Clinical trial NCT02234843
Conditions: Venous Thromboembolism
Keywords: Pediatric
Sponsor: Bayer
Start date: 2014-11-13; Completion date: 2019-01-30
Enrollment: 500 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate comparative efficacy and safety of rivaroxaban to standard of care in children with acute venous thromboembolism.

Detailed description:

Arms: arm 1: Rivaroxaban (tablets and oral suspension) 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. arm 2: Subcutaneous low molecular weight heparin (LMWH), subcutaneous fondaparinux and/or oral vitamin K antagonist (VKA) Dose : as per standard of care
Interventions: intervention 1: Rivaroxaban (Xarelto, BAY59-7939) intervention 2: Rivaroxaban (Xarelto, BAY59-7939) intervention 3: Standard of Care
Intervention descriptions: intervention 1: Age and body weight-adjusted dosing equivalent to 20 mg rivaroxaban in adults, once daily or twice daily, as tablets intervention 2: Age and body weight-adjusted dosing equivalent to 20 mg rivaroxaban in adults, once daily, twice daily or three times daily, as oral suspension intervention 3: LMWH (low molecular weight heparin) or fondaparinux or vitamin K antagonist (VKA) therapy.

dose : as per standard of care

Protocol documents:
Prot_000.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
Multicenter, open-label, active-controlled, randomized study to 
evaluate the efficacy and safety of body weight-adjusted rivaroxaban 
regimen compared to standard of care in children with acute venous 
thromboembolism 
NCT Number: 
NCT02234843 
Document Date: 
27-Sep-2017 
 


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Cover page of the integrated protocol
Multicenter, open-label, active-controlled, randomized study to evaluate the efficacy 
and safety of an age-and body weight-adjusted rivaroxaban regimen compared to 
standard of care in children with acute venous thromboembolism 
EINSTEIN Junior Phase III: oral rivaroxaban in children with venous thrombosis
This protocol version is an integration of the following documents / sections:
Original protocol, Version 1.0, dated 12 Mar 2014
Amendment 1 (local amendment Japan), dated 21 Oct 2014
Amendment 2 (local amendment Canada), dated 28 Oct 2014
Amendment 3 (local amendment Germany), dated 02 Dec 2014
Amendment 4 (described in Section 16.1)
forming integrated protocol Version 2.0, dated 21 Jul 2015
Amendment 5 (local amendment Canada), dated 21 Jul 2015
Amendment 6 (local amendment Japan), dated 28 Jul 2015
Amendment 7 (local amendment Canada), dated 20 Oct 2015
Amendment 8 (described in Section 16.2)
forming integrated protocol Version 3.0, dated 20 Sep 2016
Amendment 9 (local amendment Canada), dated 20 Dec 2016
Amendment 10 (described in Section 16.3)
forming integrated protocol Version 4.0, dated 11 Jan 2017
Amendment 11 (local amendment Japan), dated 07 Mar 2017
Amendment 12 (described in Section 16.4) 
forming integrated protocol version 5.0, dated 27 SEP 2017
This document integrates the original protocol and all global amendments.


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Multicenter, open-label, active-controlled, randomized study to evaluate the efficacy 
and safety of an age-and body weight-adjusted rivaroxaban regimen compared to 
standard of care in children with acute venous thromboembolism
EINSTEIN Junior Phase III: oral rivaroxaban in children with venous thrombosis
Test drug:
BAY 59-7939/rivaroxaban
Clinical study phase:
III
27 SEP 2017
EudraCT no.:
2014-000565-47
Version no.: 5.0
Study no.:
BAY 59-7939/14372
Sponsor:
Non-US territory: Bayer AG, D-51368 Leverkusen, Germany
US territory: 
Bayer Healthcare Pharmaceuticals Inc., 
100 Bayer Boulevard, P.O. Box 915, 
Whippany NJ 07981-0915, USA
1
24-hour medical emergency contact
Telephone: 
Email:
Non-emergency medical and protocol issues contact
2, 3
Bayer U.S. LLC
Pharmaceuticals, 
100 Bayer Boulevard
P.O. Box 915
Whippany, NJ 07981
United States
Tel: 
E-Mail: 
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 AG is not permitted. 1
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.
                                                                                                                                      
1 The sponsor information was changed via Amendment 8 (see Section 16.2.2.1)
2 The non-emergency medical and protocol issues contact was changed via Amendment 8 (see Section 16.2.2.1)
3 The non-emergency medical and protocol issues contact was changed via Amendment 12 (see Section 16.4.2.1)
PPD
PPD
PPD
PPD
PPD


27 SEP 2017 
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Medically responsible person of Bayer agrees to the content of the final clinical study 
protocol as presented. 
 
Global Clinical Leader 
Date: 
0 '2.-.-
OtTo {3 
20 II Signature: 
PPD
PPD


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Study center’s principal investigator agrees to the content of the final clinical study 
protocol as presented.
Name:
Affiliation:
Date:
Signature:
Rivaroxaban (BAY-59-7939, JNJ-39039039) is being co-developed under a collaboration and 
license agreement between Bayer AG and Ortho McNeil Pharmaceuticals, Inc. (OMP) dated 
01 Oct 2005.  
 
 
 
  
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.
4
                                                                                                                                      
4 The sponsor name was changed via Amendment 8 (see Section 16.2.2.2)
PPD


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Synopsis
Title
Multicenter, open-label, active-controlled, randomized study to evaluate 
the efficacy and safety of an age-and body weight-adjusted rivaroxaban 
regimen compared to standard of care in children with acute venous 
thromboembolism.
Short title
EINSTEIN Junior Phase III: oral rivaroxaban in children with venous 
thrombosis
Clinical study phase
III
Study objectives
The primary efficacy objective is:

To assess the incidence of symptomatic recurrent venous 
thromboembolism.
The secondary efficacy objective is:

To assess the incidence of symptomatic recurrent venous 
thromboembolism and asymptomatic deterioration on repeat 
imaging.
The principal safety objective is:

To assess the incidence of overt major and clinically relevant 
non-major bleeding.
An additional objective is:

To characterize the pharmacokinetic / pharmacodynamic profile 
of rivaroxaban.
Experimental study drug
Rivaroxaban
Name of active ingredient
Rivaroxaban 
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 once daily.
Route of administration
Oral tablets or oral suspension
Comparator study drug
Subcutaneous low molecular weight heparin (LMWH), subcutaneous 
fondaparinux, intravenous unfractionated heparin (UFH) and/or oral 
vitamin K antagonist (VKA)
5
Dose
As per standard of care
Indication
Children aged birth to < 18 years 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, cerebral vein and sinus thrombosis, mesenteric vein 
thrombosis, portal vein thrombosis, renal vein thrombosis, or catheter-
related thrombosis.
6
                                                                                                                                      
5 The missing comparator “unfractionated heparin” was added in the synopsis for consistency throughout the protocol via 
Amendment 4 (see Section 16.1.2.1).
6 The indication was modified via Amendment 12 to include children aged from birth to < 18 years (see Section 16.4.2.2)


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Diagnosis and main criteria 
for inclusion
Children aged birth to < 18 years with acute venous thromboembolism 
confirmed by diagnostic imaging.
7
Study design
Open-label, active-controlled, multicenter, randomized study
Methodology
8
Children aged birth to < 18 years with confirmed venous 
thromboembolism who receive initial treatment with therapeutic dosages 
of unfractionated heparin (UFH), low molecular weight heparin 
(LMWH), or fondaparinux are potentially eligible for the study.
Initial treatment with UFH, LMWH or fondaparinux will be administered 
for at least 5 days.

Randomization can be done during the first 9 days of initial 
treatment and will be in a 2 (rivaroxaban): 1 (standard of care 
[SOC]) fashion. Children randomized to rivaroxaban will start 
rivaroxaban the day following the last administration of initial 
therapy with UFH, LMWH, or fondaparinux but with a minimal 
duration of initial therapy of 5 days and a maximum duration of 
9 days.

The first administration of rivaroxaban will be started: 4 hours 
after discontinuation of UFH

12 hours after discontinuation of LMWH with a b.i.d. regimen, 
and 

24 hours after discontinuation of fondaparinux or LMWH with 
an o.d. regimen
Children randomized to SOC can continue UFH, LMWH, or 
fondaparinux or can switch to vitamin K antagonist (VKA) therapy. If 
VKA therapy is planned it can be initiated any time after randomization. 
Initial therapy with UFH, LMWH, or fondaparinux can be stopped after 
a minimum of 5 days and only if the international normalized ratio (INR) 
is above 2 on two separate occasions, 24 hours apart. 
In children randomized to rivaroxaban in whom VKA therapy was 
already initiated before randomization, VKA therapy should be stopped 
and the switch to rivaroxaban should be made as described in Section 
5.1.1.3.
The main study treatment period is for a total of 3 months at which time 
the diagnostic imaging test, which was obtained at baseline, will be 
repeated, if clinically feasible.  However, in children younger than 2 
years with catheter-related thrombosis, the main study treatment period is 
for a total of 1 month at which time the repeat imaging will be 
performed. In all children, except those < 2 years with catheter-related 
thrombosis, the decision is made to stop study treatment at 3 months or 
to continue for an additional 3 months. In children who completed 6 
months of treatment, the decision is made to stop study treatment or to 
continue for an additional 3 months. Then, in children who completed 9 
months of treatment, the decision is made to stop study treatment or to 
continue for an additional 3 months.  In children < 2 years with catheter-
related thrombosis, the decision is made to stop study treatment at 1 
                                                                                                                                      
7 Diagnosis and main criteria for diagnosis was modified via Amendment 12 to include children from birth 
(see Section 16.4.2.2)
8 Methodology section in Synopsis was modified via Amendment 12 to include children from birth and to highlight different 
treatment duration in children <2 with catheter related thrombosis ( see Section 16.4.2.2)


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month or to continue for an additional month.  Then, in children who 
completed 2 months of treatment, the decision is made to stop study 
treatment or to continue for an additional month.
Regardless of the duration of study treatment (<3, 3, 6, 9 or 12 months), 
an additional 1-month post-treatment observational period will be 
completed for all children. All suspected clinical study outcomes and 
baseline and repeat thrombosis imaging tests will be assessed by a 
central independent adjudication committee (CIAC) blinded to treatment 
allocation. An independent Data Monitoring Committee (DMC) will 
monitor the children’s safety and give recommendations to the steering 
committee.
9
Number of children
At least 170 children are needed for this study, of whom 80 in the age 
group 12 to < 18 years, 30 in the age group 6 to < 12 years, 20 in the age 
group 2 to < 6 years, and 20 in the age group birth to < 2 years, with at 
least 12 aged birth to < 6 months.
10
Inclusion/exclusion criteria
Inclusion
11
1.
Children aged birth to < 18 years with confirmed venous 
thromboembolism who receive initial treatment with therapeutic 
dosages of UFH, LMWH or fondaparinux and require 
anticoagulant therapy for at least 90 days. However, children aged
birth to < 2 years with catheter-related thrombosis require 
anticoagulant therapy for at least 30 days. 
2.
Informed consent provided and, if applicable, child assent 
provided
3.
For children younger than 6 months: 
- Gestational age at birth of at least 37 weeks.
- Oral feeding/nasogastric/gastric feeding for at least 10 days.
- Body weight ≥2600 g.
Exclusion
12
1.
Active bleeding or bleeding risk contraindicating anticoagulant 
therapy 
2.
An estimated glomerular filtration rate (eGFR) 
< 30 mL/min/1.73 m2 (in children younger than 1 year,  serum 
creatinine results above 97.5th percentile excludes participation, 
see Table 17–1)
3.
Hepatic disease which is associated with either: coagulopathy 
leading to a clinically relevant bleeding risk, or alanine 
aminotransferase (ALT) > 5x upper level of normal (ULN) or 
total bilirubin (TB) > 2x ULN with direct bilirubin > 20% of the 
total
4.
Platelet count < 50 x 109/L
5.
Sustained uncontrolled hypertension defined as systolic and/or 
                                                                                                                                      
9 The methodology section in the synopsis was modified via Amendment 8 (see Section 16.2.2.3)
10 The number of children was modified via Amendment 12 (see Section 16.4.2.2)
11 Inclusion criterion 1 was modified and criterion 3 was added via Amendment 12 ( see Section 16.4.2.2)
12 Exclusion criteria 1, 5, 7, and 8 were modified via Amendment 8 (see Section 16.2.2.3)


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diastolic blood pressure > 95th age percentile (See Appendix 3)
13
6.
Life expectancy < 3 months
7.
Concomitant use of strong inhibitors of both cytochrome P450 
isoenzyme 3A4 (CYP3A4) and P-glycoprotein (P-gp), including 
but not limited to all human immunodeficiency virus protease 
inhibitors and the following azole-antimycotics agents: 
ketoconazole, itraconazole, voriconazole, posaconazole, if used 
systemically (fluconazole is allowed)
13
8.
Concomitant use of strong inducers of CYP3A4, including but not 
limited to rifampicin, rifabutin, phenobarbital, phenytoin and
carbamazepine
9.
Childbearing potential without proper contraceptive measures, 
pregnancy or breast feeding
10. Hypersensitivity or any other contraindication listed in the local 
labeling for the comparator treatment or experimental treatment 
11. Inability to cooperate with the study procedures 
12. Previous assignment to treatment during this study
13
13. Participation in a study with an investigational drug or medical 
device within 30 days prior to randomization
Primary efficacy outcome 
The composite of all symptomatic recurrent venous thromboembolism.
Secondary efficacy outcome
The composite of all symptomatic recurrent venous thromboembolism 
and asymptomatic deterioration on repeat imaging.
Principal safety outcome
The composite of overt major and clinically relevant non-major bleeding. 
Other outcomes
Results of pharmacokinetics (PK)/ pharmacodynamics (PD) analyses
Primary efficacy outcome 
analysis
Incidence proportions and cumulative incidences will be calculated for 
the primary efficacy outcome at the end of the main study treatment 
period.
14
Secondary efficacy outcome 
analysis
Incidence proportions and cumulative incidences will be calculated for 
the secondary efficacy outcome at the end of the main study treatment 
period.
15
                                                                                                                                      
13 Exclusion criterion 5, 7 and 12 were modified for consistency throughout the protocol and minor clarification via 
Amendment 4 (see Section 16.1.2.1).
14 Primary efficacy outcome analysis was modified via Amendment 12 (see Section 16.4.2.2)
15 Secondary efficacy outcome analysis was modified via Amendment 12 (see Section 16.4.2.2)


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Other efficacy outcome 
analysis
Incidence proportions will be calculated for the primary efficacy 
outcome in the extended treatment period at 3 as well as 6, 9 and 12 
months (see study flow charts).
16
Principal safety outcome 
analysis
Incidence proportions and cumulative incidences will be calculated for 
the principal safety outcome at the end of the main study treatment 
period.
17
Other safety outcome analysis
Incidence proportions will be calculated for the principal safety outcome 
in the extended treatment period at 3 as well as 6, 9 and 12 months (see 
study flow charts).
18
                                                                                                                                      
16 Other efficacy outcome analysis was modified via Amendment 12 (see Section 16.4.2.2)
17 Principal safety outcome analysis was modified via Amendment 12 (see Section 16.4.2.2)
18 Other safety outcome analysis was modified via Amendment 12 (see Section 16.4.2.2)


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Table 0–1
Flow chart for all children except children aged < 2 years with catheter 
related thrombosis (see Table 2) 
19    20
Main Treatment period
Extended treatment period 
with blocks of 3 months
30-day 
post study 
treatment
Visit 
1
1a
2
3
4
5
6
7
8
Days
Before 
random.
After 
random.
2+1 days 
after start
t.i.d.riva-
roxaban p
Day 30
7 days
Day 60
7 days
Day 90
7 days
Day 180
7 days
Day 270
7 days
Day 360 
7 days
30 7 days
After last 
visit
Contact
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit or 
phone 
Obtain informed consent/child 
assent 
●
Check in-/exclusion criteria
●
Obtain demographic data
●
Check medical history
●
Record concomitant 
medication/anticoagulants
●
Obtain height/length/body 
weight/blood pressure
●
Check Hb, platelets, creatinine, 
ALT, total and direct bilirubin 
●a
Perform urine pregnancy test, if 
applicable
●
Randomize patient using IxRS 
b
●
Dispense study medication 
●
●
●
● c
●c
●c
Dispense additional supplies 
(devices for oral suspension)
●
●
●
● c
●c
●c
Instruct how to take study 
medication n
●
Send baseline adjudication 
package
●
Check for adverse events
●
●
●
●
●
●
●
●
●
Check for device-related 
adverse events o
●
●
●
●
●
●
●
●
Obtain body weight 
●d
●d
●d
●d
●d
Assess duration and intensity 
of menstruation, if applicable  21
●
●
●
●
●
●
Check for study outcomes e
●
●
●
●
●
●
●
●
Check study drug 
accountability and compliance 
●
●
●
●
●
●
Check changes in concomitant 
medication
●
●
●
●
●
●
●
●
Obtain Hb, platelets, ALT, total 
and direct bilirubin 
●
Repeat imaging and send 
adjudication package f
●
Perform post-thrombotic 
syndrome assessment m
●
●
●
●
Complete eCRF 
●
●
●
●
●
●
●
●
●
●
Comparator group only
If INR-adjusted VKA g
1 INR per 2 weeks
continued on next page
                                                                                                                                      
19 The study flow chart was modified via Amendment 8 (see Section 16.2.2.3) and Amendment 10 (see Section 16.3.2.1)
20 The study flow chart was modified via Amendment 12 (see Section 16.4.2.2)
21 Assessment of menstrual bleeding was added from visit 1 to visit 7 via Amendment 4 (see Section 16.1.2.1).


