Old text:
[…]
Please note that Bayer HealthCare AG merges with Bayer AG, an affiliated company within 
the Bayer Group, effective as of 1st July 2016. Thereby, Bayer HealthCare AG ceases to exist 
and Bayer AG becomes its legal successor and automatically takes over all of the Bayer 
HealthCare AG’s rights, obligations and liabilities by law. As a result of the above mentioned 
merger, Bayer AG assumes the role of the sponsor for these trials. Detailed information on 
the merger will be provided in due time.
[…]
Bayer HealthCare AG, D-51368 Leverkusen, Germany
[…]
  
Telephone: 
Email:  
[…]
PPD
PPD
PPD
PPD


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New text:
[…]
Non-US territory: Bayer AG, D-51368 Leverkusen, Germany
US territory: Bayer Healthcare Pharmaceuticals Inc.,
100 Bayer Boulevard, P.O. Box 915,
Whippany NJ 07981-0915, USA 
[…]
  
Telephone: 
Email:  
[…]
Synopsis
16.3.2.2
This section was modified based on Change 3.
Old text:
[…]
Dose(s)
Age- and body weight-adjusted twice daily dosing of rivaroxaban to 
achieve a similar exposure as that observed in adults treated for venous 
thromboembolism (VTE) with 20 mg rivaroxaban once daily
[…]
Methodology
Children with confirmed arterial or venous thrombosis who have been 
treated with anticoagulant therapy for at least five days.
Children will receive an age- and body weight-adjusted rivaroxaban 
regimen using an oral suspension (1 mg/mL) for a total of 7 days followed 
by an observational period of another 30 days. Rivaroxaban will be 
administered twice daily.
An ultrasound will be performed at day 1 and 8 of rivaroxaban treatment to 
document asymptomatic changes. In addition, children will be monitored 
for the occurrence of symptomatic recurrent thrombosis and bleedings.
All suspected clinical study outcomes and baseline and repeat ultrasound 
imaging tests will be assessed by a Central Independent Adjudication 
Committee (CIAC).
An independent data monitoring committee (DMC) will monitor the 
children’s safety and give recommendations to the steering committee.
[…]
PPD
PPD
PPD
PPD


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Table 2: Flow chart: pharmacokinetics and pharmacodynamics
Pharmacokinetics 
and 
pharmacodynamics 
(PK/PD) a
Visit 1
Visit 2
Visit 3
Visit 4
Rivaroxaban 
treatment days
Screen
day -10 to 
day 1
Treatment 
day 1
Treatment 
day 2
Treatment
day 3
Treatment
day 4 to 7
Day 8
Rivaroxaban 
administration
1st
dose
2nd
dose
1st
dose
2nd
dose
1st
dose
2nd
dose
1st
dose
2nd
dose
PK/PD time points
0.5 to 
1.5 hr 
post 
dose
2-4 hr
post 
dose
2-8 hr 
post 
dose
10-16 hr 
after last 
dose at day 
7
Obtain blood sample 
for PK b
●
●
●
●
Obtain blood sample 
for PD c
●
●
●
hr = hour(s), PD = pharmacodynamics, PK = pharmacokinetics
a The approximate total blood volume taken per child for PK/PD is 6.6 mL. Always draw the PD sample as the last sample.
b Blood volume per PK sample is approximately 0.6 mL; total blood volume for all PK samples is 2.4 mL.
c Blood volume per PD sample is approximately 1.4 mL; total blood volume for all PD samples is 4.2 mL.
New text:
[…]
Dose(s)
Age- and body weight-adjusted three times daily dosing of rivaroxaban to 
achieve a similar exposure as that observed in adults treated for venous 
thromboembolism (VTE) with 20 mg rivaroxaban once daily
[…]
Methodology
Children with confirmed arterial or venous thrombosis who have been 
treated with anticoagulant therapy for at least five days.
Children will receive an age- and body weight-adjusted rivaroxaban 
regimen using an oral suspension (1 mg/mL) for a total of 7 days followed 
by an observational period of another 30 days. Rivaroxaban will be 
administered three times daily.
An ultrasound will be performed at day 1 and 8 of rivaroxaban treatment to 
document asymptomatic changes. In addition, children will be monitored 
for the occurrence of symptomatic recurrent thrombosis and bleedings.
All suspected clinical study outcomes and baseline and repeat ultrasound 
imaging tests will be assessed by a Central Independent Adjudication 
Committee (CIAC).
An independent data monitoring committee (DMC) will monitor the 
children’s safety and give recommendations to the steering committee.
[…]


