Clinical trial NCT02309411
Conditions: Venous Thromboembolism
Keywords: Pediatric
Sponsor: Bayer
Start date: 2015-01-15; Completion date: 2017-04-05
Enrollment: 46 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out whether rivaroxaban is safe to use in children and how long it stays 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:

Arms: arm 1: 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
Interventions: intervention 1: Rivaroxaban (Xarelto, BAY59-7939)
Intervention descriptions: intervention 1: With age and body-weight adjusted twice daily dosing of rivaroxaban as Oral Suspension to achieve a similar exposure as that observed in adults treated with 20 mg rivaroxaban once daily, and no other anticoagulant

Protocol documents:
Prot_000.pdf: 
 
Document Type: Study Protocol 
Official Title: 
30-day, single-arm study of the safety, efficacy and the 
pharmacokinetic and pharmacodynamic properties of oral 
rivaroxaban in young children with various manifestations of 
venous thrombosis 
NCT Number: 
NCT02309411 
Document Date: 
14 Apr 2015 
 


Integrated Clinical Study Protocol
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Cover page of the integrated protocol
30-day, single-arm study of the safety, efficacy and the pharmacokinetic and 
pharmacodynamic properties of oral rivaroxaban in young children with various 
manifestations of venous thrombosis1
This protocol version is an integration of the following documents / sections:

Original protocol, Version 1.0, dated 04 Mar 2014

Amendment 1 (global amendment described in Section 16.1)
forming integrated protocol Version 2.0, dated 02 Sep 2014

Amendment 2 (local amendment Japan), dated 21 Oct 2014

Amendment 3 (local amendment Canada), dated 28 Oct 2014

Amendment 4 (global amendment described in Section 16.2)
forming integrated protocol Version 3.0, dated 14 Apr 2015
This document integrates the original protocol and all global amendments.
                                                                                                                                                      
1 Title was modified via Amendment 4 (see Section 16.2.2.1)


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Title page
30-day, single-arm study of the safety, efficacy and the pharmacokinetic and 
pharmacodynamic properties of oral rivaroxaban in young children with various 
manifestations of venous thrombosis2
EINSTEIN Junior Phase II-part B: oral rivaroxaban in young children with venous 
thrombosis
Test drug:
BAY 59-7939/rivaroxaban
Clinical study phase:
II
Date:
14 Apr 2015
EudraCT no.:
2014-000566-22
Version no.: 3.0
Study no.:
BAY 59-7939/14374
Sponsor:
Bayer HealthCare AG,  D-51368 Leverkusen, Germany
24-hour medical emergency contact
Telephone: 
Email:
Non-emergency medical and protocol issues contact  
Bayer HealthCare Pharmaceuticals
Brazil
Telephone: 
Email:
The study will be conducted in compliance with the protocol, International Conference on 
Harmonization-Good Clinical Practice (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 this study. Reproduction or disclosure of this document - whether in part or 
in full - to parties not associated with this study, or its use for any other purpose, without the 
prior written consent of Bayer Health Care 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.
                                                                                                                                                      
2 Title was modified via Amendment 4 (see Section 16.2.2.1)
PPD
PPD
PPD
PPD
PPD
PPD
PPD


EB Bayer HealthCare 
14 Apr 2015 
Integrated Clinical Study Protocol 
No. BA Y 59-7939/14374 
Version 3.0 
Medically responsible person of Bayer 
The signatory agrees to the content of the final clinical study protocol as presented. 
 
Date: 
Signature: 
, 
Page: 3 of79 
PPD
PPD
PPD


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Study center’s principal investigator
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
Affiliation:
Date:
Signature:


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Synopsis - amended
Title
30-day, single-arm study of the safety, efficacy and the 
pharmacokinetic and pharmacodynamic properties of oral 
rivaroxaban in young children with various manifestations of 
venous thrombosis.3
Short title
Einstein Junior Phase II-part B: Oral rivaroxaban in young 
children with venous thrombosis
Clinical study phase
II 
Study objectives
The primary objective is:

to assess the incidence of major bleeding and clinically 
relevant non-major bleeding
The secondary objectives are:

to assess the incidence of recurrent venous 
thromboembolism

to assess asymptomatic deterioration in the thrombotic 
burden on repeat imaging

to characterize the pharmacokinetic/pharmacodynamic 
profile of a 30-day treatment with oral rivaroxaban.
Experimental study 
drug
Rivaroxaban
Name of active 
ingredient
Rivaroxaban 
Dose
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 4
Route of administration
Oral suspension 
Duration of treatment
30 days
Comparator study drug
Not applicable5
Name of active 
ingredient
Not applicable5
Dose
Not applicable5
Route of administration
Not applicable5
Duration of treatment
Not applicable5
                                                                                                                                                      
3 Title was modified via Amendment 4 (see Section 16.2.2.1)
4 Error in the dose frequency was corrected in amendment 1 (see Section 16.1.2.1)
5 Comparator arm was removed via Amendment 4 (see Section 16.2.2.2)


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Indication
Young children with documented venous thrombosis, 
including deep vein thrombosis of the lower extremity, caval 
vein thrombosis, right atrial thrombosis, pulmonary embolism, 
deep vein thrombosis of the upper extremity, subclavian vein 
thrombosis, jugular vein thrombosis, and cerebral vein and 
sinus thrombosis,  mesenteric vein thrombosis, portal vein 
thrombosis, renal vein thrombosis or catheter-related 
thrombosis
Diagnosis and main 
criteria for inclusion
Children aged 6 months to < 6 years with documented 
symptomatic or asymptomatic venous thrombosis treated for 
at least 2 months or, in case of catheter-related thrombosis, 
treated for at least 6 weeks with LMWH, fondaparinux and/or 
VKA.6
The imaging of the index thrombotic event will be confirmed 
by the central independent adjudication committee (CIAC).
Study design
Single-arm, multicenter study7
Methodology
Children will receive rivaroxaban according to an age- and 
body weight-adjusted regimen.
The study treatment period is for a total of 30 days followed 
by an observational period of another 30 days. 
All suspected clinical study outcomes and baseline and repeat 
thrombosis imaging tests will be assessed by a CIAC.
An independent data monitoring committee (DMC) will 
monitor the children’s safety and give recommendations to the 
steering committee. 8
Number of children
20 children (10 per age group) treated with rivaroxaban. 9
                                                                                                                                                      
6 Inclusion criteria modified via Amendment 4 (see Section 16.2.2.2)
7 Title was modified via Amendment 4 (see Section 16.2.2.1)
8 Comparator arm was removed via Amendment 4 (see Section 16.2.2.2)
9 Total number of subjects was reduced via Amendment 4 (see Section 16.2.2.2)


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Inclusion/exclusion 
criteria
Inclusion
1. Children aged 6 months to < 6 years who have been 
treated for at least 2 months or, in case of catheter 
related thrombosis, for at least 6 weeks with LMWH, 
fondaparinux and/or VKA for documented 
symptomatic or asymptomatic venous thrombosis 
2. Hemoglobin, platelets, creatinine, alanine 
aminotransferase (ALT) and bilirubin evaluated 
within 10 days prior to Visit 210
3. Informed consent provided 
Exclusion
1. Active bleeding or high risk for bleeding 
contraindicating anticoagulant therapy
2. Symptomatic progression of venous thrombosis 
during preceding anticoagulant treatment
3. Planned invasive procedures, including lumbar 
puncture and removal of non-peripherally placed 
central lines during study treatment
4. An estimated glomerular filtration rate (eGFR) 
< 30 mL/min/1.73 m2
5. Hepatic disease which is associated with either: 
coagulopathy leading to a clinically relevant bleeding 
risk, or ALT > 5x upper level of normal (ULN) or 
total bilirubin > 2x ULN with direct bilirubin > 20% 
of the total
6. Platelet count < 50 x 109/L  11
7. Hypertension defined as > 95th age percentile 12
8. Life expectancy < 3 months
9. Concomitant use of strong inhibitors of both 
cytochrome P450 isoenzyme 3A4 (CYP3A4) and 
P-glycoprotein (P-gp), i.e. all human 
immunodeficiency virus protease inhibitors and the 
following azole-antimycotics agents: ketoconazole, 
itraconazole, voriconazole, posaconazole, if used 
systemically (fluconazole is allowed)
                                                                                                                                                      
10 Comparator arm was removed via Amendment 4 (see Section 16.2.2.2)
11 Definition of thrombocytopenia adjusted via Amendment 4 (see Section 16.2.2.2)
12 see Figure 1–1 and Table 1–1


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Inclusion/exclusion 
criteria (continued)
10. Concomitant use of strong inducers of CYP3A4, i.e.
rifampicin, rifabutin, phenobarbital, phenytoin and 
carbamazepine
11. Hypersensitivity or any other contraindication listed in 
the local labeling for the experimental treatment
12. Inability to cooperate with the study procedures 
13. Previous enrollment to this study
14. Participation in a study with an investigational drug or 
medical device within 30 days prior to Visit 2. 13
Primary outcome 
Composite of major and clinically relevant non-major 
bleeding 
Secondary outcome
Composite of all recurrent venous thromboembolism and 
asymptomatic deterioration on repeat imaging; results of 
pharmacokinetics (PK) / pharmacodynamics (PD).
Statistical Analysis Plan
The incidence of the composite of major and clinically 
relevant non-major bleeding and the incidence of 
symptomatic recurrent venous thromboembolism, and 
asymptomatic deterioration in the thrombotic burden on 
repeat imaging will be summarized descriptively. 
Quantitative data will be described by summary statistics and 
presented by age.
Results of PK/PD analyses will be assessed descriptively. 14
                                                                                                                                                      
13 Comparator arm was removed via Amendment 4 (see Section 16.2.2.2)
14 Statistical Analysis Plan modified via Amendment 4 (see Section 16.2.2.2)


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Figure 1–1: Flow chart
Screen a
Treatment period 
30 day post study 
treatment contact
Visit 
1
2
3
4
5
Days
Day -60 
to
Day -10
Day 1
Day 15
5 days
Day 30
± 3 days
Day 60
7 days
Obtain informed consent
●
Check in-/exclusion criteria
●
Obtain demographic data
●
Check medical history
●
●
Record anticoagulant medication
●
●
Obtain height/length, and  blood  
pressure
●
Obtain body weight
●
●
Check Hb, platelets, creatinine, 
ALT, bilirubin
●b
Send baseline adjudication 
package 
●
Review the CIAC decision for 
index thrombotic event for final 
eligibility c
●
Re-confirm in-/exclusion criteria c
●
Provide  patient details to IxRS
●
Dispense study medication
Instruct how to take study 
medication
Provide study booklet
Provide  Rivaroxaban Oral 
Suspension Handling Guidelines to 
parents
●
●
●
●
Record all concomitant 
medication
●
●
●
●
Check for study outcomes d
●
●
●
Check adverse events
●
●
●
●
Check Hb, platelets, ALT, 
bilirubin
●
Check drug accountability and 
compliance e
●
●
Repeat imaging and send 
adjudication package
●
Check if anticoagulant treatment 
continued after Visit 4
●
Complete eCRF 
●
●
●
●
●
Pharmacokinetics and 
pharmacodynamics f
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Time point (hours)
0.5-1.5 hr post 
dose
2.5-4 hr   
post 
dose
2-8 hr
post dose
10-16 hr 
post dose
Obtain blood sample for 
pharmacokinetics h
●
●
●
●
Obtain blood sample for 
pharmacodynamics i,j
●
●
●
Administer rivaroxaban  at study 
site k
●
●
Complete Taste-and-Texture
Questionnaire l
●
for footnotes please see following page


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a The screening visit can be performed up to 60 days prior 
to Visit 2, but should not be less than 10 days prior to 
Visit 2. Please contact the adjudication office in case the 
available period prior to Visit 2 is less than 10 days.
b Results should be available within 10 days prior to 
Visit 2, if not obtain blood sample at visit 2.      
c Done before the study drug intake.
d If suspected outcome occurred, the adjudication package 
needs to be compiled and sent to the adjudication office.
f The approximate total blood volume taken per child is 
10 mL if blood taken via venipuncture, and 22 mL if 
blood taken via central venous line or peripheral 
catheter.
g PK/PD sampling only if the child received rivaroxaban 
for more than 3 days
h Blood volume per PK sample is 1.2 mL; total 
blood volume for all PK samples is 4.8 mL
i Blood volume per PD sample is 1.8 mL; total 
blood volume for all PD samples is 5.4 mL
j Always draw the pharmacodynamic sample as the 
last sample
k For switching from heparin, 
LMWH/fondaparinux, VKA see section 5.1.1
l Taste and texture questionnaire to be completed in 
part before and after the study drug intake (only 
children > 4 years old) 15
eCRF: electronic case report form; Hb: 
Hemoglobin; INR: International normalized 
ratio; IxRS: interactive voice/web response 
system
                                                                                                                                                      
15 Flow chart modified via Amendment 4 (see Section 16.2.2.2)


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Blood pressure levels for children
Figure 1–2: Age percentiles for blood pressure in children from birth to 12 months of 
age
Source: (15)
Table 1–1: Age and Height percentiles for blood pressure in children from 1 to 6 
years of age
Boys
Systolic blood pressure, mmHg
Diastolic blood pressure, mmHg
Age
Percentile of height
Percentile of height
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
1
98
99
101
103
104
106
106
54
54
55
56
57
58
58
2
101
102
104
106
108
109
110
59
59
60
61
62
63
63
3
104
105
107
109
110
112
113
63
63
64
65
66
67
67
4
106
107
109
110
112
114
115
66
67
68
69
70
71
71
5
108
109
110
112
114
115
116
69
70
71
72
73
74
74
6
109
110
112
114
115
117
117
72
72
73
74
75
76
76
Girls
Systolic blood pressure, mmHg
Diastolic blood pressure, mmHg
Age
Percentile of height
Percentile of height
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
1
100
101
102
104
105
106
107
56
57
57
58
59
59
60
2
102
103
104
105
107
108
109
61
62
62
63
64
65
65
3
104
104
105
107
108
109
110
65
66
66
67
68
68
69
4
105
106
107
108
110
111
112
68
68
    69
70
71
71
72
5
107
107
108
110
111
112
113
70
71
71
72
73
73
74
6
108
109
110
111
113
114
115
72
72
73
74
74
75
76
Shown are 95th percentiles for blood pressure. Source: (14)


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Table of contents
Cover page of the integrated protocol....................................................................................... 1
Title page................................................................................................................................... 2
Medically responsible person of Bayer..................................................................................... 3
Study center’s principal investigator......................................................................................... 4
Synopsis - amended................................................................................................................... 5
Table of contents..................................................................................................................... 12
List of tables............................................................................................................................ 15
List of figures .......................................................................................................................... 15
List of abbreviations................................................................................................................ 16
1.
Introduction - amended .................................................................................................... 18
1.1
Rivaroxaban.............................................................................................................. 19
1.2
Various manifestations of venous thrombosis.......................................................... 19
1.3
Rationale of the study and risk-benefit assessment - amended ................................ 19
2.
Study objectives ............................................................................................................... 20
3.
Study design - amended ................................................................................................... 21
4.
Study population .............................................................................................................. 22
4.1
Planned number of children - amended.................................................................... 22
4.2
Inclusion criteria - amended ..................................................................................... 22
4.3
Exclusion criteria - amended .................................................................................... 22
4.4
Concomitant medication - amended......................................................................... 23
5.
Treatment regimen - amended.......................................................................................... 23
5.1
Treatment - amended................................................................................................ 23
5.1.1
Rivaroxaban - amended .................................................................................... 23
5.1.1.1
Switching from VKA to rivaroxaban - amended ...................................... 24
5.1.1.2
Switching from heparin/fondaparinux to rivaroxaban - amended............. 24
5.1.1.3
Switching from rivaroxaban to heparin/fondaparinux - amended............. 25
5.1.1.4
Switching from rivaroxaban to VKA - amended ...................................... 25
5.1.2
Comparator group - amended ........................................................................... 25
5.2
Subject identification - amended .............................................................................. 25
5.3
Duration of study treatment...................................................................................... 25
5.4
Formulation and dose ............................................................................................... 25
5.4.1
Rivaroxaban - amended .................................................................................... 25
5.4.2
Comparator - amended...................................................................................... 26
5.5
Packaging, labeling, and storage - amended............................................................. 26
5.6
Treatment assignment - amended............................................................................. 26
5.7
Dosage and administration - amended...................................................................... 26
5.8
Treatment compliance - amended............................................................................. 26
5.8.1
Rivaroxaban ...................................................................................................... 26
6.
Study Procedures.............................................................................................................. 27
6.1
Study visits - amended.............................................................................................. 27
6.2
Visit 1 - Screening visit at 60 to 10 days before Visit 2 - amended ......................... 27
6.3
Visit 2 - Treatment visit at Day 1 - amended ........................................................... 28
6.4
Visit 3 - Treatment visit at Day 15 (+/- 5 days) - amended...................................... 29
6.5
Visit 4 - End of study treatment visit at Day 30 (+/- 3 days) - amended.................. 30


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6.6
Visit 5 - 30 day post treatment contact at Day 60 (+/- 7 days)................................. 31
6.7
Unscheduled visits.................................................................................................... 31
6.8
Safety outcomes........................................................................................................ 31
6.9
Recommendations before and after invasive procedures and surgical intervention -
amended.................................................................................................................... 32
6.10
Management of bleeding in children - amended ...................................................... 32
6.11
Efficacy outcome...................................................................................................... 32
6.12
PK/PD assessments - amended................................................................................. 32
6.13
Study booklet - amended .......................................................................................... 33
6.14
Study committees ..................................................................................................... 33
6.14.1
Steering committee ........................................................................................... 33
6.14.2
Central independent adjudication committee (CIAC) ...................................... 34
6.14.3
Data monitoring committee (DMC).................................................................. 34
7.
Statistical and analytical methods .................................................................................... 34
7.1
General considerations ............................................................................................. 34
7.2
Analysis sets - amended ........................................................................................... 35
7.3
Demographic and other baseline characteristics - amended..................................... 35
7.4
Safety analysis - amended ........................................................................................ 35
7.5
Efficacy analysis - amended..................................................................................... 35
7.6
PK/PD analysis......................................................................................................... 35
7.7
Interim analyses........................................................................................................ 36
7.8
Determination of sample size - amended ................................................................. 36
7.9
Adverse events (AE) - amended............................................................................... 36
7.9.1
Definitions......................................................................................................... 36
7.9.1.1
Adverse event (AE) ................................................................................... 36
7.9.1.2
Serious adverse event (SAE)..................................................................... 37
7.9.1.3
Unexpected AEs ........................................................................................ 37
7.9.2
Relationship of AE to the study drug................................................................ 37
7.9.3
Causal relationship to protocol-required procedure.......................................... 37
7.9.4
Intensity of an AE, action taken and outcome .................................................. 38
7.9.5
Assessments and documentation of adverse events.......................................... 38
7.9.6
Reporting of serious adverse events.................................................................. 38
7.9.7
Study specific exceptions to the (S)AE reporting............................................. 38
7.9.8
Expected AEs.................................................................................................... 39
7.9.9
AEs of special safety interest - amended .......................................................... 39
7.10
Premature discontinuation of study medication ....................................................... 39
7.11
Appropriateness of procedures/measurements ......................................................... 40
8.
Data handling and quality assurance................................................................................ 40
8.1
Data processing......................................................................................................... 40
8.2
Audit and inspection................................................................................................. 40
8.3
Archiving.................................................................................................................. 40
9.
Premature termination of the study.................................................................................. 41
10. Ethical and legal aspects .................................................................................................. 41
10.1
Ethical and legal conduct of the study...................................................................... 41
10.2
Child information and consent ................................................................................. 42
11. Investigators and other study participants........................................................................ 43