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Table 0-1
Flow chart (continued)
Main Treatment period
Extended treatment period with 
blocks of 3 months
30-day 
post study 
treatment
Visit 
1
1a
2
3
4
5
6
7
8
Days
Before 
random
After 
random.
2+1 days after 
start t.i.d.
rivaroxaban p
Day 30
7 days
Day 60
7 days
Day 90
7 days
Day 180
7 days
Day 270
7 days
Day 360 
7 days
30 7 days
After last 
visit
Contact
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit or 
phone 
Pharmacokinetics (PK) and pharmacodynamics (PD) for rivaroxaban using o.d. regimen h
If suspension, complete pre-
dosing Taste-and-Texture 
questionnaire in children 4 to 
< 18 years
●
Administer rivaroxaban at 
study site
●
●
Take up to 240 mL of liquid 
immediately after dosing
●
●
If suspension, complete post-
dosing Taste-and-Texture 
questionnaire in children 4 to 
< 18 years
●
Obtain PK blood sample i
●
●
●
●
Obtain PD blood sample j, k
● 
●
●
●
Time point for PK/PD blood 
sample (hours)
0.5-
1.5hr 
post 
dose
2.5-
4hr 
post 
dose
2-8hr 
post 
dose
20-24 hr 
after dose 
on 
previous
day 
Pharmacokinetics (PK) and pharmacodynamics (PD) for rivaroxaban using b.i.d. regimen h
If suspension, complete pre-
dosing Taste-and-Texture 
questionnaire in children 4 to 
< 18 years
●
Administer rivaroxaban at 
study site
●
●
Take up to 240 mL of liquid 
immediately after dosing
●
●
If suspension, then complete 
post- dosing Taste-and-
Texture questionnaire in 
children 4 to < 18 years
●
Obtain PK blood sample i
●
●
●
●
Obtain PD blood sample j, k
● l
●
●
●
Time point for PK/PD blood 
sample (hours) if dosing 
continues beyond Day 90
0.5-
1.5hr 
post 
dose
2.5-
4hr 
post 
dose
2-8hr 
post 
dose
10-16 hr 
after last 
evening 
dose, give 
next dose 
after 
PK/PD 
samples
Time point for PK/PD blood 
sample (hours) if dosing does 
not continue beyond Day 90
0.5-
1.5hr 
post 
dose
2.5-
4hr 
post 
dose
2-8hr 
post 
dose
10-16 hr 
after last 
evening 
dose
continued on next page


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Table 0-1
Flow chart (continued)
Main Treatment period
Extended treatment period with 
blocks of 3 months
30-day 
post study 
treatment
Visit 
1
1a
2
3
4
5
6
7
8
Days
Before 
random
After 
random.
2+1 days after 
start t.i.d
rivaroxaban p
Day 30
7 days
Day 60
7 days
Day 90
7 days
Day 180
7 days
Day 270
7 days
Day 360 
7 days
30 7 days
After last 
visit
Contact
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit or 
phone 
Pharmacokinetics (PK) and pharmacodynamics (PD) for rivaroxaban using t.i.d. regimen h
Administer rivaroxaban at 
study site
●
●
●
Take up to 120 mL of liquid 
immediately after dosing
●
●
●
Obtain PK blood sample i
●
●
●q
●q
●
Obtain PD blood sample j, k
●q
●
●
Time point for PK/PD blood 
sample (hours) if dosing 
continues beyond Day 90
0.5-
3hr 
post 
dose
7-8hr 
post 
dose
0.5-
3hr 
post 
dose
7-8hr 
post 
dose
2-6hr 
post 
dose
10-16hr 
after last 
evening 
dose, give 
next dose 
after PD 
sample
Time point for PK/PD blood 
sample (hours) if dosing does 
not continue beyond Day 90
0.5-
3hr 
post 
dose
7-8hr 
post 
dose
0.5-
3hr 
post 
dose
7-8hr 
post 
dose
2-6hr 
post 
dose
10-16hr 
after last 
evening 
dose
Footnotes:
a
Blood sample should be obtained within a maximum of 5 
days prior to randomization.
b
Randomization can be done during the first 9 days of 
initial therapy with UFH, LMWH or fondaparinux.
c
If study treatment is continued, provide study medication
d
Adjust dosage of study medication, if change in body 
weight. Additional visits can be planned to accommodate 
dose adjustment of study medication, if applicable. 
e
If suspected outcome occurred, the adjudication package 
needs to be compiled and sent to the adjudication office.
f
After the main study treatment period of 3 months, the 
diagnostic imaging test which was obtained at baseline will 
be repeated, if clinically feasible.
g
VKA compliance will be ensured by minimum of 1 INR 
per 2 weeks.
h
The approximate total blood volume taken per child for 
PK/PD is 12 mL if blood taken via venipuncture (for t.i.d. 
regimen it is 7.2 mL), and up to 24 mL if blood taken via 
central venous line or peripheral catheter (see 
Section 6.14).
i
Blood volume per PK sample is approximately 1.2 mL (for 
t.i.d. regimen it is 0.6 mL); total blood volume for all PK 
samples is 4.8 mL for o.d. and b.i.d. regimen and 3 mL for
t.i.d. regimen.
j
Blood volume per PD sample is approximately 1.8 mL (for t.i.d. 
regimen it is 1.4 mL); total blood volume for all PD samples is 
7.2 mL for o.d. and b.i.d. regimen and 4.2 mL for t.i.d. regimen.
k 
Always draw the PD sample as the last sample.
l
PD sample will not be collected at 0.5-1.5 hr after rivaroxaban 
intake for children < 6 years. Please note that this is different than in 
children <2 years with catheter related thrombosis
m
Only in children ≥12 years with lower or upper extremity DVT 
n
In addition, provide Rivaroxaban Oral Suspension Handling 
Instructions, if applicable, and Study Booklet
o
Only applicable for children treated with oral suspension
p
Only in children treated with rivaroxaban t.i.d. regimen. If visit 1a 
falls on a weekend and cannot take place, the visit must be 
scheduled for the following Monday.
q
Visit 2 will be modified for children weighing < 3250 grams.  The 
PK and PD samples taken 0.5 to 3 hours post-dose will be taken on 
a dosing day within the visit window (total volume to be drawn is 
2.0 mL), and the 7-8 hour post-dose PK sample (total volume to be 
drawn is 0.6 ml) may be taken on the following dosing day within 
the visit window.  This modification may only occur in children 
weighing less than 3250 kg at the time of visit 2.
o.d. = once daily dosing
b.i.d. = twice daily dosing
t.i.d. = three times daily dosing
eCRF = electronic case report form;
IxRS = interactive voice/ web response system
PTS = post-thrombotic syndrome


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Table 0–2 Flow chart for children aged < 2 years with catheter related 
thrombosis 22
Main Treatment period
Extended 
treatment period 
with blocks of 30 
days
30-day post 
study treatment
Visit 
1
1a
2
3
4
8
Days
Before 
random.
After 
random.
2+1 days 
after start 
t.i.d.
rivaroxaban 
m
Day 30
7 days
Day 60
7 days
Day 90
7 days
30 7 days
After last visitr
Contact
Visit
Visit
Visit
Visit
Visit
Visit
Visit 
Obtain informed consent
●
Check in-/exclusion criteria
●
Obtain demographic data
●
Check medical history
●
Record concomitant 
medication/anticoagulants
●
Obtain height/length/body 
weight/blood pressure
●
Check Hb, platelets, creatinine, 
ALT, total and direct bilirubin 
●a
Randomize patient using IxRS 
b
●
Dispense study medication 
●
●
●c
●c
Dispense additional supplies 
(devices for oral suspension)
●
●
●c
●c
Instruct how to take study 
medication l
●
Send baseline adjudication 
package
●
Check for adverse events
●
●
●
●
●
●
Check for device-related 
adverse events 
●
●
●
●
●
Obtain body weight 
●d
●d
●d
Check for study outcomes e
●
●
●
●
●
Check study drug 
accountability and compliance 
●
●
●
Check changes in concomitant 
medication
●
●
●
●
●
Obtain Hb, platelets, ALT, 
total and direct bilirubin 
●
Repeat imaging and send 
adjudication package f
●
Complete eCRF 
●
●
●
●
●
●
●
Comparator group only
If INR-adjusted VKA g
1 INR per 2 weeks
                                                                                                                                      
22 The flow chart for children <2 years with catheter related thrombosis was added via Amendment 12 (see Section 16.4.2.2)


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Table 0-2
Flow chart for children < 2 years of age with catheter related 
thrombosis (continued)
Main Treatment period
Extended 
treatment period 
with blocks of 30 
days
30-day post 
study treatment
Visit 
1
1a
2
3
4
8
Days
Before 
random
After 
random.
2+1 days 
after start 
t.i.d 
rivaroxaban 
m
Day 30
7 days
Day 60
7 days
Day 90
7 days
30 7 days
After last visitr
Contact
Visit
Visit
Visit
Visit
Visit
Visit
Visit 
Pharmacokinetics (PK) and pharmacodynamics (PD) for rivaroxaban using b.i.d. regimenh
Administer rivaroxaban at 
study site
●
●
Take up to 240 mL of liquid 
immediately after dosing
●
●
Obtain PK blood sample i
●
●
●
●
Obtain PD blood sample j, k
●
●
●
● o
Time point for PK/PD blood 
sample (hours) 
10-16hr 
after 
last 
evening 
dose, 
give 
next 
dose 
after 
PK
sample
0.5-
1.5hr 
post 
dose
2.5-4hr 
post 
dose
2-8hr 
post dose
PK and PD for rivaroxaban using t.i.d. regimenh
Administer rivaroxaban at 
study site
●
●
●
Take up to 120 mL of liquid 
immediately after dosing
●
●
●
Obtain PK blood sample i
●
●
●o
●o
●
Obtain PD blood sample j, k
●o
●
● n
Time point for PK/PD blood 
sample (hours)
0.5-
3hr 
post 
dose
7-8hr 
post 
dose
0.5-3hr post 
dose
7-8hr post 
dose
2-6hr 
post dose


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Footnotes:
a
Blood sample should be obtained within a maximum 
of 5 days prior to randomization.
b
Randomization can be done during the first 9 days of 
initial therapy with UFH, LMWH or fondaparinux.
c
If study treatment is continued, provide study 
medication
d
Adjust dosage of study medication and treatment 
regimen, if change in body weight. Additional visits 
can be planned to accommodate dose adjustment of 
study medication, if applicable. 
e
If suspected outcome occurred, the adjudication 
package needs to be compiled and sent to the 
adjudication office.
f
After the main study treatment period of 1 month,  
the diagnostic imaging test which was obtained at 
baseline will be repeated, if clinically feasible.
g
VKA compliance will be ensured by minimum of 1 
INR per 2 weeks.
h
The approximate total blood volume taken per child 
for PK/PD is 12 mL for b.i.d.and 7.2 mL for t.i.d. if 
blood taken via venipuncture, and up to 24 mL if 
blood taken via central venous line or peripheral 
catheter (see Section 6.14).
i
Blood volume per PK sample is approximately 1.2 
mL for b.i.d. and 0.6 mL for t.i.d.; total blood volume 
for all PK samples is 4.8 mL for b.i.d. and 3 mL for 
t.i.d.
j
Blood volume per PD sample is approximately 1.8 mL for 
b.i.d. and 1.4 mL for t.i.d.; total blood volume for all PD 
samples is 7.2 mL for b.i.d. and 4.2 mL for t.i.d.
k 
Always draw the PD sample as the last sample.
l
In addition, provide Rivaroxaban Oral Suspension Handling 
Instructions, and Study Booklet
m
Only in children treated with rivaroxaban t.i.d. regimen. If 
visit 1a falls on a weekend and cannot take place, the visit 
must be scheduled for the following Monday.
n
Visit 8 cannot be conducted by phone in children who are 
aged < 2 with catheter-related thrombosis, as a PD sample 
must be collected at this visit.  If the patient is started on 
another anticoagulant during the 30 day post study treatment 
period, the PD sample needs to be taken at least 8 hours 
after last dose of rivaroxaban and before initiation of a new 
anticoagulant.
o
Visit 2 will be modified for children weighing < 3250 
grams.  The PK and PD samples taken 0.5 to 3 hours post-
dose will be taken on a dosing day within the visit window 
(total volume to be drawn is 2.0 mL), and the 7-8 hour post-
dose PK sample (total volume to be drawn is 0.6 ml) may be 
taken on the following dosing day within the visit window.  
This modification may only occur in children weighing less 
than 3250 kg at the time of visit 2. 
o.d. = once daily dosing
b.i.d. = twice daily dosing
t.i.d. = three times daily dosing
eCRF = electronic case report form;
IxRS = interactive voice/ web response system
PTS = post-thrombotic syndrome


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Table of contents
Cover page of the integrated protocol.................................................................................... 1
Medically responsible person of Bayer agrees to the content of the final clinical study 
protocol as presented. ....................................................................................................... 3
Study center’s principal investigator agrees to the content of the final clinical study 
protocol as presented. ....................................................................................................... 4
Synopsis..................................................................................................................................... 5
Table of contents..................................................................................................................... 16
Table of Tables ....................................................................................................................... 22
Table of Figures...................................................................................................................... 22
Abbreviations.......................................................................................................................... 23
1.
Introduction..................................................................................................................... 24
1.1
Rivaroxaban................................................................................................................... 25
1.2
Various manifestations of venous thrombosis............................................................... 26
1.3
Rationale of the study and risk-benefit assessment ....................................................... 26
2.
Study objectives............................................................................................................... 27
3.
Study design..................................................................................................................... 27
4.
Study population ............................................................................................................. 31
4.1
Planned number of children........................................................................................... 31
4.2
Inclusion criteria ............................................................................................................ 31
4.3
Exclusion criteria ........................................................................................................... 31
4.4
Concomitant medication................................................................................................ 32
5.
Treatment groups and regimens.................................................................................... 32
5.1
Method of treatment allocation...................................................................................... 32
5.1.1
Rivaroxaban group ..................................................................................................... 33
5.1.1.1
Switching from heparin/fondaparinux to rivaroxaban ............................................ 34
5.1.1.2
Switching from rivaroxaban to heparin/fondaparinux ............................................ 34
5.1.1.3
Switching from rivaroxaban to VKA and vice-versa.............................................. 34
5.1.2
Comparator group....................................................................................................... 34
5.2
Subject identification ..................................................................................................... 35
5.3
Duration of study treatment ........................................................................................... 35
5.4
Formulation and dose..................................................................................................... 36
5.4.1
Rivaroxaban................................................................................................................ 36
5.4.2
Comparator................................................................................................................. 36
5.5
Packaging, labeling, and storage.................................................................................... 36
5.6
Treatment assignment.................................................................................................... 37
5.7
Dosage and administration............................................................................................. 37
5.8
Study treatment delivery and compliance assessment................................................... 38


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5.8.1
Rivaroxaban................................................................................................................ 38
5.8.2
Vitamin K antagonists ................................................................................................ 38
5.8.3
Low molecular weight heparin/fondaparinux............................................................. 38
5.9
Devices for preparation and administration of rivaroxaban oral suspension................. 38
6.
Study Procedures ............................................................................................................ 39
6.1
Study visits..................................................................................................................... 39
6.2
Visit 1 - Randomization Visit ........................................................................................ 39
6.3
Visit 1a (2+1 days after start t.i.d. rivaroxaban) ............................................................ 40
6.4
Visit 2 at Day 30 (± 7 days)........................................................................................... 41
6.5
Visit 3 at Day 60 (± 7 days)........................................................................................... 43
6.6
Visit 4 at Day 90 (± 7 days)........................................................................................... 45
6.7
Visit 5, Visit 6, and Visit 7 at Day 180, Day 270, Day 360 (± 7 days) ......................... 46
6.8
Visit 8, 30-day post study treatment contact (30 days ±7 days after last visit) ............. 47
6.9
Unscheduled visits ......................................................................................................... 47
6.10
Safety outcomes............................................................................................................. 48
6.11
Recommendations before and after invasive procedures and surgical intervention...... 48
6.12
Management of bleeding in children ............................................................................. 49
6.13
Efficacy outcomes.......................................................................................................... 49
6.14
PK/PD assessments........................................................................................................ 49
6.15
Study booklet ................................................................................................................. 51
6.16
Study committees........................................................................................................... 51
6.16.1
Steering committee..................................................................................................... 51
6.16.2
Central independent adjudication committee (CIAC)................................................ 52
6.16.3
Data monitoring committee (DMC) ........................................................................... 52
7.
Statistical and analytical methods ................................................................................. 52
7.1
General considerations................................................................................................... 52
7.2
Analysis sets .................................................................................................................. 52
7.3
Demographic and other baseline characteristics............................................................ 53
7.4
Bleeding analysis ........................................................................................................... 53
7.5
Efficacy analysis............................................................................................................ 53
7.6
PK/PD analysis .............................................................................................................. 54
7.7
Interim analyses ............................................................................................................. 54
7.8
Determination of sample size......................................................................................... 54
7.9
Adverse events............................................................................................................... 54
7.9.1
Definitions .................................................................................................................. 54
7.9.1.1
Adverse event (AE)................................................................................................. 54
7.9.1.2
Serious adverse event (SAE)................................................................................... 55
7.9.1.3
Unexpected AEs...................................................................................................... 55
7.9.2
Relationship of AE to the study drug ......................................................................... 55
7.9.3
Causal relationship to protocol-required procedure ................................................... 56
7.9.4
Intensity of an AE, action taken and outcome............................................................ 56
7.9.5
Assessments and documentation of adverse events ................................................... 56
7.9.6
Reporting of serious adverse events ........................................................................... 56
7.9.7
Study specific exceptions to the (S)AE reporting ...................................................... 57