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Table 2: Flow chart: pharmacokinetics and pharmacodynamics 
PK and PD a
Visit 1
Visit 2
Visit 3
Visit 4
Rivaroxaban 
treatment 
days
Screen
day -10 
to day 1
Treatment 
day 1
Treatment day 2
Treatment
day 3
Treatment
day 4 to 7
Day 8
Rivaroxaban 
administration
1st
dose
2nd
dose
3rd 
dose
1st
dose
2nd
dose
3rd
dose
1st
dose
2nd
dose
3rd 
dose
1st
dose
2nd
dose
3rd 
dose
PK/PD time 
points
0.5 to 3
hr post 
dose
7 to 8hr
post 
dose
0.5 to 
3 hr 
post 
dose
7 to 8hr
post 
dose
10-16 hr 
after last 
dose at 
day 7
Obtain blood 
sample for PK b
●
●
●
●
Obtain blood 
sample for PD c
●
●
●d
hr = hour(s), PD = pharmacodynamics, PK = pharmacokinetics
a The approximate total blood volume taken per child for PK/PD is 6.6 mL. Always draw the PD sample as the last sample.
b Blood volume per PK sample is approximately 0.6 mL; total blood volume for all PK samples is 2.4 mL.
c Blood volume per PD sample is approximately 1.4 mL; total blood volume for all PD samples is 4.2 mL.
d If continued treatment with anticoagulants is necessary, administer the anticoagulant after last sample is taken for rivaroxaban.
Section 1 Introduction
16.3.2.3
This section was modified based on Change 3.
Old text:
[…]
In this phase I/II study, children with confirmed symptomatic or asymptomatic arterial or
venous thrombosis will be treated for 7 days with the age- and body weight-adjusted 
rivaroxaban twice daily dosing regimen to achieve a similar exposure as that observed in 
adults treated for VTE with 20 mg rivaroxaban once daily.
[…]


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New text:
[…]
In this phase I/II study, children with confirmed symptomatic or asymptomatic arterial or 
venous thrombosis will be treated for 7 days with the age- and body weight-adjusted 
rivaroxaban three times daily dosing regimen to achieve a similar exposure as that observed in 
adults treated for VTE with 20 mg rivaroxaban once daily.
[…]
Section 3.1  Study description
16.3.2.4
This section was modified based on Change 3.
Old text:
[…]
Neonates and infants aged less than 6 months who pass the screen of in- and exclusion 
criteria, who have been treated for at least five days with heparin and /or VKA for confirmed 
symptomatic or asymptomatic arterial or venous thrombosis are eligible for the study. Study 
treatment consists of a 7-day treatment with an age- and body weight-adjusted twice daily oral 
rivaroxaban dosing to achieve a similar exposure as that observed in adults treated for venous 
thromboembolism (VTE) with 20 mg rivaroxaban once daily. Rivaroxaban will be provided 
as granules for preparation of an oral suspension (1 mg/mL after re-suspension) using a b.i.d. 
regimen with 12-hour intervals.
[…]
New text:
[…]
Neonates and infants aged less than 6 months who pass the screen of in- and exclusion 
criteria, who have been treated for at least five days with heparin and /or VKA for confirmed 
symptomatic or asymptomatic arterial or venous thrombosis are eligible for the study. Study 
treatment consists of a 7-day treatment with an age- and body weight-adjusted three times
daily oral rivaroxaban dosing to achieve a similar exposure as that observed in adults treated 
for venous thromboembolism (VTE) with 20 mg rivaroxaban once daily. Rivaroxaban will be 
provided as granules for preparation of an oral suspension (1 mg/mL after re-suspension) 
using a t.i.d. regimen with 8-hour intervals.
[…]