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12. Publication policy............................................................................................................. 43
13. Insurance for children ...................................................................................................... 43
14. Confidentiality.................................................................................................................. 43
15. Reference list.................................................................................................................... 44
16. Protocol amendments....................................................................................................... 46
16.1
Amendment 1 ........................................................................................................... 46
16.1.1
Overview of changes......................................................................................... 46
16.1.1.1
Modification 1: Correction of erroneous dosing information ................... 46
16.1.1.2
Modification 2: Adjustment of suspension information............................ 46
16.1.2
Changes to the protocol text.............................................................................. 46
16.1.2.1
Synopsis..................................................................................................... 47
16.1.2.2
Section 5.1.1  Rivaroxaban group ............................................................. 49
16.1.2.3
Section 6.3  Visit 2 - Randomization visit at Day 1................................... 50
16.1.2.4
Section 6.4  Visit 3 - Treatment visit at Day 15 (+/- 5 days) .................... 52
16.1.2.5
Section 6.5 Visit 4 - End of study treatment visit at Day 30 (+/- 3 days) . 53
16.2
Amendment 4 ........................................................................................................... 54
16.2.1
Overview of changes......................................................................................... 54
16.2.1.1
Change 1: Minor clarifications for consistency......................................... 54
16.2.1.2
Change 2: Comparator arm was removed ................................................. 54
16.2.1.3
Change 3: Total number of subjects was reduced..................................... 55
16.2.1.4
Change 4: Modification of inclusion criterion 1 ....................................... 55
16.2.1.5
Change 5: Addition of switch from rivaroxaban to standard of care ........ 55
16.2.1.6
Change 6: Modification of exclusion criterion 6....................................... 56
16.2.2
Changes to the protocol text.............................................................................. 56
16.2.2.1
Title page................................................................................................... 56
16.2.2.2
Synopsis..................................................................................................... 56
16.2.2.3
Section 1: Introduction .............................................................................. 61
16.2.2.4
Section 1.3: Rationale of the study and risk-benefit assessment............... 62
16.2.2.5
Section 3: Study design ............................................................................. 62
16.2.2.6
Section 4.1: Planned number of children .................................................. 63
16.2.2.7
Section 4.2: Inclusion criteria.................................................................... 63
16.2.2.8
Section 4.3: Exclusion criteria................................................................... 64
16.2.2.9
Section 4.4: Concomitant medication........................................................ 65
16.2.2.10
Section 5: Treatment groups and regimens ............................................... 65
16.2.2.11
Section 5.1: Treatment............................................................................... 66
16.2.2.12
Section 5.1.1: Rivaroxaban group ............................................................. 66
16.2.2.13
Section 5.1.1.1: Switching from VKA to rivaroxaban .............................. 66
16.2.2.14
Section 5.1.1.2: Switching from heparin/fondaparinux to rivaroxaban .... 67
16.2.2.15
New Section 5.1.1.3: Switching from rivaroxaban to heparin/fondaparinux
67
16.2.2.16
New Section 5.1.1.4: Switching from rivaroxaban to VKA...................... 67
16.2.2.17
Section 5.1.2: Comparator group............................................................... 67
16.2.2.18
Section 5.2: Subject identification............................................................. 68
16.2.2.19
Section 5.4.1: Rivaroxaban........................................................................ 68
16.2.2.20
Section 5.4.2: Comparator......................................................................... 68
16.2.2.21
Section 5.5: Packaging, labeling, and storage ........................................... 68


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16.2.2.22
Section 5.6: Treatment assignment............................................................ 69
16.2.2.23
Section 5.7: Dosage and administration .................................................... 69
16.2.2.24
Section 5.8: Treatment compliance ........................................................... 70
16.2.2.25
Section 6.1: Study visits ............................................................................ 70
16.2.2.26
Section 6.2: Visit 1 - Screening visit at 60 to 10 days before Visit 2........ 71
16.2.2.27
Section 6.3. Visit 2 - Treatment visit at Day 1 .......................................... 72
16.2.2.28
Section 6.4: Visit 3 - Treatment visit at Day 15 (+/- 5 days) .................... 74
16.2.2.29
Section 6.5: Visit 4 - End of study treatment visit at Day 30 (+/- 3 days) 74
16.2.2.30
Section 6.9: Recommendations before and after invasive procedures and 
surgical intervention .................................................................................. 75
16.2.2.31
Section 6.10: Management of bleeding in children................................... 75
16.2.2.32
Section 6.12: PK/PD assessments ............................................................. 75
16.2.2.33
Section 6.13: Study booklet....................................................................... 76
16.2.2.34
Section 7.2: Analysis sets.......................................................................... 76
16.2.2.35
Section 7.3: Demographic and other baseline characteristics ................... 76
16.2.2.36
Section 7.4: Safety analysis....................................................................... 77
16.2.2.37
Section 7.5: Efficacy analysis.................................................................... 77
16.2.2.38
Section 7.8: Determination of sample size................................................ 77
16.2.2.39
Section 7.9: Adverse events (AE) ............................................................. 78
16.2.2.40
Section 7.9.9: AEs of special safety interest ............................................. 78
17. Appendices....................................................................................................................... 79
17.1
Methods and measurements...................................................................................... 79
17.2
Estimated glomerular filtration rate.......................................................................... 79
List of tables
Table 1–1: Age and Height percentiles for blood pressure in children from 1 to 6 years of 
age..................................................................................................................... 11
Table 5–1: Rivaroxaban dosing schedule................................................................................. 24
List of figures
Figure 1–1: Flow chart ............................................................................................................... 9
Figure 1–2: Age percentiles for blood pressure in children from birth to 12 months of age... 11


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List of abbreviations
ACCP
American College of Chest Physicians
AE
adverse event
AG
Aktiengesellschaft, joint stock company
ALT
alanine aminotransferase
anti-Xa
anti-factor Xa activity
aPTT
activated or adjusted partial thromboplastin time
BAY
sponsor’s reference number for drugs
BHC
Bayer HealthCare
b.i.d.
twice daily
CCDS
Company Core Data Sheet
CIAC
central independent adjudication committee
CNS
Central nervous system
CRO
contract research organization
CT
computed tomography
CYP3A4
cytochrome P450 isoenzyme 3A4
dL
deciliter
DMC
data monitoring committee
DVT
deep vein thrombosis
eCRF
electronic case report form
e.g.
exempli gratia, for example
eGFR
estimated glomerular filtration rate
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trial (number)
FAS
full analysis set
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
Hb
Hemoglobin
IB
investigator’s brochure
ICH
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceutical for Human Use
IDMS
isotope dilution mass spectrometry
i.e.
id est, that is
IEC
Independent Ethics Committee
INR
international normalized ratio 
IRB
Institutional Review Board
IxRS
interactive voice/web response system
LLC
Liability Limited Company
LMWH
low molecular weight heparin
LOS
listing only set
MedDRA
Medical Dictionary for Regulatory Activities
mL
milliliter
mmHg
millimeters of mercury
MR(I)
Magnetic resonance (imaging)
NSAIDs
non-steroid anti-inflammatory drugs
o.d.
once daily
OMP
Ortho McNeil Pharmaceuticals, Inc.
PD
Pharmacodynamics
PE
pulmonary embolism
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PPS
per protocol set
RAVE
internet/web-based electronic data capture computer system


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SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
SCr
serum creatinine
SID
child identification number
SUSAR
Suspected Unexpected Serious Adverse Reaction
TOSCA
Tools for Syntactic Corpus Analysis database system
u
Units
UFH
unfractionated heparin
ULN
upper limit of normal
VKA
vitamin K antagonist
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), bodyweight-adjusted 
subcutaneous low molecular weight heparin (LMWH), or bodyweight-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, this 
includes the requirement for intravenous or subcutaneous injection and monitoring of the 
activated partial thromboplastin time (aPTT). For VKA, this includes 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 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 venous thromboembolism.  To accomplish this goal, it 
will be necessary to evaluate a pediatric age- and body weight adapted dosing regimen, and to 
address the safety and efficacy of rivaroxaban.16
The study will be initiated with the age group between 2 and less than 6 years. Once the age-
and body weight adjusted dosing regimen has been finally confirmed for the age group
between 6 months and less than 2 years in phase I, and approved by the data monitoring 
committee and steering committee, enrollment will be extended to this age group. Before 
enrollment of this age group is implemented and the interactive voice/web response system 
(IxRS) is activated, the investigators and their Institutional Review Boards (IRBs) will receive 
a formal notification, specifying the exposure results and safety outcomes.
In this phase II study, children with confirmed venous thrombosis will be treated for 30 days 
with the age- and body weight adapted rivaroxaban dosing regimen to achieve an exposure 
that is equivalent to the 20 mg rivaroxaban dose in adults.
                                                                                                                                                      
16 Comparator arm was removed via Amendment 4 (see Section 16.2.2.3)


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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 venous thromboembolism (VTE) following elective hip or knee replacement 
surgery, for treatment and secondary prevention of deep-vein thrombosis (DVT) and 
pulmonary embolism (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
Various manifestations of venous thrombosis 
Compared with adults, venous thrombosis is rare in children.  Venous thrombosis in children 
is often provoked by a variety of risk factors and rarely is idiopathic in nature.(6) Expressions 
of venous thrombosis that usually require anticoagulant therapy include deep vein thrombosis 
of the lower extremity, caval vein thrombosis, renal vein thrombosis, right atrial thrombosis, 
pulmonary embolism, deep vein thrombosis of the upper extremity, subclavian vein 
thrombosis, jugular vein thrombosis, mesenteric vein thrombosis, portal vein thrombosis, and 
cerebral vein and sinus thrombosis.
A Canadian registry published in 1994 highlighted that central venous lines were the single 
most important predisposing cause of venous thrombosis in children (33%), whereas inherited 
coagulation disorders accounted for 9%.  Venous thrombosis was associated with cancer 
(23%), congenital heart disease (15%), and trauma (15%).(7) The only randomized venous 
thrombosis treatment study in children (the REVIVE study) confirmed that cancer and
infections followed by congenital heart disease were the most frequently reported risk 
factors.(8)
In the REVIVE study, children with cerebral vein and sinus thrombosis were at that time 
excluded due to lack of consensus on the need for anticoagulation.  Risk factors for recurrent 
VTE in the European collaborative pediatric database on cerebral venous thrombosis include 
age at onset, absence of anticoagulant treatment, persistent venous occlusion, or presence of 
the prothrombin gene mutation.(9) The current treatment recommendation for cerebral vein and 
sinus thrombosis is therapeutic doses of anticoagulants.(10)
Currently, the recommendations for the initial treatment of various manifestations of venous 
thrombosis is activated partial thromboplastin time (aPTT) adjusted unfractionated heparin 
(UFH), body weight adjusted low molecular weight heparin (LMWH) or fondaparinux.  For 
subsequent treatment, either INR titrated vitamin K antagonist (VKA) or body weight 
adjusted LMWH is recommended.  For cases of catheter-related thrombosis, the current 
American College of Chest Physicians (ACCP) guidelines recommend a total duration of 
anticoagulation of between 6 weeks and 3 months (10).
1.3
Rationale of the study and risk-benefit assessment - amended
Treatment with heparins and VKA is limited because of 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 


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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 children with thrombotic disease, it is 
mandatory to assess the efficacy and safety in a step-wise approach. Anticoagulant treatment 
for the acute episode of venous thrombosis is characterized by a high risk for recurrent 
thrombotic complications (although significantly reduced compared to no anticoagulant 
treatment) combined with a high risk for bleeding. Typically, these risks diminish 
considerably after the first month of anticoagulant treatment and remain stable thereafter. 
Therefore, we elected to evaluate the selected rivaroxaban dose regimen after the completion 
of a minimum period of 2 months or, in the case of catheter related thrombosis, treatment for 
at least 6 weeks with standard of care medication.17 If this study reveals that the selected 
rivaroxaban dose regimen is safe and without evidence of loss of efficacy, subsequent studies 
might evaluate rivaroxaban also for the treatment in children with symptomatic VTE. 
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 EINSTEIN PE (11) studies in adults, 
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 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 (AEs) 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.
2.
Study objectives
The primary objective is:

to assess the incidence of major bleeding and clinically relevant non-major bleeding
The secondary objectives are:

to assess the incidence of recurrent symptomatic venous thromboembolism

to assess asymptomatic deterioration in the thrombotic burden on repeat imaging

to characterize the pharmacokinetic/pharmacodynamic profile of a 30-day treatment 
with oral rivaroxaban.
                                                                                                                                                      
17 Section modified via Amendment 4 (see Section 16.2.2.4)


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3.
Study design - amended
This is a single-arm, multicenter study evaluating the safety, efficacy and PK/PD profile of a 
30-day treatment with age- and body weight-adjusted oral rivaroxaban in children aged 
between 6 months and < 6 years with various manifestations of symptomatic and 
asymptomatic venous thrombosis.18
The study will be initiated with the age group between 2 and less than 6 years. Once the age-
and body weight adjusted dosing regimen has been finally confirmed for the age group 
between 6 months and less than 2 years in phase I, and approved by the data monitoring 
committee and steering committee, enrollment will be extended to this age group. Before 
enrollment of this age group is implemented and the IxRS is activated, the investigators and 
their IRBs will receive a formal notification, specifying the exposure results and safety 
outcomes.
Study description
Children who have been treated for at least 2 months or in case of catheter-related thrombosis, 
treated for at least 6 weeks with LMWH, fondaparinux and/or VKA for symptomatic or 
asymptomatic venous thrombosis will receive age- and body weight-adjusted rivaroxaban. 
Before first study treatment administration, the documented index thrombotic event will be 
confirmed by the central adjudication committee (CIAC) for the child to be eligible for the 
study.
Allocation to treatment will be done centrally by an interactive voice/web response system 
(IxRS). The investigator will provide the IxRS with study center identification, the child’s 
date of birth (day, month and year), gender, weight and clinical presentation.
Please refer to the IxRS manual for further details.
The IxRS will initially restrict enrollment to children in the age group between 2 and less than
6 years. Once the age-and body weight adjusted dosing regimen has been confirmed for the 
age group 6 months to < 2 years, the IxRS will allow enrollment for this age group as well.
Children will receive rivaroxaban for a total of 30 days.18
The treatment period will be followed by a 30-day post study treatment period, regardless of 
the duration of study drug administration. After cessation of study treatment, 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 symptomatic recurrent venous thromboembolism and 
asymptomatic deterioration in thrombotic burden on repeat imaging. All suspected recurrent 
VTEs, asymptomatic deterioration 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 Monitoring Committee (DMC) will monitor the children’s safety during 
the study and give recommendations to the steering committee.
For all children, visits are scheduled at regular time points (see Figure 1–1). Enrolled children 
who are not treated or those with premature discontinuation of study drug will at least be seen 
                                                                                                                                                      
18 Comparator arm was removed via Amendment 4 (see Section 16.2.2.5)


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at the end of the study treatment period.19 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 Figure 1–1).
4.
Study population
4.1
Planned number of children - amended
Twenty children (10 per age group) are planned to be treated with rivaroxaban. Enrolment 
will start with the 2 to < 6 year age group, followed by the 6 months to < 2 year age group
upon availability of the age and body weight adapted dosing regimen for the age group 6 
months to < 2 years.20
4.2
Inclusion criteria - amended
1. Children aged between 6 months to < 6 years who have been treated for at least 2 months 
or, in case of catheter related thrombosis, for at least 6 weeks with LMWH, fondaparinux 
and/or VKA for documented symptomatic or asymptomatic venous thrombosis 
2. Hemoglobin, platelets, creatinine and alanine aminotransferase (ALT) and bilirubin 
evaluated within 10 days prior to Visit 2
3. Informed consent provided. 21
4.3
Exclusion criteria - amended
1. Active bleeding or high risk for bleeding contraindicating anticoagulant therapy
2. Symptomatic progression of venous thrombosis during preceding anticoagulant treatment
3. Planned invasive procedures, including lumbar puncture and removal of non-peripherally 
placed central lines during study treatment.
4. An estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2
5. Hepatic disease which is associated either: with coagulopathy leading to a clinically 
relevant bleeding risk, or ALT > 5x upper level of normal (ULN), or total bilirubin 
> 2x ULN with direct bilirubin > 20% of the total.
6. Platelet count < 50 x 109/L22
7. Hypertension defined as > 95th age percentile
8. Life expectancy < 3 months
9. Concomitant use of strong inhibitors of both CYP3A4 and P-gp, i.e. all human 
immunodeficiency virus protease inhibitors and the following azole-antimycotics agents: 
ketoconazole, itraconazole, voriconazole, posaconazole, if used systemically
(fluconazole is allowed)
                                                                                                                                                      
19 Comparator arm was removed via Amendment 4 (see Section 16.2.2.5)
20 Total number of subjects was reduced via Amendment 4 (see Section 16.2.2.6)
21 Inclusion criteria modified via Amendment 4 (see Section 16.2.2.7)
22 Definition of thrombocytopenia adjusted via Amendment 4 (see Section 16.2.2.8)


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10.Concomitant use of strong inducers of CYP3A4, i.e. rifampicin, rifabutin, phenobarbital, 
phenytoin and carbamazepine
11.Hypersensitivity or any other contraindication listed in the local labeling for the 
experimental treatment 
12.Inability to cooperate with the study procedures 
13.Previous participation in this study
14.Participation in a study with an investigational drug or medical device within 30 days 
prior to Visit 2. 23
4.4
Concomitant medication - amended
Concomitant medications include either continuation of a treatment started before Visit 2, or 
addition of a new treatment during the study. Non-steroidal anti-inflammatory drugs
(NSAIDs) and antiplatelet agents are strongly discouraged since they increase the risk for 
bleeding in patients treated with anticoagulants. However, if such medication is indicated, the 
lowest possible dosage should be selected. 
Central venous lines and peripheral catheters that are used in this study should only be flushed 
with saline. Heparin flushes are not allowed.
Concomitant use of strong inhibitors of both CYP3A4 and P-gp, i.e. all human 
immunodeficiency virus protease inhibitors and azole-antimycotics agents (i.e. ketoconazole, 
itraconazole, voriconazole, posaconazole; concomitant treatment with fluconazole is allowed), 
if used systemically, is not allowed, as well as concomitant use of strong inducers of CYP3A4 
(i.e. rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine). 
Any previous anticoagulant medication taken within 90 days prior to Visit 2 will be 
documented.  Anticoagulant use after the study treatment period will also be documented. 24
5.
Treatment regimen - amended
5.1
Treatment - amended
In this study, only rivaroxaban will be used. 25,26
5.1.1
Rivaroxaban - amended
Age- and body weight-adjusted rivaroxaban will be administered twice daily (12 hours apart) 
as oral suspension based on the results from the phase I study (12892).25
A Taste- and-Texture Questionnaire, using a visual analog scale, will be used to determine the 
acceptance of the oral suspension in children older than 4 years.
Rivaroxaban will be taken in the morning and in the evening within 2 hours after a meal. If a 
rivaroxaban dose was missed, the child should take rivaroxaban immediately to ensure intake 
                                                                                                                                                      