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7.9.8
Expected AEs ............................................................................................................. 57
7.9.9
AEs of special interest................................................................................................ 57
7.9.10
Adverse events related to devices used for preparation and administration of 
rivaroxaban oral suspension ....................................................................................... 57
7.9.10.1
Definitions............................................................................................................... 57
7.9.10.2
Device Malfunction or Failure and Medical Device Reporting.............................. 58
7.10
Premature discontinuation of study drug....................................................................... 59
7.11
Pregnancies .................................................................................................................... 59
7.12
Appropriateness of procedures/measurements .............................................................. 60
8.
Data handling and quality assurance............................................................................ 60
8.1
Data processing.............................................................................................................. 60
8.2
Audit and inspection ...................................................................................................... 60
8.3
Archiving ....................................................................................................................... 60
9.
Premature termination of the study.............................................................................. 61
10. Ethical and legal aspects................................................................................................. 61
10.1
Ethical and legal conduct of the study........................................................................... 61
10.2
Child information and consent....................................................................................... 62
11. Investigators and other study participants................................................................... 63
12. Publication policy............................................................................................................ 63
13. Insurance for children .................................................................................................... 63
14. Confidentiality................................................................................................................. 63
15. References ........................................................................................................................ 64
16. Protocol amendments...................................................................................................... 65
16.1
Amendment 4................................................................................................................. 65
16.1.1
Overview of changes .................................................................................................. 65
16.1.1.1
Modification 1: Minor clarifications for consistency.............................................. 65
16.1.1.2
Modification 2: Implementation of dosing regimen for children from 6 to 
<12 years ................................................................................................................. 66
16.1.1.3
Modification 3:  Inclusion of menstruation intensity assessments.......................... 66
16.1.1.4
Modification 4:  Addition of information on how to treat children turning 2, 6, 12 
or 18 years ............................................................................................................... 66
16.1.1.5
Modification 5:  Addition of allowing heparin flushes for catheters ...................... 67
16.1.1.6
Modification 6: Addition of instructions on how to take rivaroxaban with an o.d. 
and b.i.d. regimen in children aged 6 to < 12 years ................................................ 67
16.1.1.7
Modification 7: Addition of handling instructions for missed doses...................... 67
16.1.2
Changes to the protocol text....................................................................................... 68
16.1.2.1
Synopsis .................................................................................................................. 68
16.1.2.2
Section 3  Study design........................................................................................... 69
16.1.2.3
Section 4.3  Exclusion criteria................................................................................. 70
16.1.2.4
Section 5.1  Method of treatment allocation ........................................................... 70
16.1.2.5
Section 5.1.1  Rivaroxaban group........................................................................... 72


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16.1.2.6
Section 5.3  Duration of study treatment................................................................. 74
16.1.2.7
Section 6.2  Visit 1 - Randomization Visit.............................................................. 74
16.1.2.8
Section 6.3  Visit 2 at Day 30 (± 7 days) ................................................................ 75
16.1.2.9
Section 6.4  Visit 3 at Day 60 (± 7 days) ................................................................ 75
16.1.2.10 Section 6.5  Visit 4 at Day 90 (± 7 days) ................................................................ 76
16.1.2.11 Section  6.6 Visit 5, Visit 6, and Visit 7 at Day 180, Day 270, Day 360 (± 7 days)76
16.1.2.12 Section 6.13  PK/PD assessments ........................................................................... 77
16.1.2.13 Section 7.4  Bleeding analysis................................................................................. 77
16.1.2.14 New Section 17.5  Appendix 5: Dosing table for children from 6 to <12 years..... 77
16.2
Amendment 8................................................................................................................. 78
16.2.1
Overview of changes .................................................................................................. 78
16.2.1.1
Modification 1: Change of sponsorship information .............................................. 78
16.2.1.2
Modification 2: Change of non-emergency medical and protocol issues contact... 79
16.2.1.3
Modification 3: Extension of the randomization timeframe ................................... 79
16.2.1.4
Modification 4: Addition of information for switch from VKA to rivaroxaban..... 80
16.2.1.5
Modification 5: Update of exclusion criterion 1..................................................... 80
16.2.1.6
Modification 6: Clarification of exclusion criterion 5 ............................................ 80
16.2.1.7
Modification 7: Clarification of concomitant medication in exclusion criteria 7 
and 8........................................................................................................................ 81
16.2.1.8
Modification 8: Addition of body weight assessment at Visits 2 and 3.................. 81
16.2.1.9
Modification 9: Addition of post-thrombotic syndrome assessment ...................... 82
16.2.1.10 Modification 10: Age range for assessment of oral suspension Taste- and- Texture82
16.2.1.11 Modification 11: Introduction of additional supplies for preparation and 
administration of oral suspension............................................................................ 82
16.2.1.12 Modification 12: Start of enrollment in cohorts 6 months to less than 2 years and 
2 to less than 6 years ............................................................................................... 83
16.2.1.13 Modification 13: Introduction of oral suspension................................................... 84
16.2.1.14 Modification 14: Update of phase II results............................................................ 84
16.2.1.15 Modification 15: Minor clarifications for consistency............................................ 85
16.2.1.16 Modification 16: Treatment duration for children randomized last into the study. 85
16.2.1.17 Modification 17: Update of rivaroxaban oral suspension information ................... 86
16.2.1.18 Modification 18: Addition for statistical analysis of Taste- and Texture 
questionnaire and PTS............................................................................................. 86
16.2.1.19 Modification 19: Reporting of device-related adverse events ................................ 87
16.2.1.20 Modification 20: Addition of calculation constants for eGFR calculation............. 87
16.2.2
Changes to the protocol text....................................................................................... 87
16.2.2.1
Title page................................................................................................................. 88
16.2.2.2
Study center’s principal investigator agrees to the content of the final clinical 
study protocol as presented. .................................................................................... 89
16.2.2.3
Synopsis .................................................................................................................. 90
16.2.2.4
Section 1.  Introduction ........................................................................................... 94
16.2.2.5
Section 3  Study design........................................................................................... 94
16.2.2.6
Section 4.3  Exclusion criteria................................................................................. 97
16.2.2.7
Section 4.4  Concomitant medication ..................................................................... 98
16.2.2.8
Section 5.1.1  Rivaroxaban group........................................................................... 98


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16.2.2.9
Section 5.3  Duration of study treatment............................................................... 100
16.2.2.10 Section 5.4.1  Rivaroxaban ................................................................................... 101
16.2.2.11 Section 5.5 Packaging and labeling, and storage .................................................. 102
16.2.2.12 Section 5.8 Study treatment delivery and compliance assessment ....................... 103
16.2.2.13 Section 5.9  Devices for preparation and administration of rivaroxaban oral 
suspension ............................................................................................................. 103
16.2.2.14 Section 6.2  Visit 1 – Randomization Visit........................................................... 104
16.2.2.15 Section 6.3 Visit 2 at Day 30 (± 7 days) ............................................................... 105
16.2.2.16 Section 6.4  Visit 3 at Day 60 (± 7 days) .............................................................. 107
16.2.2.17 Section 6.5  Visit 4 at Day 90 (± 7 days) .............................................................. 109
16.2.2.18 Section 6.5.1  Visit 5, Visit 6, and Visit 7 at Day 180, Day 270, Day 360 (± 7 
days) ...................................................................................................................... 110
16.2.2.19 Section 6.7  30-day post study treatment contact (30 days ±7 days after last visit)111
16.2.2.20 Section 7.5  Efficacy analysis ............................................................................... 112
16.2.2.21 Section 7.9.10  Adverse events related to devices used for preparation and 
administration of rivaroxaban oral suspension...................................................... 112
16.2.2.22 Section 15.  References ......................................................................................... 114
16.2.2.23 Section 17.2  Appendix 2: Estimated glomerular filtration rate ........................... 115
16.2.2.24 Section 17.4  Appendix 4: Dosing table for children from 6 months to 18 years. 116
16.2.2.25 Section 17.5 Appendix 5: Dosing table for children from 6 to <12 years ............ 117
16.3
Amendment 10............................................................................................................. 118
16.3.1
Overview of changes ................................................................................................ 118
16.3.1.1
Modification 1: Addition of Visit 1a for rivaroxaban PK assessment.................. 118
16.3.1.2
Modification 2: Addition of dosing regimen for children with body weight 
between 6 and less than 12 kg............................................................................... 118
16.3.1.3
Modification 3: Correction of erroneous description for major protocol deviation 
documentation....................................................................................................... 119
16.3.2
Changes to the protocol text..................................................................................... 120
16.3.2.1
Synopsis ................................................................................................................ 120
16.3.2.2
Section 3. Study design......................................................................................... 124
16.3.2.3
Section 5.1.1 Rivaroxaban group .......................................................................... 125
16.3.2.4
Section 6.2 Visit 1 - Randomization Visit............................................................. 125
16.3.2.5
Section 6.3 Visit 1a (2+1 days after start t.i.d. rivaroxaban)................................. 126
16.3.2.6
Section 6.4 Visit 2 at Day 30 (± 7 days) ............................................................... 127
16.3.2.7
Section 6.5 Visit 3 at Day 60 (± 7 days) ............................................................... 129
16.3.2.8
Section 6.6 Visit 4 at Day 90 (± 7 days) ............................................................... 131
16.3.2.9
Section 6.14 PK/PD assessments .......................................................................... 132
16.3.2.10 Section 7.2 Analysis sets....................................................................................... 133
16.4
Amendment 12............................................................................................................. 133
16.4.1
Overview of changes ................................................................................................ 133
16.4.1.1
Modification 1: Introducing new dosing information for children with body 
weight between 2.6 and <6 kg, and inclusion of children aged birth to 6 months 133
16.4.1.2
Modification 2: Minor clarifications for consistency............................................ 134
16.4.2
Changes to the protocol text..................................................................................... 134
16.4.2.1
Title page............................................................................................................... 134


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16.4.2.2
Synopsis ................................................................................................................ 135
16.4.2.3
Section 1 Introduction ........................................................................................... 143
16.4.2.4
Section 3 Study design.......................................................................................... 144
16.4.2.5
Section 4.1 planned number of children................................................................ 147
16.4.2.6
Section 4.2 Inclusion criteria................................................................................. 147
16.4.2.7
Section 4.3 Exclusion criteria................................................................................ 147
16.4.2.8
Section 5.1.1 Rivaroxaban group .......................................................................... 148
16.4.2.9
Section 5.3 Duration of study treatment................................................................ 149
16.4.2.10 Section 5.4.1 Rivaroxaban .................................................................................... 150
16.4.2.11 Section 5.5 Packaging, labeling and storage......................................................... 150
16.4.2.12 Section 5.8 Study treatment and compliance assessment ..................................... 150
16.4.2.13 Section 6.1 Study visits ......................................................................................... 151
16.4.2.14 Section 6.3 Visit 1a (2+1 days after start t.i.d rivaroxaban).................................. 151
16.4.2.15 Section 6.4 Visit 2 at Day 30 (± 7 days) ............................................................... 152
16.4.2.16 Section 6.5 Visit 3 at Day 60 (± 7 days) ............................................................... 153
16.4.2.17 Section 6.6 Visit 4 at Day 90 (± 7 days) ............................................................... 154
16.4.2.18 Section 6.8 Visit 8, 30 day post study treatment contact (30 days ± 7 days after 
last visit)................................................................................................................ 155
16.4.2.19 Section 6.14 PK/PD assessments .......................................................................... 156
16.4.2.20 Section 7.4 Bleeding analysis................................................................................ 157
16.4.2.21 Section 7.5 Efficacy analysis ................................................................................ 158
16.4.2.22 Section 7.8 Determination of sample size............................................................. 159
16.4.2.23 Section 15 References ........................................................................................... 159
16.4.2.24 Section 17.2 Appendix 2: Estimated glomerular filtration rate ............................ 159
16.4.2.25 Section 17.4 Appendix 4: Dosing table for children from birth to 18 years......... 160
17. Appendices..................................................................................................................... 162
17.1
Appendix 1: Methods and measurements.................................................................... 162
17.2
Appendix 2: Estimated glomerular filtration rate........................................................ 162
17.3
Appendix 3: Reference values for blood pressure in children..................................... 164
17.4
Appendix 4: Dosing table for children from birth to 18 years..................................... 167


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Table of Tables
Table 0–1 Flow chart for all children except children aged < 2 years with catheter related 
thrombosis (see Table 2)     .................................................................................... 10
Table 0–2 Flow chart for children aged < 2 years with catheter related thrombosis ............ 13
Table 5–1 Identity of test drug ............................................................................................... 36
Table 5–2 Overview of comparator treatment........................................................................ 37
Table 17–1 Serum creatinine 97.5th percentile in children aged < 1 [18] ................................ 163
Table 17–2 Body weight-adjusted rivaroxaban dosing schedule for children aged birth 
to < 18 years     ..................................................................................................... 167
Table of Figures
Figure 1
Age-specific percentiles of blood pressure in children from birth to 12 months 164
Figure 2
95th blood pressure percentiles by age and height percentiles in children from 
1 to 17 years ........................................................................................................ 165


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Abbreviations
ACCP
American College of Chest Physicians
LOS
listing only set
AE
adverse event
MedDRA
Medical Dictionary for Regulatory 
Activities
ALT
alanine aminotransferase
MR
Magnetic resonance
anti-Xa
anti-factor Xa activity
MRI
magnetic resonance imaging
aPTT
activated partial thromboplastin time
NSAIDs
non-steroid anti-inflammatory drugs
b.i.d.
twice daily
o.d.
once daily
CCDS
Company Core Data Sheet
PD
pharmacodynamics
CIAC
Central independent adjudication 
committee
PE
pulmonary embolism
CNS
central nervous system
P-gp
P-glycoprotein
CT
computed tomography
PK
pharmacokinetic(s)
CYP3A4
cytochrome P450 isoenzyme 3A4
PP
polypropylene
DMC
data monitoring committee
PPS
per protocol set
DVT
deep vein thrombosis
PTC
Product Technical Complaint
eCRF
electronic case report form
SAE
serious adverse event
eGFR
estimated glomerular filtration rate
SAP
statistical analysis plan
EU
European Union
s.c.
subcutaneously
GCP
Good Clinical Practice
SCr
serum creatinine
GMP
Good Manufacturing Practice
SID
child identification number
HDPE
High density polyethylene
SOC
Standard of care
IB
investigator’s brochure
SUSAR
suspected unexpected serious adverse 
reactions
ICH
International Conference on 
Harmonization
TB
total bilirubin
IDMS
isotope dilution mass spectrometry
t.i.d.
three times daily
IEC
Independent Ethics Committee
TOSCA
Tools for Syntactic Corpus Analysis
INN
International non-proprietary name
U
Units
INR
international normalized ratio 
UFH
unfractionated heparin
IRB
Institutional Review Board
ULN
upper limit of normal
IxRS
interactive voice/web response system
US 
United States
LDD
Liquid Dosing Devices
VKA
vitamin K antagonist
LMWH
low molecular weight heparin
VTE
venous thromboembolism


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1.
Introduction
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 two large phase III studies and was compared to body weight adjusted LMWH 
and INR titrated VKA in patients with symptomatic deep vein thrombosis and pulmonary 
thromboembolism. The pooled analysis demonstrated clear non-inferiority for the primary 
efficacy outcome and an improved safety profile in terms of the occurrence of major bleeding
in adults.[5]
The goal of the rivaroxaban pediatric program is to make rivaroxaban available to children for 
treatment and secondary prevention of venous thromboembolism. It is anticipated that similar 
exposure in children, as compared to adults, will result in a similar safety and efficacy profile 
in children. To accomplish this goal, an age-and body weight-adjusted dosing regimen is 
being evaluated in a phase II program in children aged 6 months to18 years with various 
manifestations of venous thrombosis. These children will receive rivaroxaban during the last 
month of their regular anticoagulant treatment.
In phase II, enrollment of children aged 6 months to less than 18 years has been completed.
Rivaroxaban was well tolerated, no recurrent venous thromboembolism and/or major bleeding 
were observed and PK/PD results were in the expected range for children weighing more than 
12 kg.
23  
24
                                                                                                                                      