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Section 5.1.1  Rivaroxaban regimen
16.3.2.5
This section was modified based on Change 3.
Old text:
[…]
Age- and body weight-adjusted rivaroxaban will be administered twice daily (approximately 
12 hours apart) as oral suspension. Rivaroxaban will be taken in the morning and evening 
immediately before or (early) during feeding.
If a rivaroxaban dose was missed, the child should take rivaroxaban immediately to ensure 
intake of the total daily dose per day. In this case, two oral suspension doses may be taken at 
once. Thereafter, the child should continue with the regular b.i.d. rivaroxaban administrations.
[…]
Table 3: Rivaroxaban dosing schedule
Body weight [kg]
Oral suspension dose (b.i.d.)
Total daily dose
Min
Max
[mg]
[mg]
2.6
<3
0.5
1.0
3
<4
0.6
1.2
4
<5
0.9
1.8
5
<6
1.2
2.4
6
<7
1.6
3.2
7
<8
1.9
3.8
8
<9
2.5
5.0
9
<10
2.7
5.4
10
<12
2.9
5.8
12
<20
3.2
6.4
[…]
New text:
[…]
Age- and body weight-adjusted rivaroxaban will be administered three times daily 
approximately 8 hours apart as oral suspension. The oral suspension will be administered
immediately before or (early) during feeding. 
Originally, the study started with a b.i.d. regimen. Rivaroxaban was well tolerated in the 5 
children treated according to the b.i.d. regimen and there were no bleeding events. 
Furthermore, no symptomatic recurrent venous thromboembolic complications occurred. 


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Repeat imaging of the thrombosis in two children with a persistent thrombosis at the start of 
rivaroxaban treatment showed normalization and substantial regression of the thrombosis, 
respectively, after the 7-day treatment with rivaroxaban. 
However, PK results of the first 5 children enrolled with the b.i.d. regiment indicate lower 
rivaroxaban exposure (AUCss,24h) and Ctrough concentrations than initially expected by the PK 
model. Based on these observations, the Data Monitoring Committee recommended to change 
the dosing regimen from a b.i.d. (approx. 12-hour intervals) to a t.i.d. (approx. 8-hour 
intervals) schedule applying the same individual doses previously administered twice daily. 
This recommendation was endorsed by the steering committee.
Following implementation of Amendment 5, children will be dosed according to the t.i.d. 
schedule (according to Table 3). The 50% increase of the total daily dose will increase the 
exposure, and the shortening of the dosing interval from 12 to 8 hours (t.i.d. schedule) aims to 
increase the Ctrough concentrations. 
If a rivaroxaban individual dose was missed, the t.i.d. administration schedule with approx. 
8-hour intervals should be resumed without compensating for the missed dose.
[…]
Table 3: Rivaroxaban dosing schedule 
Body weight [kg]
Oral suspension dose (t.i.d.)
Total daily dose
Min
Max
[mg]
[mg]
2.6
<3
0.5
1.5
3
<4
0.6
1.8
4
<5
0.9
2.7
5
<6
1.2
3.6
6
<7
1.6
4.8
7
<8
1.9
5.7
8
<9
2.5
7.5
9
<10
2.7
8.1
10
<12
2.9
8.7
* to be administered every 8 hours
[…]


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Section 6.3  Visit 2 – Treatment visit at Day 1
16.3.2.6
This section was modified based on Change 3.
Old text:
[…]

At 0.5-1.5 hr after rivaroxaban, collect only a PK blood sample.

At 2.0-4 hr after rivaroxaban intake, collect a PK blood sample followed by the PD 
sample.

Document the exact time of each blood sampling for PK/PD.

Obtain ultrasound and prepare an adjudication package to be sent to the adjudication 
office.
[…]
New text:
[…]

At 0.5-3 hr after rivaroxaban, collect only a PK blood sample.

At 7-8 hr after rivaroxaban intake, collect a PK blood sample followed by the PD 
sample.

Document the exact time of each blood sampling for PK/PD.

Obtain ultrasound and prepare an adjudication package to be sent to the adjudication 
office. In case other diagnostic tests were performed to visualize the clot, these should 
be sent as well.
[…]


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Section 6.4  Visit 3 – Treatment visit at Day 3
16.3.2.7
This section was modified based on Change 3.
Old text:
[…]

At 2–8 hr after rivaroxaban, collect a post-dose PK blood sample followed by the PD 
blood sample.

Document the exact time of blood sampling for PK/PD.

Check changes in concomitant medications.