23 Comparator arm was removed via Amendment 4 (see Section 16.2.2.8)
24 Concomitant medication instructions modified via Amendment 4 (see Section 16.2.2.9)
25 Section title modified via Amendment 4 (see Section 16.2.2.10 and Section 16.2.2.12)
26 Comparator arm was removed via Amendment 4 (see Section 16.2.2.11)


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of the maximum daily dose per day. In this case, two oral suspension doses may be taken at 
once. The child should continue with the regular twice daily intake as recommended on the 
following day.
Instructions on how to prepare the rivaroxaban oral suspension are provided in the 
Rivaroxaban 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 
manual. The training will be documented.27
The age- and body weight-adjusted rivaroxaban dosing schedule is provided in Table 5–1. 
Table 5–1: Rivaroxaban dosing schedule
Age group
Body 
weight
[kg]
Min
Max
Oral suspension 
dose (b.i.d.) 
Maximum daily dose
≥ 6 months to < 6 years
3
<4
0.7 mg
1.4 mg
4
<5
0.9 mg
1.8 mg
5
<6
1.4 mg
2.8 mg
6
<7
1.8 mg
3.6 mg
7
<8
2.2 mg
4.4 mg
8
<9
3.2 mg
6.4 mg
9
<10
3.2 mg
6.4 mg
10
<12
3.4 mg
6.8 mg
12
<14
4.0 mg
8.0 mg
14
<16
4.0 mg
8.0 mg
16
<20
4.0 mg
8.0 mg
20
<30
5.0 mg
10.0 mg
30
<40
7.5 mg
15.0 mg
40
<50
7.5 mg
15.0 mg
5.1.1.1
Switching from VKA to rivaroxaban - amended
If a child is on VKA therapy and has a supra-therapeutic INR (> 3.0), rivaroxaban 
administration should be delayed. In case of an INR between 2.5 to 3.0, the first rivaroxaban 
dose should be delayed to the next day. If the INR is below 2.5, the first rivaroxaban dose can 
be taken at Visit 2. VKA therapy must be stopped before rivaroxaban treatment commences.28
5.1.1.2
Switching from heparin/fondaparinux to rivaroxaban - amended
If the child received heparin treatment before study treatment with rivaroxaban, rivaroxaban 
administration should be planned 4 hours after stopping the infusion of UFH, 6 - 12 hours 
                                                                                                                                                      
27 Instructions about the oral suspension administration were adjusted and information about the Rivaroxaban 
Oral Suspension Handling Guidelines were added in Amendment 1 (see Section 16.1.2.2)
28 Section modified via Amendment 4 (see Section 16.2.2.13)


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after the last injection of LMWH with a twice-daily regimen, or 12 - 24 hours after the last 
injection of fondaparinux or LMWH with a once-daily regimen.29 Heparin/fondaparinux 
treatment cannot be continued after the start of rivaroxaban treatment in these children.
5.1.1.3
Switching from rivaroxaban to heparin/fondaparinux - amended
Children who switch from rivaroxaban to heparin /fondaparinux can switch at the time of the 
next scheduled dose. 30
5.1.1.4
Switching from rivaroxaban to VKA - amended
Children who switch from rivaroxaban to VKA need to continue rivaroxaban for 48 hours 
after the first dose of VKA. After 2 days of co-administration, an INR should be obtained 
prior to the next scheduled dose of rivaroxaban. Co-administration of rivaroxaban and VKA is 
advised to continue until the INR is ≥ 2.0.30
5.1.2
Comparator group - amended
This single-arm study does not include comparator treatment.31
5.2
Subject identification - amended
Upon signing the informed consent, each child will be assigned unique 9-digit child 
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.31
5.3
Duration of study treatment
Children will receive study treatment for a period of 30 days. 
5.4
Formulation and dose
5.4.1
Rivaroxaban - amended
Rivaroxaban will be provided by Bayer as a 0.1% (1mg/ml) suspension. 32 Rivaroxaban will 
be dosed according to body weight groups (see Table 5–1). Since children with a glomerular 
filtration rate below 30 mL/min/1.73 m2 are excluded from the study, a dose adaptation is not 
indicated. 
                                                                                                                                                      
29 Section modified via Amendment 4 (see Section 16.2.2.14)
30 Addition of switch from rivaroxaban to standard of care via Amendment 4 (see Section 16.2.2.15 and Section 
16.2.2.16)
31 Comparator arm was removed via Amendment 4 (see Section 16.2.2.17 and Section 16.2.2.18)
32 Section modified via Amendment 4 (see Section  16.2.2.19)


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5.4.2
Comparator - amended
This single-arm study does not include comparator treatment.33
5.5
Packaging, labeling, and storage - amended
Rivaroxaban will be provided by Bayer and labeled according to local law and regulation. 
All study medication will be labeled according to local law and legislation. Also, 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.
All study medication need to be stored at the investigational site according to the labeled 
storage advice and in accordance with Good Clinical Practice (GCP) and Good 
Manufacturing Practice (GMP) requirements. Rivaroxaban oral suspension should not be 
frozen and should be stored at a temperature not exceeding 25°C. The study drug is to be 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 
study medication via IxRS and will use the study medication only for this study and in 
accordance with this protocol. Receipt, distribution, return and destruction (if any) of the 
study medication must be properly documented according to specified procedures.33
5.6
Treatment assignment - amended
Not applicable.33
5.7
Dosage and administration - amended
Rivaroxaban will be dosed according to body weight as oral 0.1% suspension.33
5.8
Treatment compliance - amended
5.8.1
Rivaroxaban
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 study medication should be kept 
securely in the original containers in a designated locked container until retrieved or 
dispensed. 33
                                                                                                                                                      
33 Comparator arm was removed via Amendment 4 (see Section 16.2.2.20, 16.2.2.21, 16.2.2.22, 16.2.2.23 and 
16.2.2.24)


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6.
Study Procedures 
6.1
Study visits - amended
The study has 5 planned visits (see Figure 1–1). 
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 venous thrombosis. This visit will take place 60 to 10 days before Visit 2.
Visit 2 is the first study drug administration day and will be a hospital visit. Eligible children 
will receive rivaroxaban for 30 days.
Visit 3 and Visit 4 are the treatment and end of treatment visits, respectively. These visits will 
be hospital visits which will take place at Day 15 ± 5 days, and Day 30 ± 3 days, respectively. 
At visit 2, 3 and 4, PK/PD blood samples will be drawn. At Visit 4, the study medication will 
be stopped. After cessation of study treatment, 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 60 ± 7 days. This visit will be the last study visit.
In children who prematurely discontinue study medication, visit 5 will take place 30 ± 7 days 
after premature discontinuation. 34
6.2
Visit 1 - Screening visit at 60 to 10 days before Visit 2 - amended
The parents/legal guardians will be given explanation about the study and will be given 
sufficient time to consider participation of their child in the study.  Parents/legal guardians 
who are willing to have their child participating 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, height/length, blood pressure and anticoagulant 
medication will be collected. 
The images of the index venous 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.
Adverse events will not be collected between visit 1 and visit 2.  Since hemoglobin, platelet 
counts, creatinine and liver function 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, and bilirubin within 10 days prior to Visit 2 is an 
inclusion criterion for this study (see section 4.2).34
                                                                                                                                                      
34 Section modified via Amendment 4 (see Section 16.2.2.25 and 16.2.2.26)


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6.3
Visit 2 - Treatment visit at Day 1 - amended
If the CIAC confirmed the qualifying venous thrombotic event, then re-confirm eligibility. If 
results for hemoglobin, platelets, creatinine, ALT, bilirubin were not available within 10 days 
prior to Visit 2, obtain blood sample. If the child still meets the inclusion criteria and does not 
meet any of the exclusion criteria, the child can receive rivaroxaban.

If a child is on VKA therapy and has a supra-therapeutic INR (> 3.0), the first 
administration of rivaroxaban should be delayedVKA therapy should be stopped and 
the timing of the administration of the first rivaroxaban dose will depend on the INR
(see also section 5.1.1.1).
If the INR is between 2.5 to 3.0, the first rivaroxaban dose should be delayed to the next day. 
If the INR is below 2.5, the first rivaroxaban dose should be taken at Visit 2.

Collect body weight

Provide instructions how to take the study drug and give the study booklet and the 
Rivaroxaban Oral Suspension Handling Guidelines to parents

Administer first dose of rivaroxaban oral suspension

Document the volume and type of fluid used to predilute the rivaroxaban oral 
suspension, as well as the volume and type of fluid taken after the study drug 
administration.

Document the exact time of drug intake and the time and type of meal (e.g. breast 
feeding, baby bottle, porridge, breakfast, lunch, snack, dinner) the child took 2 hours 
before, during and after study drug administration.

At 0.5-1.5 hr after drug intake, collect only a PK blood sample

At 2.5-4 hr after drug intake, collect a PK blood sample followed by the PD blood
sample.35

Check for adverse events

Record all concomitant medication

Update eCRF.

Instruct to 1) document in the study booklet the exact time of the last dose taken on 
the day prior to Visit 3, 2) the exact time and type of meal the child took 2 hours 
before, during and after study drug administration, 3) the volume and type of fluid 
used to predilute the rivaroxaban oral suspension and 4) the volume and type of fluid 
taken after the study drug administration.

Instruct that on the day of visit 3, rivaroxaban should not be taken in the morning and 
medication should be brought to the hospital. 36,37
                                                                                                                                                      
35 Instructions about how to administer the oral suspension were adjusted in Amendment 1 (see Section 16.1.2.3)
36 Section modified via Amendment 1 (see Section 16.1.2.3)
37 Section modified via Amendment 4 (see Section 16.2.2.27)


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6.4
Visit 3 - Treatment visit at Day 15 (+/- 5 days) - amended

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. 

Administer the next rivaroxaban dose and document the volume and type of fluid used 
to predilute the rivaroxaban oral suspension, as well as the volume and type of fluid 
taken after the study drug administration.

Document the exact time of drug intake and type of meal the child took 2 hours 
before, during and after drug administration

Complete the Taste-and-Texture Questionnaire for children older than 4 years

At 2 – 8 hr after drug intake, 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

Update eCRF.

Inform that on the day before visit 4
-
the evening dose of rivaroxaban should be taken as late as possible (i.e. closely 
before the child goes to bed) and medication should not be taken on the day of 
visit 4
-
1) to document in the study booklet the exact time of the last dose taken on the day 
before Visit 4, 2) the exact time and type of meal the child took 2 hours before, 
during and after study drug administration, 3) the volume and type of fluid used to 
predilute the rivaroxaban oral suspension and 4) the volume and type of fluid 
taken after the study drug administration. 38, 39
If a child discontinues study treatment 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.
                                                                                                                                                      
38 Section modified via Amendment 1 (see Section 16.1.2.4)
39 Section modified via Amendment 4 (see Section 16.2.2.28)


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6.5
Visit 4 - End of study treatment visit at Day 30 (+/- 3 days) - amended
No study medication should 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. 

Obtain blood sample for hemoglobin, platelets, ALT and bilirubin

document the exact time of drug intake on the day prior to visit 4 and document the 
volume and type of fluid used to predilute the rivaroxaban oral suspension, as well as 
the volume and type of fluid taken after the study drug administration 

document the time and type of meal the child took 2 hours before, during and after 
study drug administration on the day prior to Visit 4.

at 10 – 16 hr after last drug intake, collect the 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.

Update eCRF

Repeat imaging with ultrasound should be obtained if applicable. If repeat imaging 
can be done with MRI or MR angiography, this should be done only if sedation and/or 
general anesthesia are not required. Other modalities of imaging, e.g. CT 
(angiography) scan or contrast angiography, will be obtained only if the repeat test 
was planned independently of the study. A repeat imaging adjudication package needs 
to be compiled and sent to the adjudication office.
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, or for hemoglobin, platelets, ALT or bilirubin, is 
required.40, 41
                                                                                                                                                      
40 Section modified via Amendment 1 (see Section 16.1.2.5)
41 Section modified via Amendment 4 (see Section 16.2.2.29)


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6.6
Visit 5 - 30 day post treatment contact at Day 60 (+/- 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 60 ± 7 days in children who completed the study treatment. 
However, in children who prematurely discontinue study medication, this visit will take place 
30 ± 7 days after premature discontinuation. 

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.
6.7
Unscheduled visits
If deemed necessary, it is at the investigator’s discretion to arrange additional visits.  
6.8
Safety outcomes
The primary 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, or
-
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 or
impairment of activities of daily life (such as loss of school days or hospitalization).
All other overt bleeding episodes not meeting the criteria for clinically relevant bleeding will 
be classified as trivial bleed.


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6.9
Recommendations before and after invasive procedures and surgical 
intervention - amended
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.42
6.10
Management of bleeding in children - amended
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 the PK/PD sample.
If bleeding cannot be controlled, consider administration of one of the following 
procoagulants (both according to the dosages advised in the package insert):
recombinant factor VIIa (NovoSeven®)
4-factor concentrate.
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of 
rivaroxaban.43
6.11
Efficacy outcome
The efficacy outcome will be symptomatic recurrence of venous thrombosis or asymptomatic 
deterioration.
Symptomatic recurrence of venous thrombosis or asymptomatic deterioration should be 
documented using the appropriate imaging test.
6.12
PK/PD assessments - amended
Blood samples will be taken for PK and PD measurements.44 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:
1) PK/PD samples at visit 2, 
2) PK/PD sample at visit 3, and
3) PK/PD sample at visit 4.
                                                                                                                                                      
42 Comparator arm was removed via Amendment 4 (see Section 16.2.2.30)
43 Section modified via Amendment 4 (see Section 16.2.2.31)
44 Section modified via Amendment 4 (see Section 16.2.2.32)


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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.
If rivaroxaban was temporarily stopped at the time of a study visit (e.g. if treatment was 
temporarily stopped prior to visit 3), sampling of blood for PK/PD analysis according to this 
visit’s schedule should be postponed until rivaroxaban treatment has been restarted and 
sustained for at least 3 days.
If a blood sample is taken from a central line, 3 mL of blood should be discarded.(16) In 
children from 6 months to 1 year old, it might not be possible to withdraw blood from central 
venous line due to the amount of blood required especially at visit 2. In this case, it is advised 
to withdraw blood from a peripheral catheter. If a blood sample is taken from a peripheral 
catheter, fluid is to be withdrawn from the line until all is removed and blood is sampled. An
anesthetic cream can be applied to minimize pain from drawing of blood from a vein.   
Central venous lines and peripheral catheters that are used in this study should only be flushed 
with saline. 
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 pooled and analyzed using population 
approaches to estimate the PK/PD profile of rivaroxaban. Details for the population PK/PD 
analysis will be described in a separate evaluation plan. 
6.13
Study booklet - amended
Parents/children will receive a booklet with the following information:
The local medical contact person and emergency telephone number
The visit schedule provided by the IxRS, including dates of telephone and/or hospital 
visits
Instructions to keep empty medication packages and unused study medication.
How to take rivaroxaban
Calendar to track the date and time of food and study drug intake as well as the volume 
of fluid taken. 45
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:
                                                                                                                                                      
45 Comparator arm was removed via Amendment 4 (see Section 16.2.2.33)


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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 and ancillary 
studies.
6.14.2
Central independent adjudication committee (CIAC)
All index venous thrombotic events, and all suspected recurrent venous 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 (SAEs), recurrent venous 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 - amended
Full analysis set (FAS):  This analysis set will include all enrolled children. 
Safety analysis set (SAS): This analysis set will include all enrolled children who received at 
least one dose of study medication.
Per protocol set (PPS): This population includes all enrolled children who completed the 
30-day treatment period. The PPS may also exclude major protocol deviations. Further details 
will be specified in the Statistical Analysis Plan.
Listing only set (LOS): This population includes all screening failures.46
7.3
Demographic and other baseline characteristics - amended
Summary statistics (arithmetic mean, standard deviation, median, minimum and maximum for 
quantitative variables) will be presented by age group.  Frequency tables for qualitative data 
will be provided.  Medical history findings will be summarized using Medical Dictionary for 
Regulatory Activities (MedDRA) terms.47
7.4
Safety analysis - amended
All safety analyses will be performed on the SAS population. The analysis will primarily 
focus on bleeding that occurred during or within 2 days after stop of study treatment. 
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 descriptively. 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 
descriptively for the original data as well as for the difference to baseline.  Frequency tables 
will be provided for qualitative data. 48
7.5
Efficacy analysis - amended
All efficacy analyses will be performed on the FAS population. The occurrence of recurrent 
venous thromboembolism and asymptomatic deterioration in thrombotic burden will be 
summarized by age group.49
7.6
PK/PD analysis
PK/PD modeling, using population approaches will be used to describe the pharmacokinetics 
of rivaroxaban, including potential influence of relevant co-variables, and to relate 
anticoagulant parameters of rivaroxaban with plasma concentrations. Details will be given in 
a separate detailed PK/PD evaluation plan.
                                                                                                                                                      
46 Comparator arm was removed via Amendment 4 (see Section 16.2.2.34)
47 Section was modified via Amendment 4 (see Section 16.2.2.35)
48 Comparator arm was removed via Amendment 4 (see Section 16.2.2.36)
49 Section was modified via Amendment 4 (see Section 16.2.2.37)


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7.7
Interim analyses
No interim analysis will be performed.
7.8
Determination of sample size - amended
A total of 20 children who took at least one dose of study medication are planned to be 
enrolled in the study.50 The sample size does not originate from a formal sample size 
calculation, but is based on a feasibility assessment because of the very low incidence of 
venous thrombosis in children, and on the pharmacokinetic moderate inter-individual 
variability of rivaroxaban. Based on past experience in obtaining parental consent in this 
indication, it is estimated that fewer than 10% of eligible children can be enrolled in this 
study.
7.9
Adverse events (AE) - amended
Individual listings of adverse events (including age, weight, height, gender, adverse event as 
reported, start, duration, severity and relation to study drug) will be provided.  The incidence 
of treatment-emergent adverse events will be summarized by age group using MedDRA 
preferred terms grouped by primary system organ class.51
7.9.1
Definitions
7.9.1.1
Adverse event (AE)
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.
                                                                                                                                                      
50 Total number of subjects reduced via Amendment 4 (see Section 16.2.2.38)
51 Section modified via Amendment 4 (see Section 16.2.2.39)


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7.9.1.2
Serious adverse event (SAE)
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.
7.9.1.3
Unexpected AEs
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 would be 
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, e.g. the child while on a bike is 
struck by an automobile when there is no indication that the drug caused disorientation that 
may have caused the event. 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 procedure
The assessment of a possible causal relationship between the AE and protocol-required 
procedure is based on the presence of a reasonable relationship.