23 Section was modified via Amendment 8 (see Section 16.2.2.4)
24 The Paragraph was modified via Amendment 12 (see Section 16.4.2.3)


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The study will be initiated with children in the age group between 12 and less than 18 years 
since the age-and body weight adjusted dosing regimen has been confirmed for this age group 
in the phase II study 14373 and was approved by the data monitoring committee and steering 
committee. The dosing schedule/regimen for this age group is available in Appendix 4.
Once the age-and body weight adjusted dosing regimen has been confirmed for the age group 
between 6 and less than 12 years in the phase II study 14373 and approved by the data 
monitoring committee and steering committee, the dosing schedule/regimen for this age group 
will be made available through an administrative amendment. The investigators and ethics 
committees/IRBs will receive the administrative amendment well in advance with an 
opportunity for evaluation before permission will be given to start enrolling children in this 
age group. 
Once the age-and body weight adjusted dosing regimen has been confirmed for the age group 
between 2 and less than 6 years in the phase II study 14374 and approved by the data 
monitoring committee and steering committee, the dosing schedule/regimen for this age group 
will be made available through an administrative amendment. The investigators and ethics 
committees/IRBs will receive the administrative amendment well in advance with an 
opportunity for evaluation before permission will be given to start enrolling children in this 
age group.
Once the age-and body weight adjusted dosing regimen has been confirmed for the age group 
between 6 months and less than 2 years in the phase II study 14374 and approved by the data 
monitoring committee and steering committee, the dosing schedule/regimen for this age group 
will be made available through an administrative amendment. The investigators and ethics 
committees/IRBs will receive the administrative amendment well in advance with an 
opportunity for evaluation before permission will be given to start enrolling children in this 
age group.
The age-and body weight adjusted dosing regimen has now been established for all children 
aged birth to less than 18 years from data collected in the phase I/II studies and has been 
approved by the data monitoring committee and steering committee. Table 17–2 specifies the 
dosing regimen for each age group.
25
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. 
                                                                                                                                      
25 The paragraph was added via Amendment 12 ( see Section 16.4.2.3)


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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 requires 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.[8,9]
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. The American College of Chest Physicians (ACCP) 
management guidelines for children with secondary VTE (i.e., VTE that occurred in 
association with a risk factor) in whom the risk factor has resolved recommend anticoagulant 
therapy for 3 months. In children who have ongoing risk factors, guidelines suggest continued 
anticoagulant therapy beyond 3 months. For children with idiopathic VTE, the 
recommendation is anticoagulant therapy for 6 to 12 months. For catheter-related thrombosis, 
the guidelines recommend a total duration of anticoagulation of between 6 weeks and 
3 months.[9]
1.3
Rationale of the study and risk-benefit assessment
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 
that does not require subcutaneous or intravenous injections and regular blood sampling for 
laboratory monitoring, as is the case in adults, would be desirable. 
Type of anticoagulant drug, dose and duration of treatment for VTE in children is primarily 
derived from adult data. The majority of the recommendations for dosing in children are


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based on Grade 2 level of evidence.[10] Therefore, there is a medical need for additional 
clinical studies that address the efficacy and safety of anticoagulants treatment in children.
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 studies in adults,[11]
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 and observed laboratory abnormalities, was comparable to 
enoxaparin/VKA treatment. 
2.
Study objectives
The efficacy objectives are:

To assess the incidence of symptomatic recurrent venous thromboembolism

To assess the incidence of symptomatic recurrent venous thromboembolism and 
asymptomatic deterioration on repeat imaging.
The safety objective is:

To assess the incidence of overt major and clinically relevant non-major bleeding.
Other objectives are:

To characterize the pharmacokinetic/pharmacodynamic profile of rivaroxaban.
3.
Study design
This is a multicenter, open-label, active-controlled, randomized study to evaluate the efficacy 
and safety of an age- and body weight-adjusted rivaroxaban regimen in children with acute 
venous thromboembolism.
The study will be initiated with children in the age group between 12 and less than 18 years 
since the age-and body weight adjusted dosing regimen has been confirmed for this age group 
in the phase II study 14373 and was approved by the data monitoring committee and steering 
committee. The dosing schedule/regimen for this age group is available in Appendix 4
(update: for oral suspension this is implemented through Amendment 8).


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Once the age-and body weight adjusted dosing regimen has been confirmed for the age group 
between 6 and less than 12 years in the phase II study 14373 and approved by the data 
monitoring committee and steering committee, the dosing schedule/regimen for this age group 
will be made available through an administrative amendment (For tablet, this was 
implemented through Amendment 4
26; update: for oral suspension this is implemented 
through Amendment 8).
27 The investigators and ethics committees/IRBs will receive the 
administrative amendment well in advance with an opportunity for evaluation before 
permission will be given to start enrolling children in this age group. 
Once the age-and body weight adjusted dosing regimen has been confirmed for the age group 
between 2 and less than 6 years in the phase II study 14374 and approved by the data 
monitoring committee and steering committee, the dosing schedule/regimen for this age group 
will be made available through an administrative amendment (update: implemented through 
Amendment 8). The investigators and ethics committees/IRBs will receive the administrative 
amendment well in advance with an opportunity for evaluation before permission will be 
given to start enrolling children in this age group.
Once the age-and body weight adjusted dosing regimen has been confirmed for the age group 
between 6 months and less than 2 years in the phase II study 14374 and approved by the data 
monitoring committee and steering committee, the dosing schedule/regimen for this age group 
will be made available through an administrative amendment (update: implemented through 
Amendment 8). The investigators and ethics committees/IRBs will receive the administrative 
amendment well in advance with an opportunity for evaluation before permission will be 
given to start enrolling children in this age group. 
28
The age-and body weight adjusted dosing regimen has now been established for all children 
aged birth to less than 18 years from data collected in the phase I/II studies and has been 
approved by the data monitoring committee and steering committee. Table 17–2 specifies the 
dosing regimen for each age group.
29
Amendment 8 introduced a single consistent body weight adjusted dosing schedule/regimen 
for children aged 6 months to < 18 years and body weight ≥12kg (see Table 17–2).
30 Age 
dependency is implicitly considered in this table as certain body weights are connected 
(through standard growth charts) with certain ages (with some variability, excluding extreme 
obesity) as well as with anatomical and physiological differences that affect the absorption, 
distribution, metabolism, and excretion (ADME) processes at different ages.
31
                                                                                                                                      
26 The tablet dosing regimen for children from 6 to <12 years was included via Amendment 4 (see Section 16.1.2.2).
27 The oral suspension was implemented via Amendment 8 (see Section 16.2.2.5)
28 Information of start of enrollment in cohorts 6 months to less years 2 years and 2 to less than 6 years was added via 
Amendment 8 (Section 16.2.2.5)
29 The paragraph was added via Amendment 12 (see Section 16.4.2.4)
30 A dosing regimen for children with body weight between 6 and less than 12 kg was added via Amendment 10 (see Section 
16.3.2.2)
31 A single consistent body weight adjusted dosing schedule/regimen for children aged 6 months to < 18 years was 
introduced via Amendment 8 (see Section 16.2.2.5)


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Amendment 10 introduced dosing information and a new three times daily dosing schedule 
for children with body weight between 6 and <12 kg. This new dosing regimen is based on an 
exploratory PopPK model, that considers all rivaroxaban PK data available from children 
below 2 years dosed in our phase I and phase II studies. As less data are available for younger 
children (e.g., due to sparse sampling), the model predictions have a higher level of 
uncertainty for children with lower body weight. The Steering Committee therefore 
recommended to evaluate PK around the expected Cmax and at Ctrough as soon as the steady 
state is achieved (day 2+1 after start of rivaroxaban treatment; Visit 1a). 
The PK samples obtained at Visit 1a will be shipped and analyzed for each child individually 
and will allow to determine whether the plasma concentrations are in the adult reference 
range. The results will be provided to the investigator/site and discussed in a timely manner, 
i.e. within approximately 1 to 2 weeks after sample collection. Up to now, the predictions 
from the exploratory PopPK model are confirmed by the data from children enrolled in this 
weight group.
Amendment 12 opened enrollment to children aged birth to < 6 months and introduced dosing 
information for children with a body weight between 2.6 and 6 kg. This new dosing regimen 
is based on data from all studies in children younger than 2 years, as well as an exploratory 
PopPK model, that considers all rivaroxaban PK data available from all children younger than
2 years. As the exploratory model is based on limited data (e.g., limited number of subjects, 
sparse sampling), the model predictions had a higher level of uncertainty for these children. 
However, observed data from this study (14372) and data from the phase I/II study (17618) 
that is enrolling children of this weight category, have confirmed the predictions from the 
exploratory PopPK model in all children dosed t.i.d thus far in both studies.
32
Study description
33
Children aged birth to < 18 years with confirmed acute venous thromboembolism who receive 
initial treatment with therapeutic dosages of unfractionated heparin (UFH), low molecular 
weight heparin (LMWH), or fondaparinux are potentially eligible for the study. Initial 
treatment with UFH, LMWH or fondaparinux will be administered for at least 5 days (day 1-
5).
Randomization can be done during the first 9 days of initial treatment and will be in a 
2 (rivaroxaban): 1 (standard of care [SOC]) fashion. Children randomized to rivaroxaban will 
start rivaroxaban the day following the last administration of initial therapy with UFH, 
LMWH, or fondaparinux but with a minimal duration of initial therapy of 5 days and a 
maximum duration of 9 days.
The first administration of rivaroxaban will be started:

4 hours after discontinuation of UFH

12 hours after discontinuation of LMWH with a b.i.d. regimen, and 
                                                                                                                                      
32 The paragraph was added via Amendment 12 ( see Section 16.4.2.4)
33 The study description was modified to include children in younger cohort 8from birth) and to highlight different treatment 
duration for children <2 years with catheter related thrombosis (see Section 16.4.2.4)


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
24 hours after discontinuation of fondaparinux or LMWH with an o.d. regimen.
Children randomized to standard of care can continue UFH, LMWH, or fondaparinux or can 
switch to VKA therapy. If VKA therapy is planned, it can be initiated any time after 
randomization. Initial therapy with UFH, LMWH, or fondaparinux can be stopped after a 
minimum of 5 days and only if the INR is above 2 on two separate occasions, 24 hours apart. 
In children randomized to rivaroxaban in whom VKA therapy was already initiated before 
randomization, VKA therapy should be stopped and the switch to rivaroxaban should be 
made as described in Section 5.1.1.3.
34After randomization, children will receive either 
rivaroxaban or comparator for a main study treatment period of 3 months. After the main 
study treatment period of 3 months, the diagnostic imaging test which was obtained at 
baseline will be repeated, if clinically feasible. However, in children younger than 2 years 
with catheter-related thrombosis, the main study treatment period is for a total of 1 month at 
which time the repeat imaging will be performed. 
In all children, except those aged < 2 years with catheter-related thrombosis, the decision is 
made to stop study treatment at 3 months or to continue for an additional 3 months. In 
children who completed 6 months of treatment, the decision is made to stop study treatment 
or to continue for an additional 3 months. Then, in children who completed 9 months of 
treatment, the decision is made to stop study treatment or to continue for an additional 
3 months.  In children < 2 years with catheter-related thrombosis, the decision is made to 
stop study treatment at 1 month or to continue for an additional month.  Then, in children 
who completed 2 months of treatment, the decision is made to stop study treatment or to 
continue for an additional month.
Regardless of the duration of study treatment (<3, 3, 6, 9 or 12 months), an additional 1-
month post-treatment observational period will be completed for all children. After 
cessation of study treatment, it is at the investigator’s discretion to continue with 
anticoagulants.
The primary efficacy outcome is symptomatic recurrent venous thromboembolism. The 
secondary efficacy outcome is the composite of all symptomatic recurrent venous 
thromboembolism and asymptomatic deterioration in thrombotic burden on repeat imaging.
The principal safety outcome is the composite of overt major and clinically relevant non-
major bleeding. All suspected clinical study outcomes and baseline and repeat thrombosis 
imaging tests will be assessed by a central independent adjudication committee (CIAC) 
blinded to treatment allocation. An independent data monitoring committee (DMC) will 
monitor the children’s safety and give recommendations to the steering committee.
For all children, visits are scheduled at regular time points (see Table 0–1 and Table 0–2). 
Randomized children who have not received the study drug will be seen (visit or phone 
contact) at the end of the respective main study treatment period. Children who prematurely
discontinue study drug will be seen at the end of the intended study treatment period at month 
<3, 3, 6, 9 or 12. During all contacts, the treatment and clinical course of the child will be 
evaluated. Children with suspected efficacy or safety outcomes will undergo confirmatory 
                                                                                                                                      
34 This paragraph was added via Amendment 8 (see Section 16.2.2.5)


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testing as per standard of care. Blood samples for PK/PD will be taken at defined time points 
(see Table 0–1 and Table 0–2).
In children 12 years or older with DVT of the lower or upper extremity, the incidence of the 
post-thrombotic syndrome will be assessed at month 3, 6, 9 and 12 months, if applicable, 
using the Villalta Score. [17], 35
The reason why children did not pass the screen of in- and exclusion criteria after obtaining 
informed consent/child assent will be documented.
4.
Study population
4.1
Planned number of children
36
At least 170 children are needed for this study, of whom 80 in the age group 12 to < 18 years, 
30 in the age group 6 to < 12 years, 20 in the age group 2 to < 6 years, and 20 in the age group 
birth to < 2 years, with at least 12 aged birth to < 6 months.
4.2
Inclusion criteria
1. Children aged birth to < 18 years with confirmed venous thromboembolism who receive 
initial treatment with therapeutic dosages of UFH, LMWH or fondaparinux and require 
anticoagulant therapy for at least 90 days. However, children aged birth to < 2 years with 
catheter-related thrombosis require anticoagulant therapy for at least 30 days.
37
2.
Informed consent provided and, if applicable, child assent provided
3.
For children younger than 6 months: 
- Gestational age at birth of at least 37 weeks.
- Oral feeding/nasogastric/gastric feeding for at least 10 days.
- Body weight ≥2600 g
38
4.3
Exclusion criteria
1.
Active bleeding or bleeding risk contraindicating anticoagulant therapy
39
2. An estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (in children 
younger than 1 year, serum creatinine results above 97.5th percentile excludes 
participation, see Table 17–1).
40
3.
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.
                                                                                                                                      
35 The post-thrombotic syndrome assessment was added Amendment 8 (see Section 16.2.2.5)
36 The planned number of children was incleased via Amendment 12 (see Section 16.4.2.5)
37 The inclusion criterion was modified via Amendment 12 to include children from birth (see Section 16.4.2.6)
38 The inclusion criterion 3 was added via Amendment 12 (see Section 16.4.2.6)
39 Exclusion criteria 1, 5, 7 and 8 were modified via Amendment 8 (see Section 16.2.2.6)
40 The exclusion criterion 2 was modified via Amendment 12 to instruct that serum creatinine value should be used instead 
of eGRF for children <1 year (see Section 16.4.2.7)


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4.
Platelet count < 50 x 109/L.
5.
Sustained uncontrolled hypertension defined as systolic and/or diastolic blood pressure 
> 95th age percentile 39, 41
6.
Life expectancy < 3 months
7.
Concomitant use of strong inhibitors of both CYP3A4 and P-gp, including but not 
limited to all human immunodeficiency virus protease inhibitors and the following 
azole-antimycotics agents: ketoconazole, itraconazole, voriconazole, posaconazole, if 
used systemically (fluconazole is allowed). For exceptions, see Section 4.4. 39
8.
Concomitant use of strong inducers of CYP3A4, including but not limited to rifampicin, 
rifabutin, phenobarbital, phenytoin, and carbamazepine 39
9.
Childbearing potential without proper contraceptive measures, pregnancy or breast 
feeding
10. Hypersensitivity or any other contraindication listed in the local labeling for the 
comparator treatment or experimental treatment
11. Inability to cooperate with the study procedures
12. Previous assignment to treatment during this study
13. Participation in a study with an investigational drug or medical device within 30 days 
prior to randomization
4.4
Concomitant medication
Non-steroid 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 vitamin K antagonist (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 (including but not 
limited to ketoconazole, itraconazole, voriconazole, posaconazole), if used systemically, is not 
allowed, as well as concomitant use of strong inducers of CYP3A4 (including but not limited 
to rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine). Concomitant treatment 
with fluconazole is allowed.
42
5.
Treatment groups and regimens
5.1
Method of treatment allocation
Allocation to treatment will be done centrally by an interactive voice /web response system 
(IxRS). Allocation will be done in a 2 (rivaroxaban) to 1 (standard of care) fashion. 
                                                                                                                                      
41 Exclusion criterion 5, 7 and 12 was modified for minor clarification via Amendment 4 (see Section 16.1.2.3)
42 Concomitant use of strong inhibitors of both CYP3A4 and P-gp was modified via Amendment 8 (Section 16.2.2.7)