Inform that on the day before visit 4, the evening dose of rivaroxaban should be taken 
as late as possible.
[…]
New text:
[…]

At 0.5-3 hr after rivaroxaban, collect a PK blood sample followed by the PD blood 
sample.

At 7-8 hr after rivaroxaban intake, collect only a PK blood sample.

Check changes in concomitant medications.
[…]
Section 6.5  Visit 4 – Day 8
16.3.2.8
This section was modified based on Change 3.
Old text:
[…]

At 10-16 hr after last rivaroxaban intake, collect the PK blood sample followed by the 
PD blood sample, collect ALT, total and direct bilirubin sample.

Document the exact time of blood sampling for PK/PD.

Repeat ultrasound and prepare an adjudication package to be sent to the adjudication 
office. The repeat ultrasound can be performed on day 8 ± 1.
[…]


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New text:
[…]

At 10-16 hr after last rivaroxaban intake, collect ALT, total and direct bilirubin sample, 
followed by the PD blood sample. If continued treatment with anticoagulants is 
necessary, administer the anticoagulant after this sample is taken.

Document the exact time of blood sampling for PD.

Repeat ultrasound and prepare an adjudication package to be sent to the adjudication 
office. The repeat ultrasound can be performed on day 8 ± 1. In case other diagnostic 
tests were performed to visualize the clot, these should be sent as well.
[…]
Section 6.12  PK/PD assessment
16.3.2.9
This section was modified based on Change 3.
Old text:
[…]

two post-dose PK samples at visit 2 

one post-dose PD sample at visit 2

one post-dose PK/PD sample at visit 3

one post-dose PK/PD sample at visit 4
[…]
New text:
[…]

two post-dose PK samples at visit 2 

one post-dose PD sample at visit 2

two post-dose PK sample at visit 3

one post-dose PD sample at visit 3

one post-dose PD sample at visit 4
[…]


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17.
Appendices
17.1.1
Bioanalytics and pharmacokinetics
Rivaroxaban concentrations in plasma will be measured by a validated high-performance 
liquid chromatography assay with tandem mass spectrometric detection. Quality control and 
calibration samples will be analyzed concurrently with study samples. The results of quality 
check samples will be reported together with concentrations in unknown samples in the 
clinical study report. Concentrations are calculated from the chromatographic raw data in 
accordance with current Bayer guidelines. Only values above the lower limit of quantification 
are used to determine pharmacokinetic parameters.
Rivaroxaban (BAY 59-7939, JNJ-39039039) is being co-developed under a collaboration and 
license agreement between Bayer HealthCare AG and Ortho McNeil Pharmaceuticals, Inc. 
dated 01 Oct 2005. As determined by the parties, both Bayer HealthCare AG and Janssen 
Pharmaceuticals Inc. (successor in interest to Ortho McNeil Pharmaceuticals, Inc.) may use 
affiliated corporate entities to conduct this clinical study. With regard to Janssen 
Pharmaceuticals Inc., such affiliates may include Janssen Research & Development, LLC 
(formerly Johnson & Johnson Pharmaceutical Research & Development LLC), Janssen 
Scientific Affairs, LLC, and Janssen-Cilag International N.V. The term “sponsor” or 
“designee” is used to represent these various legal entities that have been identified to perform 
various clinical study services; the actual sponsor or designee is identified on the Contact 
Information page that accompanies this protocol.
17.1.2
Age percentiles for blood pressure in children
Source: 9

SAP_000.pdf: 
 
Document Type: Statistical Analysis Plan 
Official Title: 
7-day study of the safety, efficacy and the pharmacokinetic and 
pharmacodynamic properties of oral rivaroxaban in children from 
birth to less than 6 months with arterial or venous thrombosis 
NCT Number: 
NCT02564718 
Document Date: 
09 Feb 2016 
 


Statistical Analysis Plan
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Reference Number: BPD-SOP-060
Supplement Version: 6
7-day study of the safety, efficacy and the pharmacokinetic and 
pharmacodynamic properties of oral rivaroxaban in children from birth to 
less than 6 months with catheter-related arterial or venous thrombosis
EINSTEIN Junior Phase I/II in children from birth to less than 6 months
Bayer study drug
BAY 59-7939/rivaroxaban/Xarelto
Clinical study 
phase:
I/II
Date:
09 Feb 2016
Study No.:
17618
Version:
1.0
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