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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), and severe (prevents normal activities).
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 reaction/s (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 (recurrent 
venous thrombosis) 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 
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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.
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
AEs of special safety interest - amended
The following AEs are considered as AEs of special safety interest:

Concurrent elevations of ALT > 5x ULN and total bilirubin > 2x ULN

Liver injury

A platelet count below 50x109/L.52
7.10
Premature discontinuation of study medication
Children prematurely discontinue study medication 
at their own request or at the request of their parents/legally acceptable 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 30-day treatment period. If study medication 
is permanently discontinued, further treatment is at the investigator’s discretion. 
If the child or 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 the child/parent/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.
                                                                                                                                                      
52 Definition of thrombocytopenia was adjusted via Amendment 4 (see Section 16.2.2.40)


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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.
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 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 


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destroyed without Bayer’s approval. The investigator's contract will contain all regulations 
relevant for the study center.
9.
Premature termination of the study
The investigator has the right to terminate 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: 
If the risk-benefit ratio becomes unacceptable due to, for example,

safety or efficacy findings from this study 

results of parallel clinical studies.
If 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:
closures should occur only after consultation between involved parties
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 destructed 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 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 


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proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
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
Child information and consent
All relevant study information will be summarized in an integrated child information sheet,
and informed consent form provided by Bayer or the study center.  A sample child 
information and informed consent form is provided as a document separate to this protocol.  
Consent will be asked from parent(s) or legal guardian.
The investigator or designee will explain all relevant aspects of the study to the parent(s)/legal 
guardian(s) and the child, if applicable, 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 parent(s)/legal guardian(s) and the child, if applicable, 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 parent(s)/legal guardian(s) agree to sign and date the 
informed consent and have done so. Then the investigator or designee will sign and date the 
form. The parent(s)/legal guardian(s) 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 
guardians will be revised whenever important new information become available that may be 
relevant to the child's consent, or if there is an amendment to the protocol that necessitates a 
change to the content of the child information and/or the written informed consent form.  The 
investigator will inform the parents/legal guardian of changes in a timely manner and will ask 
the parents/legal guardians to confirm participation in the study by signing the revised 
informed consent form.  Revised informed consent and the child information sheet must 
receive the IEC's/IRB's approval before implementation.


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11.
Investigators and other study participants
The study coordinating investigator is 
Dr Guy A. Young, M.D., Director, Hemostasis and Thrombosis Center, Children’s Hospital 
of Los Angeles, 
 USA.
Key personnel will be listed in the study file.
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.
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
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 country 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 study 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, the children/parents/legal guardians 
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.
PPD


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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.
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.
8.
Massicotte P, Julian JA, Gent M, Shields K, Marzinotto V, Szechtman B, et al. An 
open-label randomized controlled trial of low molecular weight heparin compared to 
heparin and coumadin for the treatment of venous thromboembolic events in children: 
the REVIVE trial. Thromb Res 2003;109(2-3):85-92.
9.
Kenet G, Kirkham F, Niederstadt T, Heinecke A, Saunders D, Stoll M, et al. Risk 
factors for recurrent venous thromboembolism in the European collaborative 
paediatric database on cerebral venous thrombosis: a multicentre cohort study. Lancet 
Neurol 2007;6(7):595-603.
10.
Monagle P, Chan A, Goldemberg N, Ichord R, Journeycake J, Nowak-Gottl U, Vesely 
S. Antithrombotic therapy in neonates and children: American College of Chest 
Physicians Evidence-Based Clinical Practice Guidelines (9th Edition). Chest 
2012;144: e737S-e801S887S-968S.
11.
Buller HR, Prins MH, Lensing AW, Decousus H, Jacobson BF, Minar E et al. Oral 
Rivaroxaban for the treatment of symptomatic pulmonary embolism. N.Engl J Med 
2012;366 (14):1287-97.


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12.
Schwartz GJ, Haycock GB, Edelmann CM, Jr., Spitzer A. A simple estimate of 
glomerular filtration rate in children derived from body length and plasma creatinine. 
Pediatrics 1976 Aug;58(2):259-263.
13.
Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New 
equations to estimate GFR in children with CKD. J Am Soc Nephrol 2009 
Mar;20(3):629-637.
14.
The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in 
children and adolescents. Pediatrics 2004; 114(2 Suppl 4th Report):555-576.
15.
Report of the Second Task Force on Blood Pressure Control in Children .Pediatrics 
1987; 79(1):1-25.
16.
Cole M, Price L, Parry A, Picton S, Waters F, Marshall S, et al. A study to determine 
the minimum volume of blood necessary to be discarded from a central venous 
catheter before a valid sample is obtained in children with cancer. Pediatr Blood 
Cancer 2007;48(7):687-695.


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16.
Protocol amendments
16.1
Amendment 1
Amendment 1 is the first global amendment dated 02 Sep 2014.
16.1.1
Overview of changes
16.1.1.1
Modification 1: Correction of erroneous dosing information
The dosing for this study and information on the adult study were wrong in the previous 
version of the protocol and were corrected.
Affected protocol sections: Synopsis
16.1.1.2
Modification 2: Adjustment of suspension information
In the phase I study (#12892) the rivaroxaban oral suspension showed an unexpected PK 
profile which differed from the one of the standard tablet formulation. It was observed that the 
unexpected PK profile of the rivaroxaban oral suspension is due to a pH dependent 
precipitation of one of the ingredients in the formulation leading to a slow release of 
rivaroxaban. Data from phase I study (#12892) have shown that pre-diluting the suspension 
prior to administration helps to restore a tablet-like profile. The team decided to provide a 
high level summary of the rivaroxaban oral suspension preparation. The detailed instruction 
for preparation and administration is specified in the Rivaroxaban Oral Suspension 
Guidelines.
Affected protocol sections: Section 5.1.1  Rivaroxaban group, Section 6.3  Visit 2 -
Randomization visit at Day 1, Section 6.4  Visit 3 - Treatment visit at Day 15 (+/- 5 days), 
Section 6.5 Visit 4 - End of study treatment visit at Day 30 (+/- 3 days)
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.


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16.1.2.1
Synopsis
This section was changed as a result of Modifications 1 and 2. 
Old text:
[…]
Dose
Age and body weight-adjusted dosing of rivaroxaban to 
achieve a similar exposure as that observed in adults treated 
for venous thromboembolism (VTE) with 20 mg rivaroxaban 
twice daily
[…]
New text:
[…]
Dose
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
[…]


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Old text:
[…]
Figure 1-1:
Flow chart
Screen a
Treatment period 
30 day post study 
treatment contact
Visit 
1
2
3
4
5
Days
Day -60 
to
Day -10
Day 1
Day 15
5 days
Day 30
± 3 days
Day 60
7 days
Obtain informed consent
●
Check in-/exclusion criteria
●
Obtain demographic data
●
Check medical history
●
●
Record anticoagulant medication
●
●
Obtain height/length, and  blood  
pressure
●
Obtain body weight
●
●
Check Hb, platelets, creatinine, 
ALT, bilirubin
●b
Send baseline adjudication package 
●
Review the CIAC decision for index 
thrombotic event for final eligibility 
c
●
Re-confirm in-/exclusion criteria c 
●
Provide  patient details to  IxRS
●
Randomize patient  using  IxRS
●
Dispense study medication
Instruct how to take study 
medication
Provide study booklet
●
●
●
[…]


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New text:
[…]
Figure 1-1:
Flow chart
Screen a
Treatment period 
30 day post study 
treatment contact
Visit 
1
2
3
4
5
Days
Day -60 
to
Day -10
Day 1
Day 15
5 days
Day 30
± 3 days
Day 60
7 days
Obtain informed consent
●
Check in-/exclusion criteria
●
Obtain demographic data
●
Check medical history
●
●
Record anticoagulant medication
●
●
Obtain height/length, and  blood  
pressure
●
Obtain body weight
●
●
Check Hb, platelets, creatinine, 
ALT, bilirubin
●b
Send baseline adjudication package 
●
Review the CIAC decision for index 
thrombotic event for final eligibility 
c
●
Re-confirm in-/exclusion criteria c 
●
Provide  patient details to  IxRS
●
Randomize patient  using  IxRS
●
Dispense study medication
Instruct how to take study 
medication
Provide study booklet
Provide  Rivaroxaban Oral 
Suspension Handling Guidelines to 
parents
●
●
●
●
[…]
16.1.2.2
Section 5.1.1  Rivaroxaban group
This section was changed as a result of Modification 2. 
Old text:
[…]
The administration of the oral suspension should be immediately followed by the intake of up 
to 240 mL of liquid. A Taste and Texture Questionnaire, using a visual analog scale, will be 
used to determine the acceptance of the oral suspension in children older than 4 years.


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New text:
[…]
A Taste- and- Texture Questionnaire, using a visual analog scale, will be used to determine 
the acceptance of the oral suspension in children older than 4 years.
[…]
Old text:
[…]
Instructions on how to handle rivaroxaban oral suspension can be found in the oral suspension 
handling guidelines.
[…]
New Text:
[…]
Instructions on how to prepare the rivaroxaban oral suspension are provided in the 
Rivaroxaban 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 
manual. The training will be documented.
[…]
16.1.2.3
Section 6.3  Visit 2 - Randomization visit at Day 1
This section was changed as a result of Modification 2. 
Old text:
[…]

Provide instructions how to take the study drug and give the study booklet

Administer the assigned study drug 

In children allocated to rivaroxaban, 

administer the first rivaroxaban dose as instructed in the oral suspension 
handling guidelines.

document the exact time of drug intake and the time and type of meal (i.e.
breakfast, lunch, snack, dinner) the child took 2 hours before and after study 
drug administration. 

at 0.5-1.5 hr after drug intake, collect only a PK blood sample


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
at 2.5-4 hr after drug intake, collect a PK blood sample followed by the PD 
blood sample. 

Check for adverse events

Record all concomitant medication

Instruct that on the day of visit 3, rivaroxaban should not be taken in the morning and 
medication should be brought to the hospital

Update eCRF.
[…]
New text:
[…]

Provide instructions how to take the study drug and give the study booklet and the 
Rivaroxaban Oral Suspension Handling Guidelines to parents

Administer the assigned study drug 

In children allocated to rivaroxaban, 

administer the first rivaroxaban dose and document the volume and type of fluid 
used to predilute the rivaroxaban oral suspension, as well as the volume and type 
of fluid taken after the study drug administration.

document the exact time of drug intake and the time and type of meal (e.g. breast 
feeding, baby bottle, porridge, breakfast, lunch, snack, dinner) the child took 2 
hours before, during and after study drug administration. 

at 0.5-1.5 hr after drug intake, collect only a PK blood sample

at 2.5-4 hr after drug intake, collect a PK blood sample followed by the PD 
blood sample. 

Check for adverse events

Record all concomitant medication

Update eCRF.

In children allocated to rivaroxaban, instruct to 1) document in the study booklet the 
exact time of the last dose taken on the day prior to Visit 3, 2) the exact time and type 
of meal the child took 2 hours before, during and after study drug administration, 3) 
the volume and type of fluid used to predilute the rivaroxaban oral suspension and 4) 
the volume and type of fluid taken after the study drug administration.

Instruct that on the day of visit 3, rivaroxaban should not be taken in the morning and 
medication should be brought to the hospital
[…]


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16.1.2.4
Section 6.4  Visit 3 - Treatment visit at Day 15 (+/- 5 days)
This section was changed as a result of Modification 2. 
Old text:
[…]

In children randomized to rivaroxaban

administer the next rivaroxaban dose immediately followed by the intake of up to 
240 mL of liquid and record the type and volume of fluid taken. 

document the exact time of drug intake and type of meal (i.e. breakfast, lunch, 
snack, dinner) the child took 2 hours before and after drug administration

record the volume of fluid taken after study medication.

complete the Taste and Texture Questionnaire for children older than 4 years

at 2 – 8 hr after drug intake, 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

In children allocated to rivaroxaban, inform that on the day before visit 4
o
the evening dose of rivaroxaban should be taken as late as possible (i.e. closely 
before the child goes to bed) and medication should not be taken on the day of 
visit 4
o
Instruct to document the exact time of drug intake on the day prior to Visit 4 
and the time and type of meal (i.e. breakfast, lunch, snack, dinner) the child 
took 2 hours before and after study drug administration
o
Record the type and volume of fluid taken after study medication.

Update eCRF.
New text:
[…]

In children randomized to rivaroxaban

administer the next rivaroxaban dose and document the volume and type of fluid 
used to predilute the rivaroxaban oral suspension, as well as the volume and type 
of fluid taken after the study drug administration.

document the exact time of drug intake and type of meal the child took 2 hours 
before, during and after drug administration

complete the Taste-and-Texture Questionnaire for children older than 4 years

at 2 – 8 hr after drug intake, collect a post-dose PK blood sample followed by the 
PD blood sample 

document the exact time of blood sampling for PK/PD. 


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
Perform drug accountability and assess compliance

Check changes in concomitant medications

Update eCRF.

In children allocated to rivaroxaban, inform that on the day before visit 4
o
the evening dose of rivaroxaban should be taken as late as possible (i.e. 
closely before the child goes to bed) and medication should not be taken on 
the day of visit 4
o
1) to document in the study booklet the exact time of the last dose taken on 
the day before Visit 4, 2) the exact time and type of meal the child took 2 
hours before, during and after study drug administration, 3) the volume and 
type of fluid used to predilute the rivaroxaban oral suspension and 4) the 
volume and type of fluid taken after the study drug administration.
16.1.2.5
Section 6.5 Visit 4 - End of study treatment visit at Day 30 (+/- 3 days)
This section was changed as a result of Modification 2. 
Old text:
[…]

In children randomized to rivaroxaban

document the exact time of drug intake on the day prior to visit 4 and the time and 
type of meal (i.e breakfast, lunch, snack, dinner) the child took 2 hours before, 
during and after study drug administration

record the type and volume of fluid taken after study medication
[…]


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New text:
[…]

In children randomized to rivaroxaban

document the exact time of drug intake on the day prior to visit 4 and document 
the volume and type of fluid used to predilute the rivaroxaban oral suspension, as 
well as the volume and type of fluid taken after the study drug administration

document the time and type of meal the child took 2 hours before, during and after 
study drug administration on the day prior to Visit 4.
[…]
16.2
Amendment 4
Amendment 4 is the second global amendment dated 14 Apr 2015.
16.2.1
Overview of changes
16.2.1.1
Change 1: Minor clarifications for consistency
Changes were made to ensure consistency throughout the document. These changes do not 
affect the overall study concept.
Affected sections: Synopsis, Section 4.3: Exclusion criteria,  Section 4.4: Concomitant 
medication, Section 5.4.1: Rivaroxaban, Section 6.3. Visit 2 - Treatment visit at Day 1
Section 6.4: Visit 3 - Treatment visit at Day 15 (+/- 5 days)
16.2.1.2
Change 2: Comparator arm was removed
The comparator arm was originally included in an attempt to provide a calibrator group for 
the assessment of safety and efficacy of rivaroxaban. However, the sample size is considered 
too small to support meaningful comparison of rivaroxaban vs. standard of care with regard to 
safety and efficacy. Therefore, the comparator arm was removed. All information regarding 
the comparator arm was deleted in the protocol.
After implementation of the amendment, no further children will be treated with comparator. 
However, all data from children treated with comparator prior to this amendment will be 
analyzed as planned and reported in the CSR.
Affected sections: Title page, Synopsis, Section 1: Introduction, Section 1.3: Rationale of 
the study and risk-benefit assessment, Section 3: Study design, Section 4.2: Inclusion 
criteria, Section 4.3: Exclusion criteria, Section 4.4: Concomitant medication, Section 5: 
Treatment regimens, Section 5.1: Treatment, Section 5.1.1: Rivaroxaban , Section 5.1.1.1: 
Switching from VKA to rivaroxaban, Section 5.1.1.2: Switching from heparin/fondaparinux 


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to rivaroxaban, Section 5.1.2: Comparator group, Section 5.2: Subject identification, 
Section 5.4.2: Comparator, Section 5.5: Packaging, labeling, and storage, Section 5.6: 
Treatment assignment, Section 5.7: Dosage and administration, Section 5.8: Treatment 
compliance, Section 6.1: Study visits, Section 6.2: Visit 1 - Screening visit at 60 to 10 days 
before Visit 2, Section 6.3. Visit 2 - Treatment visit at Day 1, Section 6.4: Visit 3 - Treatment 
visit at Day 15 (+/- 5 days), Section 6.5: Visit 4 - End of study treatment visit at Day 30 (+/- 3 
days), Section 6.9: Recommendations before and after invasive procedures and surgical 
intervention, Section 6.10: Management of bleeding in children, Section 6.12: PK/PD 
assessments, Section 6.13: Study booklet, Section 7.2: Analysis sets, Section 7.3: 
Demographic and other baseline characteristics, Section 7.4: Safety analysis, Section 7.5: 
Efficacy analysis, Section 7.9: Adverse events (AE)
16.2.1.3
Change 3: Total number of subjects was reduced
As described in Change 2 (Section 16.3.1.2), the comparator arm was removed. Therefore, no 
further children need to be enrolled for this arm. This reduces the required total number of 
enrolled children from 40 to 20. The planned number of children treated with rivaroxaban (10 
per age group) remains unchanged.
Affected sections: Synopsis, Section 4.1: Planned number of children, Section 7.8: 
Determination of sample size
16.2.1.4
Change 4: Modification of inclusion criterion 1
Inclusion criterion 1 was changed to enable enrollment of children who are on long-term 
anticoagulant treatment. The text indicating that children need to be on their last month of 
intended anticoagulant treatment was removed.
Affected sections: Synopsis,  Section 3: Study design, Section 4.2: Inclusion criteria
16.2.1.5
Change 5: Addition of switch from rivaroxaban to standard of care
Change 4 (Section 16.2.1.4) implements that children can now be enrolled and treated with 
rivaroxaban during long-term anticoagulant treatment. Switching from one anticoagulant 
regimen to another occurs frequently in daily clinical practice. With the approval of 
rivaroxaban for various thrombosis conditions in adults, there is now considerable experience 
for switching patients on and off rivaroxaban therapy. Instructions on how to safely handle the 
switch form heparin/fondaparinux and VKA to rivaroxaban and vice versa are available in the 
protocol.