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The investigator will provide the IxRS with study center identification, the child’s date of 
birth (day, month and year)
43, gender, weight and clinical presentation. Allocation will be 
stratified by baseline presentation of venous thrombosis for each age group, separately, 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.
Specific procedures for treatment assignment through IxRS are contained in the IxRS manual.
5.1.1
Rivaroxaban group
44
The body weight adjusted dosing schedule for children aged birth to < 18 years is provided in 
Appendix 4 (see Section 17.4).
45
Children with body weight of ≥ 20 kg will receive rivaroxaban tablets or oral suspension. 
Children with body weight of < 20 kg will receive rivaroxaban as oral suspension.
Children with body weight of ≥ 30 kg will be treated according to a once daily (o.d.) regimen, 
irrespective of whether they receive rivaroxaban tablets or oral suspension. Children with 
body weight between 12 and < 30 kg will receive rivaroxaban twice daily (b.i.d) with a dosing 
intervals of approximately 12 hours. Children with body weight below 12 kg will receive 
rivaroxaban three times daily (t.i.d.) with dosing interval of approximately 8 hours.
Dosing regimen, including dosing frequency, will be adjusted if the child’s body weight 
changes during the study (Table 17–2). 
With a once daily regimen, rivaroxaban will be taken in the morning during or within 2 hours 
after breakfast. With a twice daily regimen the morning dose will be taken during or within 1 
hour after breakfast and the evening dose will be taken during or within 1 hour after dinner. 
With a three times daily regimen, the morning, afternoon and night doses should be taken 
during or within 30 minutes after feeding.
Each rivaroxaban dose should be immediately followed by the intake of one typical serving of 
up to 240 mL of liquid (o.d. or b.i.d regimen) or 120 mL (t.i.d. regimen). This volume will 
depend on age and may range from for example 20 mL in children aged 6 months up to 240 
mL in adolescents. 
46
Use of oral suspension
Oral suspension is available for use in children aged birth to < 18 years. 
At Visit 2, the Taste-and-Texture Questionnaire, using a three point scale, will be applied to 
determine the acceptance of the oral suspension in children from 4 to < 18 years. The pre-
                                                                                                                                      
43 A clarification was added that the day of birth has to be collected via Amendment 4 (see Section 16.1.2.4)
44 The section was modified via Amendment 12 to include children from birth ( see Section 16.4.2.8)
45 This section was modified via Amendment 8 (see Section 16.2.2.8)
46 A dosing regimen for children with body weight between 6 and less than 12 kg was added via Amendment 10 (see 
Section 16.3.2.3)


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dose part of this questionnaire needs to be completed before rivaroxaban suspension is taken, 
the post-dose part of this questionnaire needs to be completed after rivaroxaban suspension 
dose is taken and up to 240 mL of liquid has been taken.
Instructions on how to handle rivaroxaban oral suspension can be found in the Rivaroxaban 
Oral Suspension Handling Instructions.
Handling of missed doses
47
If rivaroxaban is taken with an o.d. regimen, a missed dose should be taken immediately when 
it is noticed, but only on the same day. Double dosing on a single day is not allowed. 
If rivaroxaban is taken with a b.i.d. regimen, a missed morning dose should be taken 
immediately when it is noticed, and it may be taken together with the evening dose. A missed 
evening dose can only be taken at the same evening.
If rivaroxaban is taken with a t.i.d. regimen, the t.i.d. administration schedule with 
approximately 8-hour intervals should be resumed at the next scheduled dose without 
compensating for the missed dose.
On the following day, the child should continue with the regular o.d., b.i.d. or t.i.d. regimen.
46
5.1.1.1
Switching from heparin/fondaparinux to rivaroxaban
For switching from heparin/fondaparinux to rivaroxaban, the pharmacological activity of 
UFH, LMWH and fondaparinux should be taken into account. The first administration of 
rivaroxaban should be planned 1) 4 hours after stopping the infusion of UFH, 2) 12 hours 
after the last injection of LMWH with a twice-daily regimen, or 3) 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.
5.1.1.2
Switching from rivaroxaban to heparin/fondaparinux
Children who switch from rivaroxaban to heparin/ fondaparinux can switch at the time of the 
next scheduled dose.
5.1.1.3
Switching from rivaroxaban to VKA and vice-versa
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 if 
advised to continue until the INR is ≥ 2.0. 
Children who switch from VKA to rivaroxaban should avoid using both drugs at therapeutic 
doses simultaneously. Rivaroxaban can be started if the INR is < 2.5.
5.1.2
Comparator group
Children randomized to the comparator group will continue with UFH, LMWH or 
fondaparinux or may switch to VKA therapy. VKA dosages will be adjusted to maintain the 
                                                                                                                                      
47 Missed dose handling was added via Amendment 4 (see Section 16.1.2.5).


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INR within the therapeutic range (target 2.5, range 2.0 - 3.0). UFH, LMWH or fondaparinux
can be discontinued once the INR is above 2.0 on two separate occasions, 24 hours apart.
5.2
Subject identification
Upon signing the informed consent/assent as per local requirements, each child will be 
assigned unique 9-digit child identification (SID) number by IxRS 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.
At Visit 1, Day 1, children will be assigned a unique randomization number by IxRS that will 
allow subsequent identification of treatment allocation.
5.3
Duration of study treatment
48
In all children, except those aged < 2 years with catheter-related thrombosis, the main study 
treatment period is 3 months. After that, it is up to the discretion of the treating physician to 
stop study treatment or to continue for an additional 3 months. 
In children who completed 6 months of treatment, the decision can be made to stop study 
treatment or to continue for an additional 3 months. Then, in children who completed 9 
months of treatment, the decision can be made to stop study treatment or to continue for an 
additional 3 months. Thereafter, no prolongation of study treatment can take place.
In children aged < 2 years with catheter-related thrombosis, the main study treatment period is 
1 month. After that, it is up to the discretion of the treating physician to stop study treatment 
or to continue for an additional 1 month. 
In children who completed 2 months of treatment, the decision can be made to stop study 
treatment or to continue for an additional 1 months. Thereafter, no prolongation of study 
treatment can take place.
Children who turn 2, 6, 12 or 18 years after randomization can continue their treatment
regimen.
49 Specifically children who turn 18 years after randomization are allowed to 
continue participation for the entire elected study treatment duration of 3, 6, 9 or 12 months.
Children randomized last into the study will have a minimal study treatment duration of 
3 months, except children aged < 2 years with catheter-related thrombosis, who will have a 
minimal study treatment duration of 1 month.
50
                                                                                                                                      
48 The section was modified via Amendment 12 to highlight different treatment duration for children <2 years with catheter 
related thrombosis (see Section 16.4.2.9)
49 Information for children who turn 2, 6, 12 or 18 was included (see Section 16.1.2.5)
50 Information on minimal study treatment duration was added via Amendment 8 (see Section 16.2.2.9)


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5.4
Formulation and dose
5.4.1
Rivaroxaban
Rivaroxaban will be provided by Bayer as immediate-release film-coated tablets, and as a
granules for oral suspension formulation (0.1% suspension as finally administered drug 
product), see Table 5–1. Rivaroxaban will be dosed according to body weight groups as 
detailed in the dosing schedules/regimens associated with this protocol. Since children with 
an estimated glomerular filtration rate below 30 mL/min/1.73 m2 (in children younger than 1 
year, serum creatinine results above 97.5th percentile, see Table 17–1) are excluded from the 
study, dose reduction for impaired renal function is not required.
51 52
Table 5–1
Identity of test drug
International non-
proprietary name (INN)
Rivaroxaban
Substance code number
BAY 59-7939
Formulation
Film-coated tablets
Granules for oral suspension
Composition
Active ingredient:  rivaroxaban / BAY 
59-7939 micronized
Excipients:  microcrystalline cellulose, 
croscarmellose sodium, hypromellose, 
lactose monohydrate, magnesium 
stearate, and sodium lauryl sulfate
Film-coating:  hypromellose, macrogol, 
titanium dioxide, and ferric oxide red or 
ferric oxide yellow
Active ingredient:  rivaroxaban / 
BAY 59-7939 micronized
Excipients:  microcrystalline 
cellulose and carmellose sodium, 
xanthan gum, citric acid 
anhydrous, sodium benzoate, 
flavor sweet and creamy, 
hypromellose 5 cP, sucralose, 
mannitol
Type of packaging and 
content
Type of packaging:  plastic bottle high
density polyethylene (HDPE) white 
opaque, closed with white screw cap 
polypropylene (PP) with sealing inserter 
and childproof lock
Type of packaging:  brown glass 
bottle type 3 closed with PP 
screw cap childproof lock
Strength of rivaroxaban
Tablets of 5.0, 10.0, 15.0 and 20.0 mg 1 mg per ml
5.4.2
Comparator
Comparator will be used according to approved formulations. 
5.5
Packaging, labeling, and storage
53
Rivaroxaban will be provided by Bayer and labeled according to local law and regulations. 
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 it to the sites.
                                                                                                                                      
51 Oral suspension information was updated via Amendment 8 (see Section 16.2.2.10)
52 Paragraph was modified via Amendment 12 to highlight that for children <1 year the serum creatinine value should be 
used instead of eGFR (see Section 16.4.2.10)
53 A minor modification was done in the Section to remove redundancy (see Section 16.4.2.11)


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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. Comparator provided by sites 
will be documented in the hospital/pharmacy records.
All study medication needs to be stored at the site according to the labeled storage advice in 
accordance with Good Clinical Practice (GCP) and GMP requirements. The study drug is to 
be kept in a secure area. 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.
5.6
Treatment assignment
After randomization, the randomization number will be recorded on the corresponding 
electronic case report form (eCRF). The subject identification number will have to be 
recorded on the label of the study medication.
In case UFH, LMWH, fondaparinux and/or VKA is provided locally, the compound’s name, 
dose, quantity and batch number, or a copy of the prescription has to be included in the child’s 
files.
5.7
Dosage and administration
Comparator treatment consists of locally used anticoagulants, 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.
         5 yr
240 u/kg o.d.
    5-10 yr
200 u/kg o.d.
  10-16 yr
175 u/kg o.d.
Dalteparin
129 ± 43 u/kg/dose o.d.
UFH
aPTT 1.5-2.5 prolongation
b.i.d.: twice daily; o.d.: once daily; u: units; this comparator list is not all-inclusive.[10]


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5.8
Study treatment delivery and compliance assessment
54
A 1-month supply of drug will be given at visits 1, 2, and 3, if applicable. In children who 
continue study treatment for an additional 3 months, (not applicable to children aged < 2 years 
with catheter-related thrombosis) study drug will be supplied at visit 4 covering a 3-month 
period. In children who continue the study for a third and a fourth cycle of 3 months; study 
drug will be supplied at visits 5 and 6.
All used and unused medication and additional supplies will be returned at all study visits. All 
non-used study medication will be kept securely in a designated locked container.
5.8.1
Rivaroxaban
Compliance will be evaluated by counting remaining rivaroxaban tablets or measuring 
remaining suspension. 
5.8.2
Vitamin K antagonists
Compliance with VKA treatment will be evaluated 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, 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. The time in therapeutic range (INR 2 to 3) will be calculated.
5.8.3
Low molecular weight heparin/fondaparinux
Compliance will be evaluated by counting remaining syringes.
5.9
Devices for preparation and administration of rivaroxaban oral 
suspension
The rivaroxaban granules for oral suspension will be suspended with water. In order to 
measure the appropriate volume of water, parents will be provided with 100 ml syringes. 
In addition, parents will be provided with Liquid Dosing Devices (LDDs; dosing pipettes) for 
precise, accurate and reproducible measuring of the rivaroxaban oral suspension dose volume 
and for administration to the child. 
Both supplies, the syringe and the LDDs, are class 1 devices with measuring function, which 
is considered a low risk class. 
The syringes and LDDs will be provided to the parents together with the rivaroxaban oral 
suspension as additional supplies. The use of these supplies is described in the Rivaroxaban 
Oral Suspension Handling Instructions. Any device malfunction or defect, or any use error by 
site personnel or parents will be assessed during study visits (see Section 7.9.10).
                                                                                                                                      
54 The section was modified via Amendment 12 (see Section 16.4.2.12)


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6.
Study Procedures 
6.1
Study visits
The study has 4 to 9 planned visits, depending on the elected study duration and dosing.
55
6.2
Visit 1 - Randomization Visit 
The parents/legal guardians and children will be given an explanation about the study and will 
be given sufficient time to consider their participation in the study and to ask any questions. 
Afterwards, informed consent and/or assent will be obtained (see Section 10.2). If the child 
passes the screen of inclusion and exclusion criteria, the child can be randomized.
56 Then, 

Obtain demographics and relevant medical history

Record all medication, including anticoagulant medication given for the current 
thrombosis

Obtain height/length, body weight and blood pressure

If results for hemoglobin, platelets, creatinine, ALT, total and direct bilirubin were not 
available within 5 days prior to randomization, obtain blood sample

Perform a urine pregnancy test, if applicable

Randomization can be done during the first 9 days of initial treatment and will be in a 
2 (rivaroxaban): 1 (standard of care [SOC]) fashion. Children randomized to 
rivaroxaban will start rivaroxaban the day following the last administration of initial 
therapy with UFH, LMWH, or fondaparinux but with a minimal duration of initial 
therapy of 5 days and a maximum duration of 9 days.

Dispense study medication and additional supplies (devices for oral suspension) 
57

Provide instructions on how to take the study drug and give the study booklet. If child 
will take rivaroxaban oral suspension, provide the Rivaroxaban Oral Suspension 
Handling Instructions. Train parents/child on the preparation and administration of the 
oral suspension and on the use of the liquid dosing device.

The first administration of rivaroxaban will be started: 

4 hours after discontinuation of UFH

12 hours after discontinuation of LMWH with a b.i.d. regimen, and

24 hours after discontinuation of fondaparinux or LMWH with an o.d. regimen 

Check for adverse events and device-related adverse events
                                                                                                                                      
55 The section was modified via Amendment 12 (see Section 16.4.2.13)
56 This section was updated via Amendment 8 (see Section 16.2.2.14)
57 Dispense of study medication was listed for consistency with the study flow chart via Amendment 4 (see 
Section 16.1.2.6).


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
Instruct that on the day of the next scheduled visit (visit 1a for t.i.d. regimen or visit 2 
for o.d. or b.i.d. regimen), rivaroxaban should not be taken at home and that all used 
and unused medication/supplies should be returned to the hospital
58

Update eCRF

Collect images of the index venous thrombotic event, prepare the adjudication 
package and send it to the central adjudication office. 
6.3
Visit 1a (2+1 days after start t.i.d. rivaroxaban) 
This visit will only be performed for children in the rivaroxaban t.i.d. group. If this visit falls 
on a weekend and cannot take place, the visit must be scheduled for the following Monday.

Check for potential study outcomes. If a suspected study outcome occurred, an 
adjudication package will be compiled and sent to the adjudication office.

Administer the next rivaroxaban dose immediately followed by the intake of up to 
120 mL of liquid.

Document the volume and type of liquid taken.

Document the exact time of rivaroxaban intake as well as the time and type of meal 
(i.e. breakfast, lunch, dinner) the child took during or within 30 minutes after 
rivaroxaban.
59

At 0.5-3 hours and at 7-8 hours after the rivaroxaban intake:

Collect a PK blood sample

Document the exact time of blood sampling for PK.

Check for changes in concomitant medications

Check for adverse events and device-related adverse events

Instruct that on the day of visit 2, rivaroxaban should not be taken at home and that all 
used and unused medication/supplies should be returned to the hospital

Update eCRF
60
                                                                                                                                      
58 This section was changed to implement new dosing regimen for children with body weight between 6 and less than 12 kg
via Amendment 10 (see Section 16.3.2.4)
59 The bullet was modified according to Amendment 12 ( see Section 16.4.2.14)
60 This section was added to implement new dosing regimen for children with body weight between 6 and less than 12 kg via 
Amendment 10 (see Section 16.3.2.5)


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6.4
Visit 2 at Day 30 (± 7 days)
61

Check for potential study outcomes. If a suspected study outcome occurred, an 
adjudication package will be compiled and sent to the adjudication office. 
62

Assess duration and intensity of menstruation, if applicable.
63

In children randomized to rivaroxaban: 

In case rivaroxaban is provided as tablet:

Administer the next rivaroxaban dose immediately followed by up to 240 ml of 
liquid.

In case rivaroxaban is provided as oral suspension: 

Complete the pre-dose part of the Taste- and-Texture Questionnaire only for 
children from 4 to < 18 years

Administer the next rivaroxaban dose immediately followed by up to 240 ml
(o.d. or b.i.d.) or up to 120ml (t.i.d.) of liquid.

Complete the post-dose part of the Taste- and-Texture Questionnaire only for 
children from 4 to < 18 years

Document the volume and type of liquid taken

Document the exact time of rivaroxaban intake as well as time and type of meal 
(i.e. breakfast, lunch, dinner) the child took in relation to rivaroxaban.
                                                                                                                                      
61 The section was modified via Amendment 12 ( see Section 16.4.2.15)
62 This section was updated via Amendment 8 (see Section 16.2.2.15)
63 Assessment of time and intensity of menstruation was included via Amendment 4 (see Section 16.1.2.7).