Statistical Analysis Plan
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Table of Contents
1.
Introduction....................................................................................................................... 3
2.
Study Objectives................................................................................................................ 4
3.
Study Design ...................................................................................................................... 4
4.
General Statistical Considerations .................................................................................. 5
4.1
General Principles............................................................................................................ 5
4.2
Handling of Missing Data................................................................................................ 5
4.3
Interim Analyses and Data Monitoring ........................................................................... 5
4.4
Data Rules........................................................................................................................ 6
4.5
Validity Review ............................................................................................................... 6
5.
Analysis Sets ...................................................................................................................... 6
5.1
Assignment of analysis sets ............................................................................................. 6
6.
Statistical Methodology .................................................................................................... 7
6.1
Demographic and other baseline characteristics.............................................................. 7
6.2
Safety analysis ................................................................................................................. 7
6.3
Efficacy analysis .............................................................................................................. 8
6.4
PK/PD analysis ................................................................................................................ 8
7.
Document history and changes in the planned statistical analysis............................... 8
8.
References .......................................................................................................................... 8
Abbreviations
ADS
Analysis dataset
AE
adverse event
AUC
Area under the curve
BAY
sponsor’s reference number for drugs
CV
Coefficient of variation
DMC
data monitoring committee
DVT
deep vein thrombosis
eGFR
estimated glomerular filtration rate
Hb
hemoglobin
i.e.
id est, that is
IxRS
interactive voice/web response system
MedDRA
Medical Dictionary for Regulatory Activities


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mg
milligram
min
minute
ml
milliliter
PD
pharmacodynamics
PD
pharmacodynamics
PK
pharmacokinetic(s)
SAP
statistical analysis plan
1.
Introduction
This SAP is based on the integrated clinical study protocol version 2.0 (21 Jul 2015) and its 
local amendment 2 for Canada dated 22 September 2015.
The goal of the rivaroxaban pediatric program is to make rivaroxaban available to children for 
treatment and secondary prevention of VTE. To accomplish this goal, an age- and body 
weight adjusted dosing regimen has been developed and is being evaluated in a phase III 
program in children from 6 months to less than 18 years.
Children between birth and less than 6 months will be evaluated within separate studies 
because of distinct differences in the coagulation system, presentation of venous thrombosis 
and treatment requirements.
In this phase I/II study, children with confirmed symptomatic or asymptomatic catheter 
related arterial or venous thrombosis will be treated for 7 days with the age- and body weight-
adjusted rivaroxaban twice daily dosing regimen to achieve a similar exposure as that 
observed in adults treated for VTE with 20 mg rivaroxaban once daily.
Compared with adults, thrombosis is rare in children and often is a secondary complication of 
primary underlying medical conditions or of the use of central lines.
Treatment options are limited to heparins and VKA, which are cumbersome to manage due to 
the requirement for daily subcutaneous or intravenous injections and regular blood sampling 
for laboratory monitoring followed by dose adaptations. In children, the availability of an oral 
anticoagulant treatment that does not require subcutaneous or intravenous injections and 
regular blood sampling for laboratory monitoring, as is the case in adults, would be desirable.
To carefully allow for the evaluation of rivaroxaban in neonates and children younger than 6 
months with confirmed symptomatic or asymptomatic catheter related arterial or venous 
thrombosis, we elected to evaluate the selected rivaroxaban dose regimen first in children that 
have been treated with anticoagulant therapy for at least two weeks. If this study reveals that 
the selected rivaroxaban dose regimen results in a similar exposure as that observed with 20 
mg rivaroxaban in adults, and safety and efficacy is confirmed, a subsequent study will 
evaluate the selected rivaroxaban dose regimen for the acute and continued treatment of VTE.