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Affected sections: New Section 5.1.1.3: Switching from rivaroxaban to heparin/fondaparinux, 
New Section 5.1.1.4: Switching from rivaroxaban to VKA
16.2.1.6
Change 6: Modification of exclusion criterion 6
Clinical practice supports the administration of anticoagulants with platelet counts of 
50x109/L and even lower. (8) Therefore, the platelet count threshold for exclusion of children 
was adjusted from <100x109/L to <50x109/L.
Affected sections: Synopsis, Section 4.3: Exclusion criteria, Section 7.9.9: AEs of special 
safety interest
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.
16.2.2.1
Title page
This section was modified based on Amendment Change 2.
Old text:
30-day, open-label, active-controlled, randomized study of the safety, efficacy and the 
pharmacokinetic and pharmacodynamic properties of oral rivaroxaban in young children with 
various manifestations of venous thrombosis
New text: 30-day, single-arm study of the safety, efficacy and the pharmacokinetic and pharmacodynamic 
properties of oral rivaroxaban in young children with various manifestations of venous thrombosis
16.2.2.2
Synopsis
This section was modified based on Amendment Changes 1, 2, 3, 4 and 6
Old text:
Title
30-day, open-label, active-controlled, randomized study of the safety, efficacy and the 
pharmacokinetic and pharmacodynamic properties of oral rivaroxaban in young children 
with various manifestations of venous thrombosis.
[…]
Comparator
study drug
Children continue to receive the anticoagulant treatment regimen they have received prior 
to randomization
Name of active 
ingredient
Low molecular weight heparin (LMWH), fondaparinux or vitamin K antagonist (VKA)


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Dose
As per standard of care
Route of 
administration
As per standard of care
Duration of 
treatment
30 days 
[…]
Diagnosis and 
main criteria 
for inclusion
Children aged 6 months to < 6 years with documented symptomatic or asymptomatic 
venous thrombosis treated for at least 2 months or, in case of catheter-related thrombosis, 
treated for at least 6 weeks with LMWH, fondaparinux and/or VKA and who are entering 
the last month of intended anticoagulant treatment.
The imaging of the index thrombotic event will be confirmed by the central independent 
adjudication committee (CIAC).
Study design
Open-label, active-controlled, multicenter, randomized study
Methodology
Children randomized to rivaroxaban will receive an age- and body weight-adjusted 
regimen. Children randomized to comparator continue to receive the same treatment 
regimen they received prior to randomization.
All suspected clinical study outcomes and baseline and repeat thrombosis imaging tests 
will be assessed by a CIAC blinded to treatment allocation.
An independent data monitoring committee (DMC) will monitor the children’s safety and 
give recommendations to the steering committee.
Number of 
children
40 children (20 per treatment group) 
Inclusion/ 
exclusion 
criteria
Inclusion
1.
Children aged 6 months to < 6 years who have been treated for at least 2 months 
or, in case of catheter related thrombosis, for at least 6 weeks with LMWH, 
fondaparinux and/or VKA for documented symptomatic or asymptomatic venous 
thrombosis and who will enter their last month of intended anticoagulant 
treatment
2.
Hemoglobin, platelets, creatinine, alanine aminotransferase (ALT) and bilirubin 
evaluated within 10 days prior to randomization
3.
[…]
Exclusion
[…]
6.
Platelet count < 100 x 109/L
[…]
9.
Concomitant use of strong inhibitors of both cytochrome P450 isoenzyme 3A4 
(CYP3A4) and P-glycoprotein (P-gp), i.e. all human immunodeficiency virus 
protease inhibitors and the following azole-antimycotics agents: ketoconazole, 
itraconazole, voriconazole, posaconazole, if used systemically
10. […]
11. Hypersensitivity or any other contraindication listed in the local labeling for the 
comparator treatment or experimental treatment 
12. […]
13. Previous randomization to this study 
14. Participation in a study with an investigational drug or medical device within 30 
days prior to randomization.


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[…]
Statistical 
Analysis Plan
The incidence of the composite of major and clinically relevant non-major bleeding and 
the incidence of symptomatic recurrent venous thromboembolism, and asymptomatic 
deterioration in the thrombotic burden on repeat imaging will be summarized by treatment.  
Quantitative data will be described by summary statistics and presented by treatment.
Results of PK/PD analyses will be assessed using population PK/PD methodology.
New text:
Title
30-day, single-arm study of the safety, efficacy and the pharmacokinetic and 
pharmacodynamic properties of oral rivaroxaban in young children with various 
manifestations of venous thrombosis.
[…]
Comparator 
study drug
Not applicable
Name of active 
ingredient
Not applicable
Dose
Not applicable
Route of 
administration
Not applicable
Duration of 
treatment
Not applicable
[…]
Diagnosis and 
main criteria 
for inclusion
Children aged 6 months to < 6 years with documented symptomatic or asymptomatic venous 
thrombosis treated for at least 2 months or, in case of catheter-related thrombosis, treated for 
at least 6 weeks with LMWH, fondaparinux and/or VKA.
The imaging of the index thrombotic event will be confirmed by the central independent 
adjudication committee (CIAC).
Study design
Single-arm, multicenter study
Methodology
Children will receive rivaroxaban according to an age- and body weight-adjusted regimen.
All suspected clinical study outcomes and baseline and repeat thrombosis imaging tests will 
be assessed by a CIAC
An independent data monitoring committee (DMC) will monitor the children’s safety and 
give recommendations to the steering committee.
Number of 
children
20 children (10 per age group) treated with rivaroxaban.
Inclusion/ 
exclusion 
criteria
Inclusion
1.
Children aged 6 months to < 6 years who have been treated for at least 2 months 
or, in case of catheter related thrombosis, for at least 6 weeks with LMWH, 
fondaparinux and/or VKA for documented symptomatic or asymptomatic venous 
thrombosis 
2.
Hemoglobin, platelets, creatinine, alanine aminotransferase (ALT) and bilirubin 
evaluated within 10 days prior to Visit 2
3.
[…]
Exclusion
[…]
6.
Platelet count < 50 x 109/L
[…]
9.
Concomitant use of strong inhibitors of both cytochrome P450 isoenzyme 3A4 


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(CYP3A4) and P-glycoprotein (P-gp), i.e. all human immunodeficiency virus 
protease inhibitors and the following azole-antimycotics agents: ketoconazole, 
itraconazole, voriconazole, posaconazole, if used systemically (fluconazole is 
allowed)
10. […]
11. Hypersensitivity or any other contraindication listed in the local labeling for the 
experimental treatment 
12. […]
13. Previous enrollment to this study 
14. Participation in a study with an investigational drug or medical device within 30 
days prior to Visit 2.
[…]
Statistical 
Analysis Plan
The incidence of the composite of major and clinically relevant non-major bleeding and the 
incidence of symptomatic recurrent venous thromboembolism, and asymptomatic 
deterioration in the thrombotic burden on repeat imaging will be summarized descriptively.  
Quantitative data will be described by summary statistics and presented by age.
Results of PK/PD analyses will be assessed descriptively.


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Old text:
Figure 1-1:
Flow chart
Screen a
Treatment period 
30 day post study 
treatment contact
Visit 
1
2
3
4
5
Days
Day -60 
to
Day -10
Day 1
Day 15
5 days
Day 30
± 3 days
Day 60
7 days
[…]
Provide  patient details to IxRS
●
Randomize patient  using  IxRS
●
[…]
Pharmacokinetics and 
pharmacodynamics f
Rivaroxaban group only g
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
[…]
Comparator group only
INR adjusted VKA
At least 1 INR per 2 weeks
a The screening visit can be performed up to 60 days prior 
to randomization, but should not be less than 10 days 
prior to randomization. Please contact the adjudication 
office in case the available period prior to 
randomization is less than 10 days.
b Results should be available within 10 days prior to 
randomization, if not obtain blood sample at visit 2.      
e VKA compliance will be ensured by minimum of 1 INR 
per 2 weeks.
[…]


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New text:
Figure 1-1:
Flow chart
Screen 
a
Treatment period 
30 day post study treatment contact
Visit 
1
2
3
4
5
Days Day -60 
to
Day -10
Day 1
Day 15
5 days
Day 30
± 3 days
Day 60
7 days
[…]
Provide  patient details to 
IxRS
●
[…]
Pharmacokinetics and 
pharmacodynamics f
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
[…]
a The screening visit can be performed up to 
60 days prior to Visit 2, but should not be 
less than 10 days prior to Visit 2. Please 
contact the adjudication office in case the 
available period prior to Visit 2is less than 10 
days.
b Results should be available within 10 days 
prior to Visit 2, if not obtain blood sample at 
visit 2.      
e This footnote was removed via Amendment 4.
[…]
16.2.2.3
Section 1: Introduction
This section was modified based on Amendment Change 2.
Old text:
The goal of the rivaroxaban pediatric program is to make rivaroxaban available to children for 
treatment and secondary prevention of venous thromboembolism.  To accomplish this goal, it will 
be necessary to evaluate a pediatric age- and body weight adapted dosing regimen, and to address 
the safety and efficacy of rivaroxaban versus the standard of care. 
New text: The goal of the rivaroxaban pediatric program is to make rivaroxaban available to children for 
treatment and secondary prevention of venous thromboembolism.  To accomplish this goal, it will 
be necessary to evaluate a pediatric age- and body weight adapted dosing regimen, and to address 
the safety and efficacy of rivaroxaban.


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16.2.2.4
Section 1.3: Rationale of the study and risk-benefit assessment
This section was modified based on Amendment Change 2
Old text:
[…]
Therefore, we elected to evaluate the selected rivaroxaban dose regimen after the completion of a 
minimum period of 2 months or, in the case of catheter related thrombosis, treatment for at least 6 
weeks with comparator.
[…]
New text: […]
Therefore, we elected to evaluate the selected rivaroxaban dose regimen after the completion of a 
minimum period of 2 months or, in the case of catheter related thrombosis, treatment for at least 6 
weeks with standard of care medication.
[…]
16.2.2.5
Section 3: Study design
This section was modified based on Amendment Change 2 and 4.
Old text:
This is an open-label, active-controlled, multicenter, randomized study evaluating the safety, 
efficacy and PK/PD profile of a 30-day treatment with age- and body weight-adjusted oral 
rivaroxaban in children aged between 6 months and < 6 years with various manifestations of 
symptomatic and asymptomatic venous thrombosis.
Children who have been treated for at least 2 months or in case of catheter-related thrombosis, 
treated for at least 6 weeks with LMWH, fondaparinux and/or VKA for symptomatic or 
asymptomatic venous thrombosis will be randomized to receive either age- and body weight-
adjusted rivaroxaban, or comparator (i.e. LMWH, fondaparinux or VKA), for their last month of 
intended anticoagulant treatment. Before randomization, the documented index thrombotic event 
will be confirmed by the central adjudication committee (CIAC) for the child to be eligible for the 
study.
Allocation to treatment will be done centrally by an interactive voice/web response system (IxRS). 
Allocation will be stratified by baseline presentation of venous thrombosis, i.e.
a) lower extremity DVT, caval vein thrombosis, upper extremity DVT, subclavian thrombosis, right 
atrial thrombosis and pulmonary embolism, and catheter-related thrombosis, or
b) cerebral vein and sinus thrombosis, jugular vein thrombosis, mesenteric vein thrombosis, portal 
vein thrombosis and renal vein thrombosis.
After randomization, children will receive either rivaroxaban, or comparator for a total of 30 days.
For all children, visits are scheduled at regular time points (see Figure 1-1). Randomized children 
who are not treated or those with premature discontinuation of study drug 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 
Figure 1-1).
New text: This is a single-arm, multicenter study evaluating the safety, efficacy and PK/PD profile of a 30-day 
treatment with age- and body weight-adjusted oral rivaroxaban in children aged between 6 months 
and < 6 years with various manifestations of symptomatic and asymptomatic venous thrombosis. 


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Children who have been treated for at least 2 months or in case of catheter-related thrombosis, 
treated for at least 6 weeks with LMWH, fondaparinux and/or VKA for symptomatic or 
asymptomatic venous thrombosis will receive age- and body weight-adjusted rivaroxaban. Before 
first study treatment administration, the documented index thrombotic event will be confirmed by 
the central adjudication committee (CIAC) for the child to be eligible for the study.
Allocation to treatment will be done centrally by an interactive voice/web response system (IxRS). 
The investigator will provide the IxRS with study center identification, the child’s date of birth (day, 
month and year), gender, weight and clinical presentation.
Please refer to the IxRS manual for further details.
Children will receive rivaroxaban for a total of 30 days.
For all children, visits are scheduled at regular time points (see Figure 1-1). Enrolled children who 
are not treated or those with premature discontinuation of study drug 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 
Figure 1-1).
16.2.2.6
Section 4.1: Planned number of children
This section was modified based on Amendment Change 3.
Old text:
Forty children (20 per treatment group) are planned to be enrolled in the study, of whom twenty will 
be in the 2 to < 6 year age group and twenty in the 6 months to < 2 year age group. Enrolment will 
start with the 2 to < 6 year age group, followed by the 6 months to < 2 year age group upon 
availability of the age and body weight adapted dosing regimen for the age group 6 months to < 
2 years.
New text: Twenty children (10 per age group) are planned to be treated with rivaroxaban. Enrolment will start 
with the 2 to < 6 year age group, followed by the 6 months to < 2 year age group upon availability 
of the age and body weight adapted dosing regimen for the age group 6 months to < 2 years.
16.2.2.7
Section 4.2: Inclusion criteria
This section was modified based on Amendment Change 2 and 4.
Old text:
1.
Children aged between 6 months to < 6 years who have been treated for at least 2 months or, in 
case of catheter related thrombosis, for at least 6 weeks with LMWH, fondaparinux and/or 
VKA for documented symptomatic or asymptomatic venous thrombosis and who will enter 
their last month of intended anticoagulant treatment
2.
Hemoglobin, platelets, creatinine and alanine aminotransferase (ALT) and bilirubin evaluated 
within 10 days prior to randomization
[…]
New text:
1.
Children aged between 6 months to < 6 years who have been treated for at least 2 months or, in 
case of catheter related thrombosis, for at least 6 weeks with LMWH, fondaparinux and/or 
VKA for documented symptomatic or asymptomatic venous thrombosis 
2.
Hemoglobin, platelets, creatinine and alanine aminotransferase (ALT) and bilirubin evaluated 
within 10 days prior to Visit 2
[…]


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16.2.2.8
Section 4.3: Exclusion criteria
This section was modified based on Amendment Change 1, 2 and 6.
Old text:
[…]
6.
Platelet count < 100 x 109/L
[…]
9.
Concomitant use of strong inhibitors of both CYP3A4 and P-gp, i.e. all human 
immunodeficiency virus protease inhibitors and the following azole-antimycotics agents: 
ketoconazole, itraconazole, voriconazole, posaconazole, if used systemically 
10. […]
11. Hypersensitivity or any other contraindication listed in the local labeling for the comparator 
treatment or experimental  treatment 
12. […]
13. Previous randomization to this study 
14. Participation in a study with an investigational drug or medical device within 30 days prior to 
randomization.
New text:
[…]
6. Platelet count < 50 x 109/L
[…]
9. Concomitant use of strong inhibitors of both CYP3A4 and P-gp, i.e. all human 
immunodeficiency virus protease inhibitors and the following azole-antimycotics agents: 
ketoconazole, itraconazole, voriconazole, posaconazole, if used systemically (fluconazole is 
allowed)
10. […]
11. Hypersensitivity or any other contraindication listed in the local labeling for the experimental  
treatment 
12. […]
13. Previous participation in this study 
14. Participation in a study with an investigational drug or medical device within 30 days prior to 
Visit 2.


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16.2.2.9
Section 4.4: Concomitant medication
This section was modified based on Amendment Change 1 and 2.
Old text:
Concomitant medications include either continuation of a treatment started before study 
randomization, or addition of a new treatment during the study. Non-steroidal anti-inflammatory 
drugs (NSAIDs) and antiplatelet agents are strongly discouraged since they increase the risk for 
bleeding in patients treated with heparins, fondaparinux and/or VKA or rivaroxaban. However, if 
such medication is indicated, the lowest possible dosage should be selected. 
Concomitant use of strong inhibitors of both CYP3A4 and P-gp, i.e. all human immunodeficiency 
virus protease inhibitors and azole-antimycotics agents (i.e. ketoconazole, itraconazole, 
voriconazole, posaconazole; concomitant treatment with fluconazole is allowed), if used 
systemically, is not allowed, as well as concomitant use of strong inducers of CYP3A4 (i.e. 
rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine). 
Any previous anticoagulant medication taken within 90 days prior to randomization will be 
documented.  Anticoagulant use after the study treatment period will also be documented.
New text: Concomitant medications include either continuation of a treatment started before Visit 2, or 
addition of a new treatment during the study. Non-steroidal anti-inflammatory drugs (NSAIDs) and 
antiplatelet agents are strongly discouraged since they increase the risk for bleeding in patients 
treated with anticoagulants. However, if such medication is indicated, the lowest possible dosage 
should be selected. 
Concomitant use of strong inhibitors of both CYP3A4 and P-gp, i.e. all human immunodeficiency 
virus protease inhibitors and azole-antimycotics agents (i.e. ketoconazole, itraconazole, 
voriconazole, posaconazole; concomitant treatment with fluconazole is allowed), if used 
systemically, is not allowed, as well as concomitant use of strong inducers of CYP3A4 (i.e. 
rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine). 
Any previous anticoagulant medication taken within 90 days prior to Visit 2 will be documented.  
Anticoagulant use after the study treatment period will also be documented.
16.2.2.10 Section 5: Treatment regimens
This section was modified based on Amendment Change 2.
Old text:
5. Treatment groups and regimens
New text: 5. Treatment regimen


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16.2.2.11 Section 5.1: Treatment
This section was modified based on Amendment Change 2.
Old text:
5.1: Method of treatment allocation
Allocation to treatment will be done centrally by an interactive voice/web response system (IxRS). 
Allocation will be stratified by baseline presentation of venous thrombosis i.e.
a) lower extremity DVT, caval vein thrombosis, upper extremity DVT, subclavian thrombosis, right 
atrial thrombosis, pulmonary embolism and catheter related thrombosis and
b) cerebral vein and sinus thrombosis, jugular vein thrombosis, mesenteric vein thrombosis, portal 
vein thrombosis and renal vein thrombosis.
Study treatment allocation will be done in a 1:1 ratio (rivaroxaban: standard of care), and will be 
done separately for the 2 to < 6 years age group and the 6 months to < 2 years age group.
The investigator will provide the IxRS with study center identification, the child’s date of birth 
(month and year), gender, weight and clinical presentation.
Procedures for treatment assignment through the IxRS are specified in the IxRS manual.
New text: 5.1 Treatment
In this study, only rivaroxaban will be used.
16.2.2.12 Section 5.1.1: Rivaroxaban 
This section was modified based on Amendment Change 2.
Old text:
5.1.1 Rivaroxaban group
New text: 5.1.1 Rivaroxaban
16.2.2.13 Section 5.1.1.1: Switching from VKA to rivaroxaban
This section was modified based on Amendment Change 2.
Old text:
If a child is on VKA therapy and has a supra-therapeutic INR (> 3.0), randomization into the study 
should be delayed. In case of an INR between 2.5 to 3.0, randomization can be done and, if 
allocated to rivaroxaban, the first rivaroxaban dose should be delayed to the next day. If the INR is 
below 2.5, randomization can be done and if allocated to rivaroxaban, the first rivaroxaban dose can 
be taken on the day of randomization. VKA therapy cannot be continued after randomization, if 
allocated to rivaroxaban.
New text: If a child is on VKA therapy and has a supra-therapeutic INR (> 3.0), rivaroxaban administration 
should be delayed. In case of an INR between 2.5 to 3.0, the first rivaroxaban dose should be 
delayed to the next day. If the INR is below 2.5, the first rivaroxaban dose can be taken at Visit 2.
VKA therapy must be stopped before rivaroxaban treatment commences.