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
Blood sampling for o.d. or b.i.d. regimen (tablet and oral suspension):

At 0.5-1.5 hours and at 2.5-4 hours after this rivaroxaban intake, collect the PK 
blood sample

In children 6 years or older, collect a PD blood sample after the PK blood 
sample at both time points

In children < 2years with catheter related thrombosis receiving the b.i.d. 
regimen, a PK sample will also be collected at 10-16h after last evening dose 
of rivaroxaban, but before the first morning dose.

In children < 6 years receiving rivaroxaban b.i.d, no PD sample will be 
collected after the PK sample at 0.5-1.5 hours, but a PD sample will be taken 
after the PK sample at 2.5-4 hours

Blood sampling for t.i.d. regimen (oral suspension): 

At 0.5-3 hours after this rivaroxaban intake collect the PK sample, followed by 
the PD blood sample 

At 7-8 hours after this rivaroxaban intake collect the PK blood sample

Visit 2 will be modified for children weighing < 3250 grams.  The PK and PD 
samples taken 0.5 to 3 hours post-dose will be taken on a dosing day within the 
visit window (total volume to be drawn is 2.0 mL), and the 7-8 hour post-dose 
PK sample (total volume to be drawn is 0.6 ml) may be taken on the following 
dosing day within the visit window.  This modification may only occur in 
children weighing less than 3250 kg at the time of visit 2.

Document the exact time of rivaroxaban dosing and blood sampling for PK/PD
64

Perform drug accountability and assess compliance

Obtain body weight and adjust the rivaroxaban dose, if applicable.

Dispense study medication and additional supplies (devices for oral suspension)
65

Check for changes in concomitant medications

Check for adverse events and device-related adverse events

Instruct that on the day of visit 3, rivaroxaban should not be taken at home and that all 
used and unused medication/supplies should be returned to the hospital

Update eCRF

If a child discontinued study drug permanently before visit 2, visit 2 will still need to 
take place, but no blood sampling for PK/PD is required.
                                                                                                                                      
64 This section was changed to implement new dosing regimen for children with body weight between 6 and less than 12 kg
via Amendment 10 (see Section 16.3.2.6)
65 Dispense of study medication was listed for consistency with the study flow chart via Amendment 4 (see 
Section 16.1.2.6).


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Following procedures are applicable only to children <2 years of age with catheter 
related thrombosis:

Obtain safety blood sample for hemoglobin, platelets, ALT, total and direct bilirubin.

Repeat imaging with ultrasound, if applicable. If repeat imaging can be done with 
magnetic resonance imaging (MRI) or MR angiography, this should be done only if 
sedation and/or general anesthesia are not required. Other modalities of imaging, e.g. 
computed tomography (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.

After the main 30 day study treatment period in children aged < 2 years with catheter 
related thrombosis, the decision is made to stop study treatment or to continue for an 
additional 30 days. If study treatment is stopped, the 30-day post study treatment visit
(Visit 8) will be scheduled. If study treatment is continued for 30 days, a visit (Visit 3) 
will be schedule at day 60 ± 7 days.
6.5
Visit 3 at Day 60 (± 7 days)
66

Check for potential study outcomes. If a suspected study outcome occurred, an 
adjudication package needs to be compiled and sent to the adjudication office. 
67

Assess duration and intensity of menstruation, if applicable. 
68

In children randomized to rivaroxaban (tablet or oral suspension): 

Administer the next rivaroxaban dose immediately followed by the intake of up to 
240 mL (o.d. and b.i.d. regimen) or up to 120 mL (t.i.d. regimen) of liquid.

Document the volume and type of liquid taken.

Document the exact time of rivaroxaban intake as well as the time and type of 
meal (i.e. breakfast, lunch, dinner) the child took in relation to rivaroxaban.

If rivaroxaban is given using an o.d. or b.i.d. regimen, at 2-8 hours after the
rivaroxaban intake, collect a PK blood sample followed by the PD blood sample.

If rivaroxaban is given using a t.i.d. regimen, at 2-6 hours after the rivaroxaban 
intake, collect a PK blood sample followed by the PD blood sample

Document the exact time of blood sampling for PK/PD.
                                                                                                                                      
66 The Section was updated via Amendment 12 (see Section 16.4.2.16)
67 This section was updated via Amendment 8 (see Section 16.2.2.16)
68 Assessment of time and intensity of menstruation was included via Amendment 4 (see Section 16.1.2.6).


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
Provide instructions for the day before visit 4 

If rivaroxaban is given using an o.d. regimen, take rivaroxaban on the day 
before visit 4 at noon immediately followed by the intake of up to 240 ml of 
liquid

If rivaroxaban is given using a b.i.d. regimen, take rivaroxaban as late as 
possible in the evening on the day before visit 4 immediately followed by the 
intake of up to 240ml of liquid

If rivaroxaban is given using a t.i.d. regimen, take rivaroxaban night dose 
before visit 4 as scheduled, immediately followed by the intake of up to 120 ml 
of liquid

Document the volume and type of liquid taken

Document the exact time of rivaroxaban intake as well as the time and type of 
meal (i.e. breakfast, lunch, dinner) the child took in relation to rivaroxaban.
69

Perform drug accountability and assess compliance

Obtain body weight and adjust the rivaroxaban dose, if applicable.

Dispense study medication and additional supplies (devices for oral suspension) 70

Check changes in concomitant medications

Check for adverse events and device-related adverse events

Instruct that on the day of visit 4, all used and unused medication/supplies should be 
returned to the hospital

Update eCRF

If a child discontinued study drug permanently before visit 3, visit 3 will still need to 
take place, but no blood sampling for PK/PD is required.
Following procedures are applicable only to children <2 years of age with catheter 
related thrombosis:

If study treatment is stopped, the 30-day post study treatment visit will be scheduled. 
If study treatment is continued for an additional 30 days, a visit (Visit 4) will be 
schedule at day 90 ± 7 days. If study treatment is stopped, the 30-day post study 
treatment visit will be scheduled
                                                                                                                                      
69 This section was changed to implement new dosing regimen for children with body weight between 6 and less than 12 kg 
via Amendment 10 (see Section 16.3.2.7)
70 Dispense of study medication was listed for consistency with the study flow chart via Amendment 4 (see 
Section 16.1.2.6).


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6.6
Visit 4 at Day 90 (± 7 days)
71

Check for potential study outcomes. If a suspected study outcome occurred, an 
adjudication package needs to be compiled and sent to the adjudication office.
72

Assess duration and intensity of menstruation, if applicable.
73

Obtain body weight if the child continues in the study for an additional 3 months and 
adjust the rivaroxaban dose, if applicable.

In case child continues study treatment, instruct that on the day of visit 5, all used and 
unused medication/supplies should be returned to the hospital.

In children randomized to rivaroxaban:

Document the exact time of rivaroxaban intake on the day prior to visit 4 and time 
and type of meal the child took in relation to rivaroxaban as well as the volume 
and type of liquid taken.

If rivaroxaban is given using an o.d. regimen, collect the blood sample for 
hemoglobin, platelets, ALT, total and direct bilirubin, followed by PK blood 
sample and finally the PD blood sample at 20-24h after rivaroxaban was taken on 
the previous day

If rivaroxaban is given using a b.i.d. regimen, collect the blood sample for 
hemoglobin, platelets, ALT, total and direct bilirubin, followed by PK blood 
sample and finally the PD blood sample at 10 to 16 hours after the last evening 
dose (in all children except those aged < 2 years with catheter related thrombosis).

If rivaroxaban is given using a t.i.d. regimen, collect hemoglobin, platelets, ALT, 
total and direct bilirubin, followed by the PD blood sample 10 to 16 hours after the 
last evening dose (in all children except those aged < 2 years with catheter related 
thrombosis).

If dosing continues beyond visit 4/day 90, give next dose after PD sample (in all 
children except those aged < 2 years with catheter related thrombosis)

Document the exact time of blood sampling for PK/PD.
74

Perform drug accountability and assess compliance

Dispense study medication and additional supplies (devices for oral suspension) 
75

Check changes in concomitant medications
                                                                                                                                      
71 The section was updated via Amendment 12 (see Section 16.4.2.17)
72 This section was updated via Amendment 8 (see Section 16.2.2.17)
73 Assessment of time and intensity of menstruation was included via Amendment 4 (see Section 16.1.2.6).
74 This section was changed to implement new dosing regimen for children with body weight between 6 and less than 12 kg 
via Amendment 10 (see Section 16.3.2.8)
75 Dispense of study medication was listed for consistency with the study flow chart via Amendment 4 (see 
Section 16.1.2.6).


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
Repeat imaging with ultrasound, if applicable. If repeat imaging can be done with 
magnetic resonance imaging (MRI) or MR angiography, this should be done only if 
sedation and/or general anesthesia are not required. Other modalities of imaging, e.g. 
computed tomography (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.

Check for adverse events and device-related adverse events

Perform post-thrombotic syndrome assessment (only for children ≥12 years and with 
lower or upper extremity DVT) 

Update eCRF
After the main 3-month study treatment period in all children except those aged < 2 years 
with catheter related thrombosis, the decision is made to stop study treatment or to continue 
for an additional 3 months. If study treatment is stopped, the 30-day post study treatment visit 
will be scheduled. If study treatment is continued for 3 months, a visit (Visit 5) will be 
schedule at day 180 ± 7 days. If study treatment is stopped, the 30-day post study treatment 
visit will be scheduled. If study treatment is continued for an additional 3 months, a visit 
(Visit 6) will be schedule at day 270 ± 7 days. If study treatment is stopped, the 30-day post 
study treatment visit will be scheduled. If study treatment is continued for an additional 3 
months, a visit (Visit 7) will be schedule at day 360 ± 7 days.

If a child discontinued study drug permanently before visit 4, visit 4 will still need to 
take place, but no blood sampling for PK/PD is required.
6.7
Visit 5, Visit 6, and Visit 7 at Day 180, Day 270, Day 360 (± 7 days)

Check for potential study outcomes. If a suspected study outcome occurred, 
adjudication package needs to be compiled and sent to the adjudication office.
76

Assess duration and intensity of menstruation, if applicable.
77

Obtain body weight at visits 5 and 6, if the child continues in the study for an 
additional 3 months. Adjust the rivaroxaban dose, if applicable.

Check for adverse events and device-related adverse events.

Perform post-thrombotic syndrome assessment (only for children ≥12 years and with 
lower or upper extremity DVT).

Perform drug accountability and assess compliance.

Dispense study medication and additional supplies (devices for oral suspension).
78

Check changes in concomitant medications.
                                                                                                                                      
76 This section was updated via Amendment 8 (see Section 16.2.2.18)
77 Assessment of time and intensity of menstruation was included via Amendment 4 (see Section 16.1.2.6).
78 Dispense of study medication was listed, if applicable, for consistency with the study flow chart via Amendment 4 (see 
Section 16.1.2.6).


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
Instruct that on the day of visits (visit 6 and visit 7, if applicable), all used and unused 
medication/supplies should be returned to the hospital.

Update eCRF

If a child discontinued study drug permanently before visit 5, 6, or 7, these visits will 
still need to take place.
6.8
Visit 8, 30-day post study treatment contact (30 days ±7 days after last 
visit)
79
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 (telephone contact 
cannot be conducted in children who are aged < 2 with catheter-related thrombosis) will take 
place 30 days ± 7 after the last visit of the patient. In children who prematurely discontinue 
study medication, this visit will take place 30 ±7 days after premature discontinuation. 
80

Check for potential study outcomes. If a suspected study outcome occurred, an 
adjudication package needs to be compiled and sent to the adjudication office. 

Check for adverse events.

Document if anticoagulant treatment was continued or interrupted after stopping study 
medication.

Update eCRF.
Following procedures are applicable only to children <2 years of age with catheter 
related thrombosis:

This visit cannot occur by telephone

Check changes in concomitant medications

Obtain PD blood sample
o If the patient is started on another anticoagulant during the 30 day post study 
treatment period, the PD sample needs to be taken at least 8 hours after last 
dose of rivaroxaban and before initiation of a new anticoagulant.
6.9
Unscheduled visits
If deemed necessary, it is at the investigator’s discretion to arrange additional visits.  
                                                                                                                                      
79 The Section was updated via Amendment 12 ( see Section 16.4.2.18).
80 This section was corrected via Amendment 8 (see Section 16.2.2.19).


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6.10
Safety outcomes
The primary safety outcome is the composite of overt 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.
6.11
Recommendations before and after invasive procedures and surgical 
intervention 
If an invasive procedure or surgical intervention is required, rivaroxaban should be stopped at 
least 24 hours before the intervention, if possible and based on the clinical judgment of the 
physician. 
If the procedure cannot be delayed, the increased risk of bleeding should be assessed against 
the urgency of the intervention.
Rivaroxaban should be restarted after the invasive procedure or surgical intervention within 
24 hours, provided the clinical situation allows and adequate hemostasis has been established.
For the comparator please follow the respective product label.


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6.12
Management of bleeding in children
If a child has a serious bleed during study treatment, the following routine measures could be 
considered:

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

Consider usual treatment for bleeding, including blood transfusion, and/or fresh frozen 
plasma

If the child is treated with rivaroxaban, 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):

4-factor concentrate

recombinant factor VIIa (NovoSeven®)
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of 
rivaroxaban.
6.13
Efficacy outcomes
The primary efficacy outcome will be the composite of all symptomatic recurrent venous 
thromboembolism as confirmed by the CIAC. The secondary efficacy outcome will be the 
composite of all symptomatic recurrent venous thromboembolism and asymptomatic 
deterioration on repeat imaging,[3],[10] as assessed by the CIAC.
6.14
PK/PD assessments
81
The prothrombin time, aPTT and anti-factor Xa activity (anti-Xa) will be used to assess the 
pharmacodynamic effects after administration of the study drug.
Blood samples will be taken for PK and PD measurements from children randomized to 
rivaroxaban. 
                                                                                                                                      
81 The Section was updated via Amendment 12 (see Section 16.4.2.19)


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The following blood samples will be taken in children without catheter related thrombosis and 
with

o.d. (children with body-weight > 30 kg) or b.i.d. (children with body weight 12-
30 kg) regimen:
o
two post-dose PK/PD samples at visit 2 (no PD sample at 0.5-1.5 hours for 
children < 6 years)
o
one post-dose PK/PD sample at visit 3, and
o
one pre-dose PK/PD sample at visit 4.

t.i.d. regimen (children with body-weight < 12 kg) :
o
two post-dose PK samples at visit 1a
o
two post-dose PK samples at visit 2 
o
one post-dose PD sample at visit 2, and
o
one post-dose PK/PD sample at visit 3, and
o
one pre-dose PD sample at visit 4.
82
The following blood samples will be taken in children aged < 2 years with catheter related 
thrombosis and

b.i.d regimen (children with body weight ≥12 kg):
o
one pre-dose PK sample at visit 2
o
two post-dose PK/PD samples at visit 2, and 
o
one post-dose PK/PD sample at visit 3, if occurs, and 
o
one PD sample at visit 8

t.i.d regimen (children with body weight <12 kg)
o
two post-dose PK sample at visit 1a, and 
o
two post-dose PK sample at visit 2
o
one post-dose PD sample at visit 2, and 
o
one post-dose PK/PD sample at visit 3, if occurs, and 
o
one PD sample at visit 8
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.
                                                                                                                                      
82 Blood samples were added for new dosing regimen for children with body weight between 6 and less than 12 kg via 
Amendment 10 (see Section 16.3.2.9)


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If rivaroxaban was temporarily stopped, PK/PD blood samples should only be obtained if the 
rivaroxaban has been restarted and sustained for at least 3 days.
If a blood sample is taken from a central line, it is recommended to discard 3 mL of blood. 
For small children a smaller volume can be discarded and sites can follow their own practical 
standard.[16] At visit 3, in children from 6 months to 1 year, it is advised to withdraw blood 
from a peripheral catheter rather than a central venous line to limit the volume of required 
blood. If a blood sample is taken from a peripheral catheter, fluid has to be withdrawn until all
fluid is removed. For venipunctures, an anesthetic cream can be applied. Heparin can be used 
to maintain catheter patency; however, before collecting PK/PD samples, the catheter needs to 
be flushed with saline. A first volume of (diluted) blood should be discarded, as usual.
83
Detailed information about the handling and labeling of the samples will be provided in the 
laboratory manual. To estimate the PK/PD profile of rivaroxaban, results will be pooled and 
analyzed using population approaches. Details for the population PK/PD analysis will be 
described in a separate evaluation plan
6.15
Study booklet
Parents/children will receive a booklet/patient card, specifying for both treatment groups:

The local medical contact person and local emergency telephone number

The dates of hospital visits and telephone calls, if applicable

Instructions to return empty medication packages and unused study medication

Instructions on signs and symptoms of bleeding.
For the rivaroxaban treatment group:

How to take rivaroxaban

Calendar to track the date, time and type of food and study drug intake as well as the 
volume of liquid taken 
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).
6.16
Study committees
6.16.1
Steering committee
The steering committee has the overall scientific responsibility of the study. Its tasks and 
responsibilities are:

To facilitate and approve the final protocol
                                                                                                                                      
83 Catheter flushes with heparin are added as allowed via Amendment 4 (see Section 16.1.2.12)


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
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 monitor progress of study enrollment