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2.
Study Objectives
The primary objective is:

to characterize the pharmacokinetic/pharmacodynamic profile of a 7-day treatment 
with oral rivaroxaban
The secondary objectives are:

to assess the incidence of major bleeding and clinically relevant non-major bleeding

to assess the incidence of symptomatic recurrent thromboembolism and

to assess asymptomatic deterioration in the thrombotic burden on repeat imaging
3.
Study Design
This is a non-randomized, open label, multicenter study evaluating the safety, efficacy and 
PK/PD profile of a 7-day treatment with age- and body weight-adjusted oral rivaroxaban in 
neonates and infants younger than 6 months with symptomatic or asymptomatic catheter-
related arterial or venous thrombosis.
At least 8 children are planned to be enrolled in the study.
Study treatment consists of a 7-day treatment with an age- and body weight-adjusted twice 
daily oral rivaroxaban dosing to achieve a similar exposure as that observed in adults treated 
for venous thromboembolism (VTE) with 20 mg rivaroxaban once daily. Rivaroxaban will be 
provided as an oral suspension (1 mg/mL) using a b.i.d. regimen with 12-hour intervals in the 
morning and evening during or directly after feeding. If a rivaroxaban dose was missed, the 
child should take rivaroxaban immediately to ensure intake of the total daily dose per day. In 
this case, two oral suspension doses may be taken at once. The last dose of rivaroxaban 
treatment will be followed by a 30-day post study treatment period, regardless of the duration 
of study drug administration.
The principal safety outcome is the combination of major and clinically relevant non-major 
bleeding. The efficacy outcome is the composite of all symptomatic recurrent 
thromboembolism and asymptomatic deterioration in thrombotic burden on repeat imaging. 
All suspected recurrent thromboembolism, asymptomatic deterioration in thrombotic burden 
on repeat imaging, deaths, as well as all episodes of bleeding will be evaluated by a CIAC. 
Adjudication results will be the basis for the final analyses.
The data collection tool for this study will be a validated electronic system called RAVE and 
data will be entered into a validated database or data system (Tools for Syntactic Corpus 
Analysis [TOSCA]). Study data management will be performed in accordance with applicable 
Bayer’s standards. This is applicable for data recorded on eCRF as well as for data from other 
study sources. Internationally recognized and accepted dictionaries will be used for data 
coding.


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4.
General Statistical Considerations
4.1
General Principles
The statistical evaluation will be performed by using the software package SAS release 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA). All variables will be analyzed by descriptive 
statistical methods. The number of data available and missing data, mean, standard deviation, 
minimum, median, and maximum will be calculated for metric data if not otherwise specified. 
Frequency tables will be generated for categorical data.
Summary statistics will be presented for the subjects under active treatment, data of subjects 
which did not receive any study medication will be listed only
The analysis datasets (ADS) standards for Xarelto will be applied.
4.2
Handling of Missing Data
Missing data will not be estimated by specific methods for imputation of data. Possible 
impact of missing values on the analysis will be discussed in the clinical study report.
All missing or partial data will be presented in the corresponding summary tables and in the 
subject data listing as they are recorded on the Case Report Form (CRF).
4.3
Interim Analyses and Data Monitoring
No interim analysis will be performed.


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A data monitoring committee (DMC) has the responsibility to provide the steering committee 
with recommendations related to the protection of the children’s safety, including stopping 
recruitment and study treatment. For that purpose, the DMC will regularly review all 
incidences of serious adverse events, recurrent venous or arterial thromboembolic events and 
bleeding, and PK/PD results.
4.4
Data Rules
All reported medication intake by the children that stopped at least one day before the date of 
first study drug intake will be considered as previous medication, otherwise as concomitant 
medication.
Baseline is defined as the last observation prior to the first dose of study medication.
Arithmetic means will be calculated and used for tables and figures in case of repeated 
measurements for the same subject, timepoint, laboratory, and laboratory test.
In case of laboratory measurements from different laboratories with different normal ranges, 
ULN-normalized values will be calculated and used for tables and figures, if applicable. In 
case of missing upper limit of normal information, values will be listed only.
Phase I pool reference data for rivaroxaban plasma concentration, PT, and aPTT 
measurements to be used are given in
/by-sasp/patdb/projects/597939/xa_ph1_reports/stat/test_epbka/pip/pip_data.sas7bdat,
and by the corresponding high dose age groups of the Phase I pediatric study 12892 in
/by-sasp/patdb/projects/597939/12892/dm/prod/data/ad.
4.5
Validity Review
The results of the Validity Review Meeting will be documented in the Validity Review 
Report and may comprise decisions and details relevant for statistical evaluation. Any 
relevant changes to the statistical analysis prompted by the results of the validity review 
meeting might be documented in an amendment or, if applicable, in a supplement to this SAP.
5.
Analysis Sets
5.1
Assignment of analysis sets
Final decisions regarding the assignment of subjects to analysis sets will be made during the 
Validity Review Meeting and documented in the Validity Review Report (see section 0).
Full analysis set: This analysis set will include all children from whom informed consent was 
obtained.
Safety analysis set: This analysis set will include all children who received at least one dose 
of rivaroxaban.