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16.2.2.14 Section 5.1.1.2: Switching from heparin/fondaparinux to rivaroxaban
This section was modified based on Amendment Change 2.
Old text:
If the child received heparin treatment before randomization, randomization 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, or 12 - 24 hours after the last injection of fondaparinux or LMWH with a once-
daily regimen. Heparin/fondaparinux treatment cannot be continued after the start of rivaroxaban 
treatment in these children.
New text: If the child received heparin treatment before study treatment with rivaroxaban, rivaroxaban 
administration 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, or 12 - 24 hours after the last injection of 
fondaparinux or LMWH with a once-daily regimen. Heparin/fondaparinux treatment cannot be 
continued after the start of rivaroxaban treatment in these children
16.2.2.15 New Section 5.1.1.3: Switching from rivaroxaban to 
heparin/fondaparinux
This section was modified based on Amendment Change 5.
New text: 5.1.1.3: Switching from rivaroxaban to heparin/fondaparinux
Children who switch from rivaroxaban to heparin /fondaparinux can switch at the time of the next 
scheduled dose.
16.2.2.16 New Section 5.1.1.4: Switching from rivaroxaban to VKA
This section was modified based on Amendment Change 5.
New text: 5.1.1.4: Switching from rivaroxaban to VKA
Children who switch from rivaroxaban to VKA need to continue rivaroxaban for 48 hours after the 
first dose of VKA. After 2 days of co-administration, an INR should be obtained prior to the next 
scheduled dose of rivaroxaban. Co-administration of rivaroxaban and VKA is advised to continue 
until the INR is ≥ 2.0.
16.2.2.17 Section 5.1.2: Comparator group
This section was modified based on Amendment Change 2.
Old text:
Children randomized to the comparator group will continue with the anticoagulant treatment that 
was planned prior to study randomization. Thus, children who received heparins/ fondaparinux 
before randomization, continue with it after randomization. Children, who received VKA before 
randomization, continue with VKA after randomization. VKA dosages will be adjusted to maintain 
the INR within the therapeutic range (target 2.5, range 2.0 - 3.0). VKA therapy will be administered 
according to local guidelines. If a VKA dose was missed, it can only be taken the same day. Double 
dosing on a single day is not allowed. 
New text: This single-arm study does not include comparator treatment.


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16.2.2.18 Section 5.2: Subject identification
This section was modified based on Amendment Change 2.
Old text:
SID numbers will have to be used in sequence and no number should be skipped or substituted.
At Visit 2, Day 1, children will be assigned a unique randomization number by IxRS that will allow 
subsequent identification of treatment allocation.
New text: SID numbers will have to be used in sequence and no number should be skipped or substituted.
16.2.2.19 Section 5.4.1: Rivaroxaban
This section was modified based on Amendment Change 1.
Old text:
Rivaroxaban will be provided by Bayer as a 0.1% suspension. Rivaroxaban will be dosed according 
to body weight groups (see Table 5-1). Since children with a glomerular filtration rate below 
30 mL/min/1.73 m2 are excluded from the study, a dose adaptation is not indicated. 
New text: Rivaroxaban will be provided by Bayer as a 0.1% (1mg/ml) suspension. Rivaroxaban will be dosed 
according to body weight groups (see Table 5-1). Since children with a glomerular filtration rate 
below 30 mL/min/1.73 m2 are excluded from the study, a dose adaptation is not indicated.
16.2.2.20 Section 5.4.2: Comparator
This section was modified based on Amendment Change 2.
Old text:
Comparator will be used according to approved formulations
New text: This single-arm study does not include comparator treatment.
16.2.2.21 Section 5.5: Packaging, labeling, and storage
This section was modified based on Amendment Change 2.
Old text:
Comparator will be supplied from local commercial resources and provided by sites. If required by 
local regulations, Bayer will purchase the comparator from local sources, and label and distribute to 
investigative centers.
[…]
Comparator provided by sites will be documented in the hospital/pharmacy records.


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16.2.2.22 Section 5.6: Treatment assignment
This section was modified based on Amendment Change 2.
Old text:
After randomization, the randomization number of the child will be recorded on the corresponding 
electronic case report form (eCRF). Subject identification number will have to be recorded on the 
label of the study medication.
In case LMWH, fondaparinux and/or VKA is provided by sites, the compound’s name, dose, 
quantity and batch number or a copy of the prescription must be included in the child’s files.
New text: Not applicable.
16.2.2.23 Section 5.7: Dosage and administration
This section was modified based on Amendment Change 2.
Old text:
Comparator treatment consists of locally used anticoagulants for VTE treatment, specified in Table 
5-2. 
Table 5-2:
Overview of comparator treatment
Generic name
Dosage 
Warfarin
INR 2.0-3.0
Acenocoumarol
INR 2.0-3.0
Phenprocoumon
INR 2.0-3.0
Enoxaparin
1 mg/kg  b.i.d.
Fondaparinux
0.1 mg/kg o.d.
Tinzaparin
2-12 mo
250 u/kg o.d.
1- 5 yrs
240 u/kg o.d.
5-10 yrs
200 u/kg o.d.
Dalteparin
129 ± 43 u/kg/dose o.d.
b.i.d. : twice daily; o.d.: once daily; u:units
Source: (10)
The comparator list above is not all-inclusive.
New text: Rivaroxaban will be dosed according to body weight as oral 0.1% suspension.


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16.2.2.24 Section 5.8: Treatment compliance
This section was modified based on Amendment Change 2.
Old text:
5.8.2 Vitamin K antagonists 
Compliance with VKA treatment will only be ensured by the use of INR, with a minimum of 1 INR 
per 2 weeks. The date of first and last intake with specifications of the brand and all INR values and 
the actual measurement dates will be documented. This information will be obtained directly from 
the child’s file or transmitted by the INR-monitoring physician or laboratory.
5.8.3 Low molecular weight heparin/fondaparinux
Instruction will be given to return all unused syringes at Visit 3, Visit 4 and, if applicable, at the 
premature discontinuation visit. Compliance will be evaluated by counting remaining syringes. All 
non-dispensed syringes should be kept securely in the original containers in a designated locked 
container until retrieved or dispensed.
16.2.2.25 Section 6.1: Study visits
This section was modified based on Amendment 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 venous 
thrombosis. This visit will take place 60 to 10 days before the last month of intended 
anticoagulation treatment.
Visit 2 is the randomization visit and will be a hospital visit. Eligible children will be randomized to
30 days of anticoagulation with study medication (day 1).
Visit 3 and Visit 4 are the treatment and end of treatment visits, respectively. These visits will be 
hospital visits which will take place at Day 15 ± 5 days, and Day 30 ± 3 days, respectively. At visit 
2, 3 and 4, PK/PD blood sampling will be done in the rivaroxaban group only. At Visit 4, the study 
medication will be stopped. After cessation of study treatment, it is at the investigator’s discretion to 
continue with anticoagulation, as needed. Repeat imaging will be obtained if applicable.
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 venous 
thrombosis. This visit will take place 60 to 10 days before Visit 2.
Visit 2 is the first study drug administration day and will be a hospital visit. Eligible children will 
receive rivaroxaban for 30 days.
Visit 3 and Visit 4 are the treatment and end of treatment visits, respectively. These visits will be
hospital visits which will take place at Day 15 ± 5 days, and Day 30 ± 3 days, respectively. At visit 
2, 3 and 4, PK/PD blood samples will be drawn. At Visit 4, the study medication will be stopped. 
After cessation of study treatment, it is at the investigator’s discretion to continue with 
anticoagulation, as needed. Repeat imaging will be obtained if applicable.


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16.2.2.26 Section 6.2: Visit 1 - Screening visit at 60 to 10 days before Visit 2
This section was modified based on Amendment Change 2.
Old text:
Adverse events will not be collected between visit 1 and visit 2.  Since hemoglobin, platelet counts, 
creatinine and liver function 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, and bilirubin within 10 days prior to randomization is an inclusion criterion for this 
study (see section 4.2).
New text: Adverse events will not be collected between visit 1 and visit 2.  Since hemoglobin, platelet counts, 
creatinine and liver function 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, and bilirubin within 10 days prior to Visit 2 is an inclusion criterion for this study 
(see section 4.2)


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16.2.2.27 Section 6.3. Visit 2 - Treatment visit at Day 1
This section was modified based on Amendment Change 1 and 2.
Old text:
6.3. Visit 2 - Randomization visit at Day 1
If the CIAC confirmed the qualifying venous thrombotic event, then re-confirm eligibility. If results 
for hemoglobin, platelets, creatinine, ALT, bilirubin were not available within 10 days prior to 
randomization, obtain blood sample. If the child still meets the inclusion criteria and does not meet 
any of the exclusion criteria, the child can be randomized. 

If a child is on VKA therapy and has a supra-therapeutic INR (> 3.0), randomization into 
the study should be delayed. In case of an INR below 3.0, randomization can be done.  If 
randomized to VKA, treatment with VKA should continue. If randomized to rivaroxaban, 
VKA should be stopped and the timing of the administration of the first rivaroxaban dose 
will depend on the INR (see also section 5.1.1.1).
If the INR is below 2.5, the first rivaroxaban dose should be taken on the day of randomization.
[…]

Administer the assigned study drug 

In children allocated to rivaroxaban, 

administer the first rivaroxaban dose and document the volume and type of fluid used to 
predilute the rivaroxaban oral suspension, as well as the volume and type of fluid taken 
after the study drug administration.

document the exact time of drug intake and the time and type of meal (e.g. breast feeding, 
baby bottle, porridge, breakfast, lunch, snack, dinner) the child took 2 hours before, during 
and after study drug administration. 

at 0.5-1.5 hr after drug intake, collect only a PK blood sample

at 2.5-4 hr after drug intake, collect a PK blood sample followed by the PD blood sample. 
[…]

In children allocated to rivaroxaban, instruct to 1) document in the study booklet the exact 
time of the last dose taken on the day prior to Visit 3, 2) the exact time and type of meal the 
child took 2 hours before, during and after study drug administration, 3) the volume and 
type of fluid used to predilute the rivaroxaban oral suspension and 4) the volume and type 
of fluid taken after the study drug administration.
[…]


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New text: 6.3. Visit 2 - Treatment visit at Day 1
If the CIAC confirmed the qualifying venous thrombotic event, then re-confirm eligibility. If results 
for hemoglobin, platelets, creatinine, ALT, bilirubin were not available within 10 days prior to 
Visit 2, obtain blood sample. If the child still meets the inclusion criteria and does not meet any of 
the exclusion criteria, the child can receive rivaroxaban. 

If a child is on VKA therapy and has a supra-therapeutic INR (> 3.0), the first 
administration of rivaroxaban should be delayedVKA therapy should be stopped and the 
timing of the administration of the first rivaroxaban dose will depend on the INR (see also 
section 5.1.1.1).
If the INR is below 2.5, the first rivaroxaban dose should be taken at Visit 2.
[…]

Administer first dose of rivaroxaban oral suspension

Document the volume and type of fluid used to predilute the rivaroxaban oral suspension, 
as well as the volume and type of fluid taken after the study drug administration.

Document the exact time of drug intake and the time and type of meal (e.g. breast feeding, 
baby bottle, porridge, breakfast, lunch, snack, dinner) the child took 2 hours before, during 
and after study drug administration. 

At 0.5-1.5 hr after drug intake, collect only a PK blood sample

At 2.5-4 hr after drug intake, collect a PK blood sample followed by the PD blood sample. 
[…]

Instruct to 1) document in the study booklet the exact time of the last dose taken on the day 
prior to Visit 3, 2) the exact time and type of meal the child took 2 hours before, during and 
after study drug administration, 3) the volume and type of fluid used to predilute the 
rivaroxaban oral suspension and 4) the volume and type of fluid taken after the study drug 
administration.
[…]


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16.2.2.28 Section 6.4: Visit 3 - Treatment visit at Day 15 (+/- 5 days)
This section was modified based on Amendment Change 1 and 2.
Old text:
[…]

In children randomized to rivaroxaban

administer the next rivaroxaban dose and document the volume and type of fluid used to 
predilute the rivaroxaban oral suspension, as well as the volume and type of fluid taken 
after the study drug administration.

document the exact time of drug intake and type of meal the child took 2 hours before, 
during and after drug administration

complete the Taste-and-Texture Questionnaire for children older than 4 years

at 2 – 8 hr after drug intake, collect a post-dose PK blood sample followed by the PD blood 
sample 

document the exact time of blood sampling for PK/PD. 
[…]

In children allocated to rivaroxaban, inform that on the day before visit 4
[…]
New text:
[…]

Administer the next rivaroxaban dose and document the volume and type of fluid used to 
predilute the rivaroxaban oral suspension, as well as the volume and type of fluid taken 
after the study drug administration.

Document the exact time of drug intake and type of meal the child took 2 hours before, 
during and after drug administration

Complete the Taste-and-Texture Questionnaire for children older than 4 years

At 2 – 8 hr after drug intake, collect a post-dose PK blood sample followed by the PD 
blood sample 

Document the exact time of blood sampling for PK/PD. 
[…]

Inform that on the day before visit 4
[…]
16.2.2.29 Section 6.5: Visit 4 - End of study treatment visit at Day 30 (+/- 3 days)
This section was modified based on Amendment Change 2.
Old text:
[…]

In children randomized to rivaroxaban
[…]


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16.2.2.30 Section 6.9: Recommendations before and after invasive procedures 
and surgical intervention 
This section was modified based on Amendment Change 2.
Old text:
For the comparator please follow the respective product label.
16.2.2.31 Section 6.10: Management of bleeding in children
This section was modified based on Amendment Change 2.
Old text:

Delay the next LMWH, fondaparinux, VKA or rivaroxaban administration or discontinue 
treatment, if indicated

If the child is treated with VKA, consider vitamin K administration

If the child is treated with LMWH, consider protamine sulfate administration

[…]

If the child is treated with rivaroxaban, obtain the PK/PD sample.
New text:

[…]

Obtain the PK/PD sample.
16.2.2.32 Section 6.12: PK/PD assessments
This section was modified based on Amendment Change 2.
Old text:
Blood samples will be taken for PK and PD measurements from children randomized to 
rivaroxaban. 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:
New text: Blood samples will be taken for PK and 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:


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16.2.2.33 Section 6.13: Study booklet
This section was modified based on Amendment Change 2.
Old text:
Parents/children will receive a booklet with the following information for both treatment groups:
[…]
For the rivaroxaban treatment group
[…]
For the comparator group

How to use comparator

The planned dates of blood collections for the next INR control, if VKA is used

Instruction to insert the INR values (if available).
New text: Parents/children will receive a booklet with the following information:
[…]
16.2.2.34 Section 7.2: Analysis sets
This section was modified based on Amendment Change 2.
Old text:
Full analysis set (FAS):  This analysis set will include all randomized children. 
Safety analysis set (SAS): This analysis set will include all randomized children who received at 
least one dose of study medication.
Per protocol set (PPS): This population includes all randomized children who completed the 30-day 
treatment period. The PPS may also exclude major protocol deviations. Further details will be 
specified in the Statistical Analysis Plan.
New text: Full analysis set (FAS):  This analysis set will include all enrolled children. 
Safety analysis set (SAS): This analysis set will include all enrolled children who received at least 
one dose of study medication.
Per protocol set (PPS): This population includes all enrolled children who completed the 30-day 
treatment period. The PPS may also exclude major protocol deviations. Further details will be 
specified in the Statistical Analysis Plan.
16.2.2.35 Section 7.3: Demographic and other baseline characteristics
This section was modified based on Amendment Change 2.
Old text:
Summary statistics (arithmetic mean, standard deviation, median, minimum and maximum for 
quantitative variables) will be presented by treatment.  Frequency tables for qualitative data will be 
provided.  Medical history findings will be summarized using Medical Dictionary for Regulatory 
Activities (MedDRA) terms.
New text: Summary statistics (arithmetic mean, standard deviation, median, minimum and maximum for 
quantitative variables) will be presented by age group.  Frequency tables for qualitative data will be 
provided.  Medical history findings will be summarized using Medical Dictionary for Regulatory 
Activities (MedDRA) terms. 


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16.2.2.36 Section 7.4: Safety analysis
This section was modified based on Amendment Change 2.
Old text:
Individual listings of major and clinically relevant non-major bleeding will be provided. The 
incidence of bleeding will be summarized by treatment. 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 by treatment for
the original data as well as for the difference to baseline.  Frequency tables will be provided for 
qualitative data.
New text: Individual listings of major and clinically relevant non-major bleeding will be provided. The 
incidence of bleeding will be summarized descriptively. 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 descriptively for
the original data as well as for the difference to baseline.  Frequency tables will be provided for 
qualitative data. 
16.2.2.37 Section 7.5: Efficacy analysis
This section was modified based on Amendment Change 2.
Old text:
All efficacy analyses will be performed on the FAS population. The occurrence of recurrent venous 
thromboembolism and asymptomatic deterioration in thrombotic burden will be summarized by 
treatment.
New text: All efficacy analyses will be performed on the FAS population. The occurrence of recurrent venous 
thromboembolism and asymptomatic deterioration in thrombotic burden will be summarized by age 
group.
16.2.2.38 Section 7.8: Determination of sample size
This section was modified based on Amendment Change 3.
Old text:
A total of 40 children who took at least one dose of study medication are planned to be enrolled in 
the study. The sample size does not originate from a formal sample size calculation, but is based on 
a feasibility assessment because of the very low incidence of venous thrombosis in children, and on 
the pharmacokinetic moderate inter-individual variability of rivaroxaban. Based on past experience 
in obtaining parental consent in this indication, it is estimated that fewer than 10% of eligible 
children can be enrolled in this study.
New text: A total of 20 children who took at least one dose of study medication are planned to be enrolled in 
the study. The sample size does not originate from a formal sample size calculation, but is based on 
a feasibility assessment because of the very low incidence of venous thrombosis in children, and on 
the pharmacokinetic moderate inter-individual variability of rivaroxaban. Based on past experience 
in obtaining parental consent in this indication, it is estimated that fewer than 10% of eligible 
children can be enrolled in this study.