To assist in the analysis and presentation of the results

To decide on the publication and presentation policy of final results.
6.16.2
Central independent adjudication committee (CIAC)
All index venous thrombotic events, and all suspected recurrent venous thromboembolic 
events, asymptomatic deterioration of the thrombotic burden on repeat imaging, bleeding, 
other vascular events and deaths that occur during the study and the 30-day post study
treatment period, will be evaluated by a CIAC. For all index events and study outcomes, the 
requirement to complete a worksheet and to compile an adjudication package and to send it to 
adjudication office within 2 weeks from randomization or occurrence of the event, 
respectively. The CIAC procedures will be described in an adjudication manual. Adjudication 
results will be the basis for the final analyses.
6.16.3
Data monitoring committee (DMC)
This committee 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 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. Any revision will be clearly 
identified in the final SAP, issued prior to data base lock. All efforts will be taken to avoid 
missing data in important baseline characteristics and post baseline data. Missing data 
proportions will be reported.
7.2
Analysis sets
Full analysis set: this population will include all randomized children. Safety analysis set: this 
population will include all randomized children who received at least one dose of study 
medication. Per-protocol set: the per-protocol set may exclude subjects with major protocol 
deviations. The detailed list of these deviations will be finalized prior to database lock and 
included in the protocol deviation document, the approved final list of important deviations, 


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validity findings and assignment to analysis set(s).
84 Listing only set (LOS): this population 
includes all screening failures. 
7.3
Demographic and other baseline characteristics
Summary statistics (arithmetic mean, standard deviation, median, minimum and maximum for 
quantitative variables) will be presented by treatment. Frequency tables for qualitative data 
will be provided. Medical history findings will be summarized using Medical Dictionary for 
Regulatory Activities (MedDRA) terms.
7.4
Bleeding analysis
85
All safety analyses will be performed on the safety analysis set. All bleeding events that
occurred during study treatment or within 2 days after stop of study medication will be 
summarized by treatment group. 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 during the period divided by number 
of children at risk at the beginning of the period) and cumulative incidences (time to first 
event; Kaplan-Meier) will be calculated for the primary safety outcome by treatment group at 
the end of the main study treatment period for pooled data. Incidence proportions will be 
calculated for each age stratum at the end of the main study treatment period as well. In 
addition, incidence proportions will be calculated by treatment group for each age stratum and
pooled data overall in the extended study treatment period at 2 and 3 months (for the children 
<2 years with catheter related thrombosis) and at 6, 9 and 12 months (for the other groups). 
Denominators in this case will be the number of patients at risk at the start of the respective 
period.
Incidence proportions of other bleeding outcomes and components including duration and 
intensity of menstrual bleeding will be presented descriptively.
86
7.5
Efficacy analysis
87
All efficacy analyses will be performed on the full analysis set population based on the 
outcomes confirmed by the CIAC. Incidence proportions and cumulative incidences (time to 
first event; Kaplan-Meier) will be calculated for the primary and secondary efficacy outcomes 
by treatment group at the end of the main study treatment period for pooled data. In addition,
incidence proportions will be calculated for each age stratum at the end of the main study 
treatment period. Incidence proportions will be calculated for the primary outcomes by 
treatment group for each age stratum and pooled data overall in the extended study treatment 
period at 2 and 3 months (for the children <2 years with catheter related thrombosis) and, at 6, 
                                                                                                                                      
84 The description for the major protocol deviation documentation was corrected via Amendment 10 (see Section 16.3.2.10)
85 The Section was updated via Amendment 12 (see Section 16.4.2.20)
86 Duration and intensity of menstruation was included via Amendment 4 (see Section 16.1.2.13)
87 The Section was updated and subgroup analysis added according to Amendment 12 (see Section 16.4.2.21)


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9 and 12 months (for the other groups). Denominators will be the number of patients at risk at 
the start of the respective period. 
Data of post-thrombotic syndrome assessment in children ≥ 12 years with lower or upper 
extremity DVT will be presented descriptively. Duration of treatment for the main treatment 
period (up to month 3) and the overall treatment duration will be summarized descriptively by 
treatment group.
Results for the Taste-and-Texture Questionnaire in children 4 to < 18 years who receive the 
oral suspension will be presented descriptively.
88
Subgroup analysis
Demographic and other baseline characteristics, as well as efficacy, safety and PK/PD data 
will be summarized for the main treatment period (up to the month 3 visit) for each age group 
and for combinations of age groups.
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 relation of
anticoagulant parameters of rivaroxaban with plasma concentrations. Details will be given in 
a separate PK/PD evaluation plan.
7.7
Interim analyses
No interim analysis will be performed.
7.8
Determination of sample size
89
At least 170 children 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.
7.9
Adverse events 
Individual listings of adverse events 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.
For the purpose of adverse event (AE) documentation, study drug is defined as either 
rivaroxaban or standard of care as allocated starting from randomization up to the end of 
study treatment visit.
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 
                                                                                                                                      
88 Statistical analysis of Taste- and Texture questionnaire and PTS was added via Amendment 8 (see Section 16.2.2.20)
89 The minimum number of children was increased via Amendment 12 (see Section 16.4.2.22)


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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 the study 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 randomization. If the 
condition started or deteriorated after randomization, it will be documented as adverse event.
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, e.g. 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 study drug 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 study drug. 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 study 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 study drug. Factors in assessing the 
relationship of the AE to study drug include the temporal sequence from drug administration 
(the event should occur after the study drug is given) and the length of time from study drug 


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exposure, recovery on study drug discontinuation (de-challenge), and recurrence on study 
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 drug. 
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.
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 drug 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 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
After randomization, 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 randomization up to 1 month after the last study drug administration
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.


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7.9.7
Study specific exceptions to the (S)AE reporting
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 reported as a SAE. However, if this transfer is part of 
treatment of a medical complication, it should be considered as prolonged hospitalization and 
the event should be reported as a SAE. To collect additional information about clinically 
important laboratory abnormalities, any laboratory abnormality that required cessation of the 
study drug will be captured as a SAE.
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 needs to be reported only for rivaroxaban study treatment and will be 
determined by Bayer according to the applicable reference document and according to all 
local regulations. 
7.9.9
AEs of special interest
The following AEs are of special interest:

Concurrent elevations of ALT > 5x ULN and total bilirubin > 2x ULN

A platelet count below 50 x 109/L

Allergic skin reactions, allergic systemic reactions.
7.9.10
Adverse events related to devices used for preparation and 
administration of rivaroxaban oral suspension
7.9.10.1
Definitions
7.9.10.1.1
Incident
An “Incident” is any malfunction or deterioration in the characteristics and / or performance 
of a device, as well as any inadequacy in the labeling or the instructions for use which, 
directly or indirectly, led, might lead to or might have led to the death of a patient, or user or 
of other persons or to a serious deterioration in their state of health.
Any event which meets all three basic reporting criteria (A, B and C) is considered an
“Incident”. The criteria are as follows:
A) An adverse device event has occurred. Typical adverse events in the context of device 
could be among others:

Malfunction or deterioration in the characteristics or performance, or

Degradation / destruction of the device, or 

Inappropriate therapy (e.g., underdosing or overdosing).


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B) The device is suspected to be a contributory cause of the “Incident”.
C) The event led, or might have led, to death or serious deterioration in state of health of a 
patient, or user, or other person.
7.9.10.1.2
Other Reportable Incident
An “Other Reportable Incident” is any incident that did not lead to death or serious 
deterioration in health, but it might do if it occurred again under less fortunate circumstances 
or without intervention of healthcare personnel. This may include cases without any medical 
event reported. 
7.9.10.1.3
Other Event 
An “Other Event” is any device related case that does not fulfill all the three basic “Incident” 
criteria A-C listed in the definition of an “Incident” above. 
7.9.10.1.4
Product Technical Complaint (PTC)
A PTC is any report received (written, electronic or verbal communication) about a potential 
or alleged failure of a product in its quality (including the identity, durability, reliability, 
safety, efficacy or performance) or suspect counterfeit. The complaint may or may not 
represent a potential risk to the patient. 
7.9.10.2
Device Malfunction or Failure and Medical Device Reporting
Any device complaint, malfunction, or failure including use errors will be recorded by the 
clinical/investigational site, including all relevant device information using the clinical 
investigations device complaint form, and forwarded within 24 hours to the sponsor or 
sponsor’s designee for evaluation and investigation, regardless of whether or not a medical 
event was associated with the device malfunction or failure.  
There are three different situations, in which a medical device complaint form might need to 
be filled out by the investigator:
a) When an AE is recorded, the investigator needs to check if a device malfunction or 
failure might be associated with the recorded AE.
b) When a device malfunction or device failure occurs, the investigator needs to assess 
whether an AE might have occurred in relation to the device.
c) When a device malfunction, device failure, or use error occurs, without any associated 
AE, this also needs to be captured in the form and immediately forwarded to the 
sponsor for investigation.
The details of the malfunction and medical circumstances will be captured on a Device 
Complaint Form filled out by the investigator and then returned to the sponsor or sponsor’s 
designee. The final determination of reportability is made by the sponsor and not the 
clinical/investigational site based on the medical circumstances surrounding the event.  
Investigator’s notification of the sponsor
All investigators will be instructed and trained on all relevant aspects of the investigator’s 
reporting obligations for device incidents and serious public health threats.  This information, 


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including all relevant contact details, is summarized in the investigator site file. This 
information will be updated as needed.
The manufacturer will inform the sponsor about necessary trend reports and will provide the 
required documentation after completing the respective investigation and statistical analysis. 
The sponsor will then notify the authorities of any trend reports according to all applicable 
regulations.
All devices that have malfunctioned or failed will be collected and returned to the sponsor or 
sponsor’s designee. Malfunctioned or failed devices should be:

provided with a failure description („What went wrong“), 

free of sources for contamination such as drug residues, 

clearly marked as already used at patients and shall include corresponding warning 
symbols on packaging.
7.10
Premature discontinuation of study drug
Children prematurely discontinue study drug

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 drug should be stopped for any reason.

at the (exceptional) request of Bayer.
If study drug is temporarily discontinued, it can be restarted. If study drug is permanently 
discontinued, further treatment is at the investigator’s discretion. 
If the child or parents/legal representatives withdraws consent to treatment with study drug 
(including comparator), 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 
representatives state to the investigator that they no longer authorize to continue to obtain 
outcome data, this will be respected and documented in the source records, and no further 
study data will be collected.
In all children who prematurely discontinue study drug for other reasons than withdrawal of 
informed consent, study visits will take place as planned to collect potential study outcomes 
and AEs.
7.11
Pregnancies
The investigator must report to the sponsor any pregnancy occurring in a study subject, or
in the study subject's partner, during the subject's participation in this study. The report 
should be submitted within the same timelines as an SAE, although a pregnancy per se is 
not considered an SAE. The outcome of the pregnancy should be followed up carefully,
and any outcome of the mother or child should be reported. For the pregnancy of a study
subject's partner, all efforts should be made to obtain similar information on course and 


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outcome, subject to the partner’s consent. For all reports, the forms provided are to be 
used.
7.12
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, and 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) 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 


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by the hospital, institution or private practice. If the archiving procedures do not meet the 
minimum timelines required by Bayer, alternative arrangements will be made to ensure the 
availability of the source documents for the required period. The investigator/institution will 
notify Bayer if a change in archival arrangements occurs. The investigator site file will not be 
destroyed without Bayer's approval. The investigator's contract will contain all regulations 
relevant for the study center.
9.
Premature termination of the study
The investigator has the right to terminate participation in the study at any time. 
Bayer has the right to close this study or study sites at any time, which may be due but not 
limited to the following reasons: 

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. 


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Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol. 
Modifications to the study protocol will not be implemented by either Bayer or the 
investigator without agreement by both parties. However, the investigator or Bayer may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard to 
the trial children without prior IEC/IRB/Bayer approval/favorable opinion. As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/Bayer. Any deviations from the protocol must be explained and documented by the 
investigator.
For each participating European Union (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, an 
informed consent and an informed assent form provided by Bayer or the study center. A 
sample child information and informed consent and assent form are provided as documents 
separate to this protocol. Consent will be asked from the parent(s)/ legal guardian(s) and, if 
appropriate as determined by local regulation, age and individual child capability, will be 
asked from the child, according to country-specific regulations.
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. 
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) voluntarily agree to sign 
and date the informed consent and the child provides informed consent or assent, as 
appropriate and determined by local regulation, age and individual child capability, and have 
done so. Then the investigator or designee will sign and date the forms. The parent(s)/legal 
guardian(s) and the child, if applicable, will receive a copy of the signed and dated form(s). 
The signed informed consent and the assent form will remain in the investigator site file or, if 
locally required, in the child’s file. 
The informed consent/assent form and any other written information provided to the 
child/parents/legal guardians will be revised whenever important new information becomes 
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 


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informed consent/assent form. The investigator will inform the child/parents/legal guardian of 
changes in a timely manner and will ask the parents/legal guardians and the child, if 
applicable, to confirm participation in the study by signing the revised informed consent, and, 
if applicable, will ask the child to provide informed assent as documented on the revised 
assent form. Revised informed consent/assent form and the child information sheet must 
receive the IEC's/IRB's approval before implementation.
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject’s clinical record must clearly show that informed 
consent was obtained prior to these procedures.
11.
Investigators and other study participants
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 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.


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15.
References
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, Haas S, Huisman MV, Hull RD, et al., ODIXa-DVT 
Study Investigators. 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.
17. Kahn SR, Partsch H, Vedantham S, et al. Subcommittee on Control of Anticoagulation of 
the Scientific and Standardization Committee of the International Society on Thrombosis 
and Haemostasis. Definition of post-thrombotic syndrome of the leg for use in clinical 
investigations: a recommendation for standardization. J Thromb Haemost 2009;7:879-
83.
90
18. Boer DP, Rijke YB, Hop WC et al. Reference values for serum creatinine in children 
younger than 1 year of age. Pediatr Nephrol 2010;25:2107-2113.
91
16.
Protocol amendments
16.1
Amendment 4
16.1.1
Overview of changes
Amendment 4 is the first global amendment dated 21 Jul 2015.
16.1.1.1
Modification 1: Minor clarifications for consistency
Minor, consistency and logical clarifications were made throughout the document.
Rationale:
Changes were made to ensure consistency throughout the document. These changes do not 
affect the overall study concept.
Affected protocol section: 
                                                                                                                                      
90 A reference was added via Amendment 8 (see Section 16.2.2.22)
91 A reference was added via Amendment 12 (see Section 16.4.2.23)


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Synopsis, Section 4.3  Exclusion criteria, Section 5.1  Method of treatment allocation, Section 
6.3  Visit 2 at Day 30 (± 7 days), Section 6.4  Visit 3 at Day 60 (± 7 days), Section 6.5  Visit 4 
at Day 90 (± 7 days), Section  6.6 Visit 5, Visit 6, and Visit 7 at Day 180, Day 270, Day 360 
(± 7 days), 
16.1.1.2
Modification 2: Implementation of dosing regimen for children from 6 
to <12 years
The dosing schedule/regimen for the age group from 6 to <12 years was included.
Rationale:
The body weight adjusted dosing regimen was confirmed for the age group between 6 and 
less than 12 years in the phase II study (14373). Therefore, the dosing schedule/regimen for 
this age group was included.
Affected protocol section: 
Section 3  Study design, Section 5.1.1  Rivaroxaban group, New Section 17.5  Appendix 5: 
Dosing table for children from 6 to <12 years
16.1.1.3
Modification 3:
Inclusion of menstruation intensity assessments
The protocol was adjusted throughout to reflect that the intensity of menstruation has to be 
assessed from visit 2 to visit7.
Rationale:
For sufficient evaluation of the occurrence of menorrhagia during the study treatment period, 
the intensity of menstruation has to be assessed.
Affected protocol section: 
Synopsis, Section 6.3  Visit 2 at Day 30 (± 7 days), Section 6.4  Visit 3 at Day 60 (± 7 days), 
Section 6.5  Visit 4 at Day 90 (± 7 days), Section  6.6 Visit 5, Visit 6, and Visit 7 at Day 180, 
Day 270, Day 360 (± 7 days), 
16.1.1.4
Modification 4: 
Addition of information on how to treat children 
turning 2, 6, 12 or 18 years
Information was provided on continuing age- and body-weight adjusted treatment in children 
who turn 2, 6, 12 and 18.
Rationale:
In this study, children are allocated to age cohorts form 6 months to <2 years, 2 to <6 years, 
6 to <12 years, and 12 to <18 years. If a child turns to the next highest age- group, a rule had 
to be implemented how to proceed with the treatment. Children will continue treatment 
according to age- and body weight dependent dosing of their inclusion age cohort.