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Per protocol analysis set: This population includes all children who completed the 7 day 
treatment period or had an efficacy or bleeding outcome before. This analysis set may exclude 
major protocol deviations.
Listing only set (LoS): this population includes all screening failures.
All subjects with at least 1 PK sample in accordance with the PK sampling strategy will be 
included in the PK analysis (PK analysis set).
All subjects with at least 1 blood sample for clotting parameters in accordance with the PD 
sampling strategy will be included in the PD analysis (PD analysis set).
6.
Statistical Methodology
6.1
Demographic and other baseline characteristics
Summary statistics (arithmetic mean, standard deviation, median, minimum and maximum for 
quantitative variables) will be presented by total safety analysis set. Frequency tables for 
qualitative data will be provided. Medical history findings will be summarized using Medical 
Dictionary for Regulatory Activities (MedDRA) terms.
6.2
Safety analysis
Adverse events
All safety analyses will be performed on the safety population. The analysis will primarily 
focus on bleeding that occurred during or within 2 days after stop of rivaroxaban. Bleeding 
events observed later will be described separately. Individual listings of major and clinically 
relevant non-major bleeding will be provided. The incidence of bleeding will be summarized. 
If a sufficient number of bleeding events is observed, factors which potentially influence the 
occurrence of bleeding will be assessed by appropriate statistical procedures. Quantitative 
data will be described by the summary statistics and will be presented for the original data as 
well as for the difference to baseline. Frequency tables will be provided for qualitative data.
Safety parameters
Quantitative data (hematology, blood chemistry, pulse rate) will be described by the following 
summary statistics: arithmetic mean, standard deviation, median, minimum and maximum. 
These summary statistics will be presented for the original data, as well as for the difference 
to baseline. Frequency tables will be provided for qualitative data. Laboratory data outside the 
reference range will be listed and flagged with 'L' for low and 'H' for high. Additional tables 
with all abnormal values will be presented.
Graphical displays of individual data as well as mean values with standard deviation will be 
included.


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6.3
Efficacy analysis
All efficacy analyses will be performed on the full analysis set population. The incidence of 
symptomatic recurrent venous thromboembolism and asymptomatic deterioration in 
thrombotic burden on repeat imaging will be summarized.
6.4
PK/PD analysis
Pharmacokinetic data
The concentration-times courses of rivaroxaban will be tabulated for each sampling interval. 
The following statistics will be calculated for each of the sampling intervals: arithmetic mean, 
standard deviation and coefficient of variation (CV), geometric mean, geometric standard 
deviation (re-transformed standard deviation of the logarithms) and CV, minimum, median, 
maximum value and the number of measurements. Means for any interval will only be 
calculated if at least 2/3 of the individual data were measured and were above the lower limit 
of quantification (LLOQ). For the calculation of the mean value a data point below LLOQ 
will be substituted by one half of this limit. In tables showing mean values, where values 
below LLOQ are included in the calculation of mean values, these means will be marked.
Individual and geometric mean concentration vs time curves of rivaroxaban (using the actual 
sampling times for individual plots and the planned sampling intervals for mean plots) will be 
plotted using both linear and semilogarithmic scale.
If applicable, pharmacokinetic characteristics derived via popPK modeling (tmax excluded) 
will be summarized by the statistics mentioned above. tmax will be described utilizing 
minimum, maximum and median as well as frequency counts.
Comparison with reference data will be graphically sketched.
Pharmacodynamic data
Results for pharmacodynamic data will be displayed using appropriate summary statistics and 
figures.
If applicable, the pharmacodynamic data will be analyzed for any relationship to Cmax and 
Ctrough. In addition, the PK/PD relationship will be investigated in an exploratory manner and 
compared to the reference data.
Comparison with reference data will be graphically sketched.
In case of any finding, further explorative investigations may be done.
7.
Document history and changes in the planned statistical analysis
Not applicable.
8.
References
Not applicable.