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16.2.2.39 Section 7.9: Adverse events (AE)
This section was modified based on Amendment Change 2.
Old text:
Individual listings of adverse events (including treatment group, age, weight, height, gender, 
adverse event as reported, start, duration, severity and relation to study drug) will be provided.  The 
incidence of treatment-emergent adverse events will be summarized by treatment using MedDRA 
preferred terms grouped by primary system organ class.
New text: Individual listings of adverse events (including age, weight, height, gender, adverse event as 
reported, start, duration, severity and relation to study drug) will be provided.  The incidence of 
treatment-emergent adverse events will be summarized by age group using MedDRA preferred 
terms grouped by primary system organ class.
16.2.2.40 Section 7.9.9: AEs of special safety interest
This section was modified based on Amendment Change 6.
Old text:
[…]

A platelet count below 100 x 109/L.
New text:
[…]

A platelet count below 50 x 109/L.


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17.
Appendices 
17.1
Methods and measurements
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.  
17.2
Estimated glomerular filtration rate
If serum creatinine (SCr) is measured with routine methods that have not been recalibrated to 
be traceable to isotope dilution mass spectrometry (IDMS) (e.g. the traditional Jaffé reaction), 
the eGFR should be obtained from the original Schwartz formula: (12)
eGFR (mL/min/1.73 m2) = k * height (cm) / SCr (mg/dL)
Where k is proportionality constant:
k = 0.55 in children up to 13 years of age
k = 0.70 in boys >13 years and <18 years of age (not in girls; because of the 
presumed increase in male muscle mass, the constant remains 0.55 for girls)
If SCr is measured by an enzymatic creatinine method that has been calibrated to be traceable 
to IDMS, the updated Schwartz formula should be used to obtain the eGFR: (13)
eGFR (mL/min/1.73 m2) = 0.413 * height (cm) / SCr (mg/dL)
The National Kidney Disease Education Program website 
(http://www.nkdep.nih.gov/professionals/gfr_calculators/index.htm) offers electronic 
calculators of eGFR in the pediatric population based on the updated Schwartz formula.
Note:  To express SCr in micromoles per liter, the value should be multiplied by 88.4 (1 mg/dL = 88.4 mol/L).
Rivaroxaban (BAY-59-7939, JNJ-39039039) is being co-developed under a collaboration and license agreement 
between Bayer HealthCare AG (BHC) and Ortho McNeil Pharmaceuticals, Inc. (OMP) dated 01 Oct 2005.  As 
determined by the parties, both BHC and Janssen Pharmaceuticals Inc. (successor in interest to OMP) 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.

SAP_001.pdf: 
 
Document Type: Statistical Analysis Plan 
Official Title: 
30-day, single-arm study of the safety, efficacy and the 
pharmacokinetic and pharmacodynamic properties of oral 
rivaroxaban in young children with various manifestations of 
venous thrombosis 
NCT Number: 
NCT02309411 
Document Date: 
28 Apr 2017 
 


Statistical Analysis Plan
Protocol No.: BAY 59-7939/14374
Page: 1 of 19
Reference Number: RD-OI-0119
Supplement Version: 8
30-day, single-arm study of the safety, efficacy and the pharmacokinetic 
and pharmacodynamic properties of oral rivaroxaban in young children 
with various manifestations of venous thrombosis1
EINSTEIN Junior Phase II-part B: oral rivaroxaban in young children with venous 
thrombosis
Bayer study drug
BAY 59-7939/rivaroxaban/Xarelto
Clinical study 
phase:
II
Date:
28 Apr 2017
Study No.:
14374
Version:
2.0
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.
                                                
1 Title was modified via Protocol Amendment 4
PPD


Statistical Analysis Plan
Protocol No.: BAY 59-7939/14374
Page: 2 of 19
Reference Number: RD-OI-0119
Supplement Version: 8
Table of Contents
1.
Introduction........................................................................................................................6
2.
Study Objectives ................................................................................................................6
3.
Study Design.......................................................................................................................6
3.1
Study population...............................................................................................................6
3.2
Treatment regimen............................................................................................................7
3.3
Outcomes..........................................................................................................................7
4.
General Statistical Considerations...................................................................................8
4.1
General Principles ............................................................................................................8
4.2
Handling of Dropouts.......................................................................................................8
4.3
Handling of Missing Data ................................................................................................8
4.4
Interim Analyses and Data Monitoring ............................................................................9
4.5
Data Rules ......................................................................................................................10
4.5.1
Baseline laboratory values ..........................................................................................10
4.5.2
Compliance .................................................................................................................10
4.5.2.1
Rivaroxaban.............................................................................................................10
4.5.2.2
LMWH or Fondaparinux .........................................................................................10
4.5.2.3
Vitamin K antagonists..............................................................................................11
4.6
Blind Review..................................................................................................................11
5.
Analysis Sets.....................................................................................................................11
5.1
Assignment of analysis sets............................................................................................11
6.
Statistical Methodology ...................................................................................................12
6.1
Population characteristics...............................................................................................12
6.1.1
Demography, medical history, populations for analysis.............................................12
6.1.2
Prior medication for treatment of index venous thrombosis.......................................12
6.1.3
Description of the index venous thrombosis...............................................................13
6.1.4
Concomitant medication .............................................................................................13
6.1.4.1
Tabulation of concomitant antithrombotics started after stop of study medication.13
6.2
Bleeding analysis............................................................................................................13
6.3
Efficacy...........................................................................................................................14
6.3.1
Sensitivity analysis to account for dropouts................................................................14
6.4
Pharmacokinetics / pharmacodynamics .........................................................................15
6.5
Safety..............................................................................................................................15
6.5.1
Study drug exposure and compliance .........................................................................15
6.5.1.1
Summary of treatment duration ...............................................................................15
6.5.1.2
Summary of compliance ..........................................................................................15
6.5.1.3
Summary of INR measurements for the VKA treatment.........................................15
6.5.2
Adverse events ............................................................................................................16
6.5.3
Laboratory measurements ...........................................................................................16
6.6
Pre-specified subgroup analysis .....................................................................................16
6.6.1
Analysis by baseline characteristics............................................................................16


Statistical Analysis Plan
Protocol No.: BAY 59-7939/14374
Page: 3 of 19
Reference Number: RD-OI-0119
Supplement Version: 8
6.7
Taste and texture questionnaire......................................................................................16
7.
Document history and changes in the planned statistical analysis..............................16
8.
References.........................................................................................................................18
9.
Appendix...........................................................................................................................19
9.1
Sample size and power considerations...........................................................................19
9.2
Example OpenBUGS code for sensitivity analysis of the primary efficacy outcome....19


Statistical Analysis Plan
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Page: 4 of 19
Reference Number: RD-OI-0119
Supplement Version: 8
Abbreviations
ADS
Analysis dataset
AE
adverse event
AG
Aktiengesellschaft, joint stock company
ALT
alanine aminotransferase
anti-Xa
anti-factor Xa activity
aPTT
activated or adjusted partial thromboplastin time
AUC
Area under the curve
BAY
sponsor’s reference number for drugs
b.i.d.
twice daily
CI
Confidence interval
CIAC
central independent adjudication committee 
CRF
Case Report Form
CSR
Clinical Study Report
CT
computed tomography
dL
deciliter
DMC
data monitoring committee
DVT
deep vein thrombosis
eCRF
electronic case report form
e.g.
exempli gratia, for example
eGFR
estimated glomerular filtration rate
GCP
Good Clinical Practice
Hb
hemoglobin
HR
hazard ratio
IDMS
isotope dilution mass spectrometry
i.e.
id est, that is
ICH
International Committee on Harmonization
IEC
Independent Ethics Committee
INR
international normalized ratio 
IRB
Institutional Review Board
ITT
Intent-to-treat
IxRS
interactive voice/web response system
LLOQ
Lower limit of quantification
LMWH
low molecular weight heparin
LOS
listing only set
MCMC
Monte Carlo Markov Chain
MedDRA
Medical Dictionary for Regulatory Activities
Mg
milligram
Min
minute
ml
milliliter
mmHg
millimeter of mercury
MR(I)
magnetic resonance (imaging)


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NA
Not applicable
NI
non-inferiority
o.d.
once daily
PD
pharmacodynamics
PE
pulmonary embolism
PD
pharmacodynamics
PK
pharmacokinetic(s)
PPS
Per-protocol set
SAE
serious adverse event
PT
prothrombin time
SAP
statistical analysis plan
SoC
standard of care 
TOSCA
Tools for Syntactic Corpus Analysis database system
UFH
unfractionated heparin
VKA
vitamin K antagonist
VTE
venous thromboembolism


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1.
Introduction
This SAP is based on the Clinical Study Protocol version 1.0 (04 Mar 2014), Global 
Amendment 1 (forming Integrated Protocol version 2.0, dated 02 Sep 2014), Local 
Amendment 2 (applicable to Japan only) to Clinical Study Protocol (21 Oct 2014), Local 
Amendment 3 (applicable to Canada only) to Clinical Study Protocol (28 Oct 2014), Global 
Amendment 4 (forming Integrated Protocol version 3.0, dated 14 Apr 2015), Local 
Amendment 5 (applicable to Canada only) to Clinical Study Protocol (16 Jun 2015).
“The goal of the rivaroxaban pediatric program is to make rivaroxaban available to children 
for treatment and secondary prevention of venous thromboembolism. To accomplish this 
goal, it will be necessary to evaluate a pediatric age- and body weight adapted dosing 
regimen, and to address the safety and efficacy of rivaroxaban.” 
For more details see Integrated Protocol, Section 1.
2.
Study Objectives
The primary objective is:

to assess the incidence of major bleeding and clinically relevant non-major bleeding
The secondary objectives are:

to assess the incidence of recurrent symptomatic venous thromboembolism

to assess asymptomatic deterioration in the thrombotic burden on repeat imaging

to characterize the pharmacokinetic/pharmacodynamic profile of a 30-day treatment 
with oral rivaroxaban. 
3.
Study Design
This is a single-arm, multicenter study evaluating the safety, efficacy and PK/PD profile of a
30-day treatment with age- and body weight-adjusted oral rivaroxaban in children aged
between 6 months and < 6 years with various manifestations of symptomatic and
asymptomatic venous thrombosis (Comparator arm was removed via Amendment 4; up to 
Protocol Amendment 4 it was an active-controlled randomized study). 
The treatment period will be followed by a 30-day post study treatment period, regardless of 
the duration of study drug administration. After cessation of study treatment, it is at the 
investigator’s discretion to continue with anticoagulants.
For further details see Integrated Protocol, Section 3.
3.1
Study population
Twenty children (10 per age group) are planned to be treated with rivaroxaban in total 
according to Protocol Amendment 4. Enrolment will start with the 2 to < 6 year age group, 
followed by the 6 months to < 2 year age group upon availability of the age and body weight 


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adapted dosing regimen for the age group 6 months to < 2 years (before Protocol Amendment 
4 forty children; 20 per treatment group were planned to be enrolled and randomized to either 
rivaroxaban or standard of care).
Children who have been treated for at least 2 months or in case of catheter-related 
thrombosis, treated for at least 6 weeks with LMWH, fondaparinux and/or VKA for 
symptomatic or asymptomatic venous thrombosis will receive age- and body weight-adjusted 
rivaroxaban. Before first study treatment administration, the documented index thrombotic 
event will be confirmed by the central adjudication committee (CIAC) for the child to be 
eligible for the study. For further details see Integrated Protocol, Sections 3 and 4.
3.2
Treatment regimen
In this study, only rivaroxaban will be used after Protocol Amendment 4. Allocation to 
treatment will be done centrally by an interactive voice/web response system (IxRS; before 
Protocol Amendment 4 allocation was to be stratified by baseline presentation of venous 
thrombosis and it was to be done in a 1:1 ratio for rivaroxaban: standard of care, separately 
by age groups). The IxRS will initially restrict enrollment to children in the age group 
between 2 and less than 6 years. Once the age-and body weight adjusted dosing regimen has 
been confirmed for the age group 6 months to < 2 years, the IxRS will allow enrollment for 
this age group as well.
For further details see Integrated Protocol, Sections 3 and 5.
3.3
Outcomes

The primary safety outcome is the composite of major bleeding and clinically relevant 
non major bleeding. 

Other safety outcomes:
o
all deaths
o
other vascular events (myocardial infarction, cerebrovascular accident, non-
CNS systemic embolism).

Efficacy outcomes:
o
Symptomatic recurrent VTE (composite of DVT and fatal or non-fatal PE)
o
Composite of symptomatic recurrent VTE and asymptomatic deterioration on
appropriate imaging test
All index venous thrombotic events, and all suspected recurrent venous 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. Adjudication results will be the basis for the final analyses.
For further details see Sections 6.8, 6.11 and 6.14.2 of the Integrated Protocol as well.


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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) and other specialized software can be used for 
sensitivity analysis. All variables will be analyzed by descriptive statistical methods. The 
number of data available and missing data (nmiss), mean, standard deviation, minimum, 
quartiles, median, and maximum will be calculated for metric data. Frequency tables will be 
generated for categorical data.
As children were to be randomized also to standard of care before Protocol Amendment 4 
comes into effect, data from these children will be presented separately in tables and listings 
where applicable.
The analysis datasets (ADS) standards for Xarelto will be applied.
4.2
Handling of Dropouts
For all children, visits are scheduled at regular time points (see study flow chart on Figure 1-1 
of the Integrated Protocol and Local Amendments). Enrolled children who are not treated or 
those with premature discontinuation of study drug 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 study flow chart on Figure 1-1 of the Integrated Protocol).
For further details about collecting data from children who prematurely discontinue study 
medication see Integrated Protocol Sections 3 and 7.10.
4.3
Handling of Missing Data
All missing or partial data will be presented in the subject data listing as they are recorded on 
the Case Report Form (CRF). 
The number of subjects who prematurely discontinue the study treatment and/or the study for 
any reason, as well as the reasons for premature discontinuation of study treatment will be 
reported for the treatment period. Days to end of study treatment and days to last visit will be 
listed for subjects who prematurely terminate study treatment. 
Baseline characteristics will be summarized descriptively by non-completers (prematurely 
discontinuation the study treatment and/or the study respectively) versus completers. 
The number of missing repeat imaging tests, number of missing laboratory values at baseline 
and at visit 4, number of missing weight values will be displayed by means of descriptive 
statistics for the rivaroxaban group and separately for children who randomized to standard of 
care before Protocol Amendment 4 comes into effect.
General rules


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When appropriate, the following rules will be implemented so as not to exclude subjects from 
statistical analyses due to missing or incomplete data:

Index thrombosis
For cases where start month and year are reported but day is missing, impute it with 
the complete start date of pre-treatment or if no complete start date is available, with
15. For cases where months and/or year is missing impute it with the complete start 
date of pre-treatment or if no complete start date is available, no imputation will be 
done.

Start and stop dates for pre-treatment of index events 
Missing start date will be imputed as max [(01, available month or 01, available year 
or IxRS year) and available complete date of index event]. Missing stop dates will be 
imputed as date of IxRS assignment.

Safety and efficacy clinical outcomes, adverse events
For cases where start month and year are reported but day is missing, impute the 
maximum of (date of IxRS assignment, first date of study medication, 01.month.year). 
For cases where only start year is reported, impute the maximum of (date of IxRS 
assignment, first date of study medication, 01.01.year), but not later than death date if 
the patient died.

Study medication start date
If the start day of study medication is missing then the start date  will be imputed as 
the maximum of (date of IxRS assignment, 01.month.year). Otherwise if start month 
is also missing then the start date will be imputed with the date of IxRS assignment. If 
start date and time is recorded as earlier than IxRS assignment and cannot be clarified, 
date and time of IxRS assignment will be used for the statistical analysis.
Study medication stop date
If stop date is missing and there is an adverse event with action taken ‘study medication 
discontinued permanently’ then the stop date of study medication will be imputed by the start 
date of that adverse event. 
Otherwise if the stop day is missing, but the stop month and stop year are available then the 
stop date will be imputed as minimum of [(15, month, year) and the last study visit date 
before the observational visit and death date]. If the stop day and month are missing then the 
stop date will be imputed as minimum of [the last study visit date before the observational 
visit and death date].
4.4
Interim Analyses and Data Monitoring
No interim analysis will be performed.
An independent Data Monitoring Committee (DMC) will monitor the children’s safety and 
give recommendations to the steering committee. The DMC has the responsibility to provide 
the steering committee and the sponsor 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 
thromboembolic events and bleedings. Organizational aspects, responsibilities, and processes 


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will be described in the DMC charter. For further details see also Section 6.14.3 of the 
Integrated Protocol .
4.5
Data Rules
4.5.1
Baseline laboratory values
Hemoglobin (Hb), platelets, creatinine, alanine aminotransferase (ALT), total and direct 
bilirubin prior to Visit 2 will be considered for the baseline. If a blood creatinine value is not 
available up to IxRS assignment, the value from the sample taken no later than 14 days after 
IxRS assignment will be considered. In case of more than one available lab value the non-
missing value closest to IxRS assignment will be taken. If the estimated glomerular filtration 
rate (eGFR) was not calculated then it will be calculated depending on the blood creatinine 
measurement method with original Schwartz formula or with the updated Schwartz formula 
as given in the Integrated Protocol Appendix 17.2 if all other required measurements (gender, 
age, height) are available. For patients from Japan the formula recommended by the Japanese 
Society for Pediatric Nephrology will be used as given in the Local Protocol Amendment 2 
for Japan.
As in this study there is no pre-dose PD sampling at Day 1, the 10-16 hr post dose PD value
at Visit 4 will be used as comparison/reference value per subject.
4.5.2
Compliance
4.5.2.1
Rivaroxaban 
Overall compliance will be calculated for the actual treatment period (final stop date minus 
start date + 1 day) as total volume of suspension taken divided by the total volume of 
suspension to be taken considering required dose (volume) given the weight of the child and 
b.i.d. regimen between the first intake and last intake dates in the main treatment period. The 
total volume of suspension taken will be derived as the sum of amount taken for each bottle 
dispensed. The amount administered from a bottle will be calculated as the difference 
between the dispensed and returned amount. If the difference would be negative then the 
amount administered will be 0 (the volume dispensed could be larger as nominal 45 mL). If 
the volume returned is missing, but the investigator stated in the CRF that the patient took all 
medications not returned then the amount of taken will be the amount of dispensed. If the 
amount administered is also given then this will be considered. If the volume of dispension 
taken by the patient cannot be determined for a bottle, because no bottle is returned and the 
amount administered is not stated, it will be assumed that the prescribed amount of study 
medication has been taken from the bottle unless the investigator commented it explicitly as 
non-compliance.
4.5.2.2
LMWH or Fondaparinux
This section is applicable only if a patient received LMWH or Fondaparinux as study 
medication before Protocol Amendment 4.
The visit compliance will be calculated as number of syringes administered divided by 
number of syringes to be administered between the two visits considering b.i.d. or o.d. 
regimen given the medication. In addition, Overall compliance will be calculated for the 30 


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days treatment period as total number of syringes administered divided by the total number of 
syringes to be administered considering b.i.d. or o.d. regimen between the first intake and last 
intake dates in the main treatment period. 
4.5.2.3
Vitamin K antagonists
This section is applicable only if a patient received VKA as study medication before Protocol 
Amendment 4.
The Integrated Protocol  states that at least one international normalized ratio (INR) 
measurement is required per two weeks. For calculation of compliance, the following rules 
will be applied: 
The treatment period will be split up in periods of 14+5=19 days. If the last period is shorter 
than 15 days, the actual length relative to 19 days will be calculated, i.e. less than one (for 
example, if the subject stopped study medication on day 22, his 2nd period had a relative 
length of (22-19)/ 19=0.16). The number of these periods will be the denominator for the 
calculation of compliance including the last period which can be numerically less than one. 
Using the example above, the subject’s denominator would be 1.16 (i.e. less than 2 full 
periods). If a subject received study medication for less than 19 days, the denominator will be 
one.
For the numerator it will be counted in how many periods INR measurements were done.
4.6
Blind Review
The results of the  final data assessment will be documented in the final list of important 
deviations, validity findings and assignment to analysis set(s). Any changes to the statistical 
analysis prompted by the results of the  review  of study data will be documented in an 
amendment and, 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 
review of study data and documented in the final list of important deviations, validity 
findings and assignment to analysis set(s) (see Section 4.6).
Full analysis set:  This analysis set will include all enrolled children (except screening 
failures). 
Safety analysis set: This analysis set will include all enrolled children who received at least 
one dose of study medication.
Per protocol set: This population includes all enrolled children who had at least 25 days 
study treatment. Children who discontinued study treatment earlier than 25 days due to an 
efficacy or bleeding outcome or due to death or due to a procedure defined in the study 
protocol or withrew consent will not be excluded from the per protocol set. Children with a 
calculated compliance less than 50% will be excluded from the per protocol set, calculated 


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compliance between 50% and less than 80% and greater than 120% is considered as minor 
protocol deviation. These definitions are considered as clarifications to the definitions in the 
study protocol. The per protocol set may also exclude other major protocol deviations. 
Further details will be specified in the in the Protocol Deviation Document and in the 
Validity Review Report.
In addition to the analysis population defined in the study protocol, the following 
population will be used as well.
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).
Listing only set: This population includes all screening failures. 
6.
Statistical Methodology
Treatment groups will be displayed as study medication administered. 
6.1
Population 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. Descriptive statistics will be provided for all data combined  and for each age 
cohort. Data from children received standard of care study treatment (i.e. randomized in the 
study before Protocol Amendment 4 coming into effect) will be summarized as separate
treatment group.
6.1.1
Demography, medical history, populations for analysis
Age, sex, race, ethnicity, weight, height, body mass index, systolic and diastolic blood 
pressure at baseline will be described by appropriate summary statistics. Medical history 
findings will be summarized using Medical Dictionary for Regulatory Activities (MedDRA) 
Primary System Organ Class / High Level Term / Preferred Term.
6.1.2
Prior medication for treatment of index venous thrombosis 
In the tabulation of prior medication of index event all anticoagulants will be tabulated that 
were categorized as prior medication. Type of initial treatment of the index event and 
duration of initial treatment will be summarized by descriptive statistics. If fondaparinux was 
categorized as LMWH pre-treatment of index thrombosis by the investigator, it will be 
grouped to fondaparinux for the purpose of tabulation. Duration of pre-treatment for the 
patients on rivaroxaban study medication will be calculated as min(start of rivaroxaban, stop 
date + 1 day) – start date. Duration of pre-treatment for patients randomized to standard of 
care study medication before Protocol Amendment 4 will be calculated as min(date of IxRS 
assignment, stop date + 1 day) – start date and summary statistics will be presented 
separately.


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6.1.3
Description of the index venous thrombosis
Location(s) of index venous thrombosis as specified by the investigators and as adjudicated 
by the CIAC will be tabulated overall and by age group.
6.1.4
Concomitant medication
All concomitant medications will be displayed using WHO-DD, by first (anatomical main 
group) and second level of the ATC code (therapeutic main group).
6.1.4.1
Tabulation of concomitant antithrombotics started after stop of study 
medication
Concomitant antithrombotics that started on the stop day of study medication or later will be 
grouped first by the fourth level of their ATC codes (B01AA: Vitamin K antagonists, 
B01AB: Heparin group, B01AC: Platelet aggregation inhibitors excluding heparin, B01AD: 
Enzymes, B01AE: Direct thrombin inhibitors, B01AF: Direct factor Xa inhibitors, B01AX: 
Other antithrombotic agents) or if that is not available, by the third level (B01A: 
Antithrombotic agents). The second group will be the generic names that are reported using 
the codes for DRECNO where DSEQNO1=01 and DSEQNO2=001, except Certoparin, see 
below. The rows in the tables will be sorted first by ATC class (code order) then by generic 
name codes. 
Note that certain medications can be coded by more than one DRECNO code. There are 
medications with same active ingredient, but different salt or ester component or with 
multiple ingredients may have different DRECNOs which may lead to tabulations of that 
active compound in different categories. If applicable, Certoparin sodium coded as 
DRECNO="016918" will be recoded to DRECNO="008896" and DSEQNO1="02" and 
DSEQNO2="017" to tabulate these medications under the drug name “CERTOPARIN 
SODIUM [HEPARIN-FRACTION, SODIUM SALT]”.
6.2
Bleeding analysis
All bleeding analyses will be performed on the safety analysis set based on the outcomes 
confirmed by the CIAC. Bleeding events that occurred during study treatment or within 2 
days after stop of study medication (i.e. treatment-emergent) will be summarized. Bleeding 
events observed more than 2 days after stop of study medication will be described separately. 
Individual listings of major and clinically relevant non-major bleeding events will be 
provided. 
Incidence proportions (number of children with outcome by number of children at risk at start 
of study medication) will be presented for the primary safety outcome, for major bleedings, 
for all confirmed bleedings and components for pooled data and for each age stratum and by 
baseline presentation of venous thrombosis for the rivaroxaban group and for the standard of 
care group (randomized before Protocol Amendment 4) separately.


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6.3
Efficacy
All efficacy analyses will be performed on the full analysis set population based on the 
outcomes confirmed by the CIAC. Incidence proportions will be calculated for the efficacy 
outcomes (see Section 3.3) overall and by age stratum for the rivaroxaban group and for the 
standard of care group (randomized before Protocol Amendment 4) separately. The analyses 
described above will include events up to the end of intended study treatment (30 days after 
study medication assignment) regardless of the actual stop date of study medication.
In addition if there is at least one confirmed recurrent event in the corresponding time period, 
the analyses described above will be performed counting only events that occurred during 
study treatment or within 2 days after stop of study medication (i.e. treatment-emergent) on 
the safety population as well. 
Proportion of events that occurred more than 2 days after stop of study medication up to 30 
days will be described (denominator: number of subjects entering the observational period) if 
there is at least one confirmed recurrent event in the corresponding time period.
In addition, all descriptive efficacy analyses will be performed on the per protocol population 
as a supportive analysis.
6.3.1
Sensitivity analysis to account for dropouts
Sensitivity analyses will be performed if at least one confirmed recurrent event occurred 
within the 30 days intended treatment period in order to evaluate the potential influence of 
dropouts on the incidence of the primary efficacy outcome for the treatment period up to visit 
4. In these analyses subjects with premature termination before visit (no follow-up until Day 
30) will be assumed as having hazard of recurrence of VTE (primary efficacy outcome) 1.5 
times (scenario 1) and twice (scenario 2) as high as the hazard calculated including all 
patients within each treatment group assuming informative censoring. For this sensitivity 
analysis exponential distribution for the event rates (hazard) will be assumed and the analysis 
will be performed for the rivaroxaban treatment group. This method is an application of 
methods for informative missigness odds ratio (IMOR) by White et al (5).

tj ~ exp(hnon-informative)
Pnon-informative = 1-e-( 30∙ hnon-informative)
hdropout = hnon-informative ∙IMHR 
Poverall, j = 1-e-( tj ∙hnon-informative + [30-tj] ∙ hdropout)
Poverall, mean = mean(Poverall, j)
where
tj: event times (or censoring) of patient j.
hnon-informative: hazard of the primary efficacy outcome assuming non-informative censoring 
using all patients’ data.
Pnon-informative: the cumulative event probability at Day 30 based on the exponential model.
hdropout: hazard of the primary efficacy outcome after dropping out.
Poverall, j: cumulative event probability at Day 30 calculated based on mixture of hnon-
informative up to drop out and hdropout from drop out up to Day 30 using exponential model 
for patient j.
Poverall, mean: mean of the cumulative event probability.
IMHR: informative missingness hazard ratio.


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
Prior for log hazard (non-informative censoring):
log(hnon-informative) ~ dnorm(-6.6, 1/√0.4).

Priors (informative) for IMHR: 
IMHR ~ lnN(μ, σ) where 
μ = scenario 1:  ln(1.5) = 0.405; scenario 2: ln(2) = 0.693 and 
σ = 1/√10 = 0.316.
The analysis will be done with an Bayesian Markov Chain Monte Carlo (MCMC) simulation 
approach (e.g. with OpenBUGS Version 3.2.3 or other). For an example code see Appendix, 
Section 9.2. 
6.4
Pharmacokinetics / pharmacodynamics
Individual profiles and summary statistics overall and by weight groups will be provided for 
PK/PD data. PK/PD modeling, using population approaches will be used to describe the 
pharmacokinetics of rivaroxaban, including potential influence of relevant co-variables, and 
relation of anticoagulant parameters of rivaroxaban with plasma concentrations. Details will 
be given in a separate PK/PD evaluation plan.
6.5
Safety
6.5.1
Study drug exposure and compliance
The descriptive statistics in this section will be done for all data combined and for each age 
cohort.
6.5.1.1 Summary of treatment duration
The overall treatment duration will be summarized descriptively in the safety analysis set and 
in the per protocol analysis set.
6.5.1.2 Summary of compliance
Counts and percentages will be tabulated for the following compliance categories in the 
safety analysis set:
Missing, Compliance <50%, Compliance ≥50% to <80%, Compliance ≥80%.
The volume and type of fluid used to predilute the rivaroxaban oral suspension, as well as the 
volume and type of fluid taken after the study drug administration will be summarized by 
visit, overall and by age group.
6.5.1.3 Summary of INR measurements for the VKA treatment
This section is applicable only if a patient received VKA as study medication before Protocol 
Amendment 4. Proportion of patients with INR<2, within 2 to 3 INR inclusive and INR>3 
will be summarized for the one month main treatment period using the observed INR values.


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6.5.2
Adverse events
Individual listings of adverse events (including age, weight, height, gender, adverse event as 
reported, start, duration, severity and relation to study drug) will be provided. The incidence 
of treatment-emergent adverse events will be summarized by age group, using MedDRA 
preferred terms, grouped by primary system organ class. Time window for treatment-
emergent events is defined as events occurring after start of study medication (for patients 
randomized to the standard of care group before Protocol Amendment 4 after IxRS 
assignment) until last intake of study medication plus 2 days. The incidences will be 
presented for all data combined and for each age cohort separately. Incidences of other 
vascular events and all deaths will be summarized, too.
For the purpose of adverse event (AE) documentation, study drug is defined as either 
rivaroxaban or standard of care as allocated starting from IxRS assignment up to the end of 
study treatment visit.
6.5.3
Laboratory measurements
Descriptive statistics will be presented for Hb, platelets, ALT, total and direct bilirubin at 
visit 4 (Day 30) and for their changes to baseline. The descriptive statistics will be done for 
all data combined and for each age cohort. Additional lab data at visit 3 (Day 15) and their 
changes to baseline will be summarized for patients from Canada separately. For the 
calculation of the mean value an anti-Xa activity value below LLOQ will be substituted by 
one half of this limit. In tables showing desriptive statistics, where values below LLOQ are 
included in the calculation of mean values, these means will be marked. All other lab values 
including aPTT and PT with the qualifier '< i.e less than' will be considered for descriptive 
statistics with their values without the qualifier. All lab values with the qualifier '> i.e. greater 
than' will be considered for descriptive statistics with their values without the qualifier.
6.6
Pre-specified subgroup analysis
6.6.1
Analysis by baseline characteristics 
The baseline, efficacy, bleeding and safety analyses will be done by age cohort and by 
baseline presentation of venous thrombosis as described in sections 6.1, 6.2, 6.3, 6.5.1. 
6.7
Taste and texture questionnaire
Results for the taste-and-texture questionnaire in children older than 4 years who receive the 
oral suspension will be presented descriptively as counts and proportions of responses by 
questions.
7.
Document history and changes in the planned statistical analysis
First draft of SAP was circulated with the Bayer team on 10 Dec 2014.
Version 1.0: 26 Jun 2015.


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SAP Version 2.0 dated 28 Apr 2017 was prepared to provide the following edits. None of 
them are considered to change the primary efficacy analysis and other analyses as described, 
but includes additional analyses and further clarifications:

There is a typo in the date of Version 1.0: it was finalized on 26 Jun 2015 and not in 
2014.

No by visit compliance will be calculated, because drug accountability data were not to 
be recorded at visit 3. The calculations of compliance were further specified.

The definition of the per protocol set was updated based on the decisions of the blind 
review meetings: This population includes all enrolled children who had at least 25 days 
study treatment. Children who discontinued study treatment earlier than 25 days due to an 
efficacy or bleeding outcome or due to a procedure defined in the study protocol or 
withrew consent will not be excluded from the per protocol set. If a child died having less 
than 25 days study treatment, they will not be excluded form the per protocol set. 
Children with a calculated compliance less than 50% will be excluded from the per 
protocol set, calculated compliance between 50% and less than 80% and greater than 
120% is considered as minor protocol deviation.

Added PK analysis set and PD analysis set based on the decisions of the blind review 
meetings.

Treatment groups will be displayed as study medication administered.

Antithrombotics started after stop of study medication will be displayed only.

Analysis of demographic, medical history and efficacy was further clarified, analysis of 
and PK/PD data by weigth was included.

Sensitivity analysis as described in Section 6.3.1 will be done only if at least one 
confirmed recurrent event occurred within the 30 days intended treatment period.


Statistical Analysis Plan
Protocol No.: BAY 59-7939/14374
Page: 18 of 19
Reference Number: RD-OI-0119
Supplement Version: 8
8.
References
1. The EINSTEIN investigators. Oral Rivaroxaban for Symptomatic Venous 
Thromboembolism. N Engl J Med 2010; 363: 2499-2510.
2. Buller HR, Prins MH, Lensing AW, Decousus H, Jacobson BF, Minar E, et al. Oral 
Rivaroxaban for the treatment of symptomatic pulmonary embolism. N.Engl J Med 2012; 
366 (14):1287-97.
3. Prins MH, Lensing AWA. Derivation of the non-inferiority margin for the evaluation of 
direct oral anticoagulants in the treatment of venous thromboembolism. Thromb J 2013; 
11: 13. DOI: 10.1186/1477-9560-11-13
4. Massicotte P, Julian JA, Gent M, et al. An open-label randomized controlled trial of low 
molecular weight heparin compared to heparin and coumadin for the treatment of venous 
thromboembolic events in children: the REVIVE trial. Thromb Res 2003; 109: 85-92. 
DOI:10.1016/S0049-3848(03)00059-8.
5. White IR, Welton NJ, Wood AM, Ades AE, Higgins JP. Allowing for uncertainty due to 
missing data in meta-analysis—Part 2: Hierarchical models. Stat Med. 2008; 27: 728-45.
6. Agresti A. Dealing with discreteness: making 'exact' confidence intervals for proportions, 
differences of proportions, and odds ratios more exact. Stat Methods Med Res 2003; 12: 
3-21. DOI: 10.1191/0962280203sm311ra.


Statistical Analysis Plan
Protocol No.: BAY 59-7939/14374
Page: 19 of 19
Reference Number: RD-OI-0119
Supplement Version: 8
9.
Appendix 
9.1
Sample size and power considerations
A total of 20 children who took at least one dose of rivaroxaban study medication are planned 
to be enrolled in the study according to Global Amendment 4 to the Study Protocol. This
sample size does not originate from a formal sample size calculation, but is based on a 
feasibility assessment. For observed incidences of safety and efficacy incidences see the 
results of the Einstein VTE treatment program in adults (1, 2, 3). Table 9-1 shows 95% exact
confidence intervals (Blyth–Still–Casella interval; 6) for a range of potential incidence of 
safety and efficacy clinical outcomes (see Section 3.3 for outcomes in this study).
Table 9-1: 95% exact Blyth–Still–Casella confidence intervals around the estimated 
incidences for 20 patients.
Incidence
Blyth-Still-Casella confidence interval
0/20 (0%)
0.0% to 15.4%
1/20 (5%)
0.3% to 23.1%
2/20 (10%)
1.8% to 31.5%
3/20 (15%)
4.2% to 36.1%
4/20 (20%)
7.1% to 41.1%
This study with 20 children on rivaroxaban will allow for a description of  the efficacy and 
safety outcomes as well as the PK and PD characteristics of rivaroxaban in the pediatric 
patient population.
9.2
Example OpenBUGS code for sensitivity analysis of the primary efficacy 
outcome
OpenBUGS model
Model { for (i in 1 : N) {
# Survival times bounded below by censoring times, noninformative censoring
t[i] ~ dexp(mu[i])C(t.cen[i],)
mu[i] <- exp(alpha)
             im.alpha[i] <- alpha + log.IMHR
lambda.1[i] <- -(t.obs[i] * exp(alpha) + (t.limit - t.obs[i]) * exp(im.alpha[i]))
             p.im1[i] <- 1 - exp(lambda.1[i]) 
}
alpha ~ dnorm(-6.6, 0.4)
exp.alpha <- exp(alpha)
        # IMHR = 2
        log.IMHR ~ dnorm(0.693, 10)
        # Results from informative censoring 
        CDF.1 <- 1 - exp(-(t.limit * exp.alpha))
       p.mean.im1 <- sum(p.im1[])/N1
}
Openbugs node statistics
mean
sd
MC_error
val2.5pc
median
val97.5pc
start
sample
CDF.1
0.07132
0.0552
0.003239
0.008807
0.05557
0.2108
1001
1000
alpha
-6.298
0.8361
0.05607
-8.129
-6.263
-4.842
1001
1000
p.mean.im1
0.09599
0.07443
0.004247
0.01128
0.07357
0.281
1001
1000