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Affected protocol section:
Section 5.3  Duration of study treatment
16.1.1.5
Modification 5: 
Addition of allowing heparin flushes for 
catheters
Heparins flushes were added to maintain catheter patency.
Rationale:
Heparin flushes are more effective to maintain the peripheral catheter patency that saline 
flushes. Therefore, it was decided to allow heparin flushes except for flushes before PK/PD 
samples. These have to be performed with saline to avoid biased PK/PD results.
Affected protocol section:
Section 6.13  PK/PD assessments
16.1.1.6
Modification 6: Addition of instructions on how to take rivaroxaban 
with an o.d. and b.i.d. regimen in children aged 6 to < 12 years
Instructions for rivaroxaban administration with an o.d. and b.i.d. regimen for children aged 6 
< 12 years were added.
Rationale:
The addition of the dosing table for children aged 6 to < 12 years required instructions how to 
administer rivaroxaban on an o.d. and b.i.d. regimen, respectively.
Affected sections: Section 5.1.1  Rivaroxaban group
16.1.1.7
Modification 7: Addition of handling instructions for missed doses
Instructions for handling of missed doses are provided for o.d. and bid dosing in children aged 
6 to <12 years.
Rationale: 
With the implementation of the dosing regimen for children from 6 to <12 years handling of 
missed doses needed to be clarified. Rather than adding these instructions to the section “6 to 
< 12 years age group”, the respective text was deleted in the description of the age cohort “12 
to < 18 years age group”, and a new paragraph, applicable to all age groups was added.
Affected sections: Section 5.1.1  Rivaroxaban group


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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.
16.1.2.1
Synopsis
This section was changed based on Modifications 1 and 3.
Old text:
Comparator study drug
Subcutaneous low molecular weight heparin (LMWH), subcutaneous 
fondaparinux and/or oral vitamin K antagonist (VKA)
[…]
Inclusion/exclusion criteria
[…]
5.
Hypertension defined as > 95th age percentile a
6.
[…]
7.
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
[…]
12. Participation in a study with an investigational drug or medical 
device within 30 days prior to randomization
a See Appendix 3
New text:
Comparator study drug
Subcutaneous low molecular weight heparin (LMWH), subcutaneous 
fondaparinux, intravenous unfractionated heparin (UFH) and/or oral 
vitamin K antagonist (VKA)
[…]
Inclusion/exclusion criteria
5. Hypertension defined as systolic and/or diastolic blood pressure 
> 95th age percentile (See Appendix 3) 
6. […]
7. 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)
[…]
12. Previous assignment to treatment during this study
13. Participation in a study with an investigational drug or medical device 
within 30 days prior to randomization


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Old text:
Table 1-1
Flow chart
Main Treatment period
Extended treatment period 
with blocks of 3 months
30-day post 
study 
treatment
Visit 
1
2
3
4
5
6
7
8
Days
Before 
random.
After 
random.
Day 30
7 days
Day 60
7 days
Day 90
7 days
Day 180
7 days
Day 270
7 days
Day 360 
7 days
30 7 days
After last visit 
Contact
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit or phone 
[…]
Obtain body weight d
●d
●d
●d
Check for study outcomes e
●
●
●
●
●
●
●
[…]
New text:
Table 1-1
Flow chart
Main Treatment period
Extended treatment period 
with blocks of 3 months
30-day post 
study 
treatment
Visit 
1
2
3
4
5
6
7
8
Days
Before 
random.
After 
random.
Day 30
7 days
Day 60
7 days
Day 90
7 days
Day 180
7 days
Day 270
7 days
Day 360 
7 days
30 7 days
After last visit 
Contact
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit or phone 
[…]
Obtain body weight d
●d
●d
●d
Assess duration and 
intensity of menstruation, 
if applicable
●
●
●
●
●
●
Check for study outcomes e
●
●
●
●
●
●
●
[…]
16.1.2.2
Section 3  Study design
This section was changed based on Modification 4.
Old text:
[…]
Once the age-and body weight adjusted dosing regimen has been confirmed for the age group 
between 6 and less than 12 years in the phase II study 14373 and approved by the data 
monitoring committee and steering committee, the dosing schedule/regimen for this age group 
will be made available through an administrative amendment. The investigators and ethics 
committees/IRBs will receive the administrative amendment well in advance with an 
opportunity for evaluation before permission will be given to start enrolling children in this age 
group.
[…]


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New text:
[…]
Once the age-and body weight adjusted dosing regimen has been confirmed for the age group 
between 6 and less than 12 years in the phase II study 14373 and approved by the data 
monitoring committee and steering committee, the dosing schedule/regimen for this age group 
will be made available through an administrative amendment (For tablet, this was implemented 
through Amendment 4). The investigators and ethics committees/IRBs will receive the 
administrative amendment well in advance with an opportunity for evaluation before 
permission will be given to start enrolling children in this age group.
[…]
16.1.2.3
Section 4.3  Exclusion criteria
This section was changed based on Modification 1.
Old text:
[…]
5.
Hypertension defined as > 95th age percentile
6.
Life expectancy < 3 months
7.
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. For 
exceptions, see section 4.4. 
[…]
New text:
[…]
5.
Hypertension defined as systolic and/or diastolic blood pressure > 95th age percentile 
6.
Life expectancy < 3 months
7.
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). For exceptions, see section 4.4. 
[…]
16.1.2.4
Section 5.1  Method of treatment allocation
This section was changed based on Modification 1.
Old text:
[…]
The investigator will provide the IxRS with study center identification, the child’s date of birth 
(month and year), gender, weight and clinical presentation. Allocation will be stratified by 
baseline presentation of venous thrombosis for each age group, separately, i.e.
[…]


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New text:
[…]
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. Allocation will be stratified by 
baseline presentation of venous thrombosis for each age group, separately, i.e.
[…]


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16.1.2.5
Section 5.1.1  Rivaroxaban group 
This section was changed based on Modifications 1, 2, 6 and 7.
Old text:
12 to < 18 years age group
Rivaroxaban will be dosed according to the dosing schedule/regimen for the 12 to < 18 years age 
group (see Appendix 4).
Tablets will be taken once daily in the morning within 2 hours after breakfast and immediately 
followed by the intake of up to 240 mL of liquid. If a rivaroxaban tablet dose was missed, it can 
only be taken the same day. Double dosing of tablets on a single day is not allowed.
6 to < 12 years age group
The dosing schedule/regimen will become available as an administrative amendment to this 
protocol once it has been confirmed for this age group in the phase II study 14373 and approved 
by the data monitoring committee and steering committee.
The dosing schedule/regimen will specify whether rivaroxaban tablet should be given using a 
once daily or twice daily regimen. Oral suspension will be given using a twice daily regimen.
Rivaroxaban tablets and oral suspension will be immediately followed by the intake of up to 
240 mL of liquid. 
2 to < 6 years age group
Rivaroxaban will be provided as oral suspension. The dosing schedule/regimen will become 
available as an administrative amendment to this protocol once it has been confirmed for this age 
group in the phase II study 14374 and approved by the data monitoring committee and steering 
committee.
Oral suspension will be given using a twice daily regimen and will be immediately followed by 
the intake of up to 240 mL of liquid.  
6 months to < 2 years age group
Rivaroxaban will be provided as oral suspension. The dosing schedule/regimen will become 
available as an administrative amendment to this protocol once the age-and body weight adjusted 
dosing regimen has been confirmed for this age group in the phase II study 14374 and approved 
by the data monitoring committee and steering committee.
Oral suspension will be given using a twice daily regimen and will be immediately followed by 
the intake of up to 240 mL of liquid.  
Use of oral suspension
Oral suspension will not be used in the 12 to < 18 years age group. It can be used in children 
aged 6 to < 12 years, and will be used in all children aged 6 months to < 6 years. Oral suspension
will always be taken twice daily and should be immediately followed by the intake of up to 240 
mL of liquid.  The Taste and Texture Questionnaire, using a visual analog scale, will be applied 
to determine the acceptance of the oral suspension in children from 4 to < 12 years. The pre-dose 
part of this questionnaire needs to be completed before rivaroxaban suspension is taken, the post-
dose part of this questionnaire needs to be completed after rivaroxaban suspension dose is taken 
and up to 240 mL of liquid has been taken.  
Instructions on how to handle rivaroxaban oral suspension can be found in the oral suspension 
handling instructions. 


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New text:
12 to < 18 years age group
Rivaroxaban will be dosed according to the dosing schedule/regimen for the 12 to < 18 years age 
group (see Appendix 4).
Tablets will be taken once daily in the morning within 2 hours after breakfast and immediately 
followed by the intake of up to 240 mL of liquid
6 to < 12 years age group
Rivaroxaban will be provided with the option of tablets or oral suspension. The dosing 
schedule/regimen for rivaroxaban tablet is provided in Appendix 5 (implemented through 
Amendment 4). The dosing schedule/regimen for rivaroxaban oral suspension will become 
available as an administrative amendment to this protocol once it has been confirmed for this age 
group in the phase II study 14373 and approved by the data monitoring committee and steering 
committee.
With an o.d. regimen, rivaroxaban will be taken in the morning within 2 hours after breakfast. 
With a b.i.d regimen the morning dose will be Rivaroxaban tablets taken within 2 hours after 
breakfast and the evening dose will be taken within 2 hours after dinner. Each rivaroxaban dose 
should be immediately followed by the intake of up to 240 mL of liquid. 
2 to < 6 years age group
Rivaroxaban will be provided as oral suspension. The dosing schedule/regimen will become 
available as an administrative amendment to this protocol once it has been confirmed for this age 
group in the phase II study 14374 and approved by the data monitoring committee and steering 
committee.
Oral suspension will be immediately followed by the intake of up to 240 mL of liquid.  
6 months to < 2 years age group
Rivaroxaban will be provided as oral suspension. The dosing schedule/regimen will become 
available as an administrative amendment to this protocol once the age-and body weight adjusted 
dosing regimen has been confirmed for this age group in the phase II study 14374 and approved 
by the data monitoring committee and steering committee.
Oral suspension will be immediately followed by the intake of up to 240 mL of liquid.  
Use of oral suspension
Oral suspension will not be used in the 12 to < 18 years age group. It can be used in children 
aged 6 to < 12 years, and will be used in all children aged 6 months to < 6 years. Oral suspension 
should be immediately followed by the intake of up to 240 mL of liquid.  The Taste and Texture 
Questionnaire, using a visual analog scale, will be applied to determine the acceptance of the oral 
suspension in children from 4 to < 12 years. The pre-dose part of this questionnaire needs to be 
completed before rivaroxaban suspension is taken, the post-dose part of this questionnaire needs 
to be completed after rivaroxaban suspension dose is taken and up to 240 mL of liquid has been 
taken.  
Instructions on how to handle rivaroxaban oral suspension can be found in the oral suspension 
handling instructions. 
Handling of missed doses
If rivaroxaban is taken with an o.d. regimen, a missed dose should be taken immediately when it 
is noticed, but only on the same day. Double dosing on a single day is not allowed. 
If rivaroxaban is taken with a b.i.d. regimen, a missed morning dose should be taken immediately 
when it is noticed, and it may be taken together with the evening dose. A missed evening dose 
can only be taken at the same evening.
On the following day, the child should continue with the regular o.d. or b.i.d. regimen. 


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16.1.2.6
Section 5.3  Duration of study treatment
This section was changed based on Modification 1.
Old text:
[…]
Thereafter, no prolongation of study treatment can take place. Children who turn 18 years after 
randomization are allowed to continue participation for the entire elected study treatment 
duration of 3, 6, 9 or 12 months.
[…]
New text:
[…]
Thereafter, no prolongation of study treatment can take place. Children who turn 2, 6, 12 or 18 
years after randomization can continue their treatment regimen. Specifically children who turn 18 
years after randomization are allowed to continue participation for the entire elected study 
treatment duration of 3, 6, 9 or 12 months.
[…]
16.1.2.7
Section 6.2  Visit 1 - Randomization Visit
This section was changed based on Modification 1.
Old text:
[…]
The parents/legal guardians and children will be given an explanation about the study and will be 
given sufficient time to consider their participation in the study and to ask any questions.  
Afterwards, informed consent and/or assent will be obtained (see section 10.2). If the child passes 
the screen of inclusion and exclusion criteria, the child can be randomized. Then, 

Provide instructions how to take the study drug and give the study 
booklet
[…]
New text:
[…]
The parents/legal guardians and children will be given an explanation about the study and will be 
given sufficient time to consider their participation in the study and to ask any questions.  
Afterwards, informed consent and/or assent will be obtained (see section 10.2). If the child passes 
the screen of inclusion and exclusion criteria, the child can be randomized. Then, 

Provide instructions on how to take the study drug and give the study 
booklet

Dispense study medication 
[…]


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16.1.2.8
Section 6.3  Visit 2 at Day 30 (± 7 days) 
This section was changed based on Modifications 1 and 3.
Old text:
[…]

Check for potential study outcomes. If a suspected study outcome 
occurred, an adjudication package will be compiled and sent to the 
adjudication office.
[…]
New text:
[…]

Check for potential study outcomes. If a suspected study outcome 
occurred, an adjudication package will be compiled and sent to the 
adjudication office. Assess duration and intensity of menstruation, if 
applicable. 

Dispense study medication
[…]
16.1.2.9
Section 6.4  Visit 3 at Day 60 (± 7 days)
This section was changed based on Modifications 1 and 3.
Old text:
[…]

Check for potential study outcomes. If a suspected study outcome 
occurred, an adjudication package needs to be compiled and sent to the 
adjudication office
[…]
New text:
[…]

Check for potential study outcomes. If a suspected study outcome 
occurred, an adjudication package needs to be compiled and sent to the 
adjudication office. Assess duration and intensity of menstruation, if 
applicable. 

Dispense study medication
[…]


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16.1.2.10
Section 6.5  Visit 4 at Day 90 (± 7 days) 
This section was changed based on Modifications 1 and 3.
Old text:
[…]

Check for potential study outcomes. If a suspected study outcome 
occurred, an adjudication package needs to be compiled and sent to the 
adjudication office
[…]
New text:
[…]

Check for potential study outcomes. If a suspected study outcome 
occurred, an adjudication package needs to be compiled and sent to the 
adjudication office. Assess duration and intensity of menstruation, if 
applicable. 

Dispense study medication
[…]
16.1.2.11
Section  6.6 Visit 5, Visit 6, and Visit 7 at Day 180, Day 270, Day 360 
(± 7 days)
This section was changed based on Modifications 1 and 3.
Old text:
[…]

Check for potential study outcomes. If a suspected study outcome 
occurred, adjudication package needs to be compiled and sent to the 
adjudication office.
[…]
New text:
[…]

Check for potential study outcomes. If a suspected study outcome 
occurred, adjudication package needs to be compiled and sent to the 
adjudication office. Assess duration and intensity of menstruation, if 
applicable.

Dispense study medication, if applicable.
[…]


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16.1.2.12
Section 6.13  PK/PD assessments
This section was changed based on Modifications 5.
Old text:
[…]
For venipunctures, an anesthetic cream can be applied. Central venous lines and peripheral 
catheters should only be flushed with saline. Heparin flushes are not allowed.
[…]
New text:
[…]
For venipunctures, an anesthetic cream can be applied. Heparin can be used to 
maintain catheter patency; however, before collecting PK/PD samples, the 
catheter needs to be flushed with saline. A first volume of (diluted) blood should 
be discarded, as usual.
[…]
16.1.2.13
Section 7.4  Bleeding analysis
This section was changed based on Modifications 3.
Old text:
[…]
Incidence proportions of other bleeding outcomes and components will be presented 
descriptively.
[…]
New text:
[…]
Incidence proportions of other bleeding outcomes and components including 
duration and intensity of menstrual bleeding will be presented descriptively.
[…]
16.1.2.14
New Section 17.5  Appendix 5: Dosing table for children from 6 to 
<12 years
This section was added based on Modifications 4.
New text:
Appendix 5: Dosing table for children from 6 to <12 years
Table 17-2 Body weight-adjusted rivaroxaban dosing schedule for children aged 6 to 
< 12 years


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Body weight (kg)
20 mg equivalent
Min
Max
o.d. Dose
b.i.d. Dose
Total Daily Dose
12
<20 a
-
-
20
<30
5 mg
10 mg
30
<50
15 mg
15 mg
≥ 50
20 mg
20 mg
a Children with body weight below 20 kg can only receive oral suspension. 
16.2
Amendment 8
Amendment 8 is the second global amendment dated 20 Sep 2016.
16.2.1
Overview of changes
16.2.1.1
Modification 1: Change of sponsorship information
The sponsor was changed from Bayer Healthcare AG to Bayer AG for non-US territory and 
sponsor information for Bayer Healthcare Pharmaceuticals Inc. was added for US-territory.
Rational:
 
 
Affected sections: 
Title page; Study center’s principal investigator agrees to the content of the final clinical 
study protocol as presented.
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16.2.1.2
Modification 2: Change of non-emergency medical and protocol issues 
contact
The non-emergency medical and protocol issues contact was updated.
Rational:
The update of the contact details for non-emergency medical and protocol issues reflect the 
change of the responsible Study Medical Expert.
Affected sections: 
Title page
16.2.1.3
Modification 3: Extension of the randomization timeframe
The timeframe in which randomization can be done was extended from day 1-5 to day 1-9 of 
the initial treatment.
Rational:
Children with venous thrombosis are often referred by their doctors to expert centers for 
institution of continued anticoagulation following initial heparinization. The original time 
window limited randomization to day 1-5. Therefore, children referred on days 6-9 were not 
eligible for the study, although they could have started study medication on day 6-9 as 
required by the study protocol. The extension of the time window for randomization from day 
1-5 to day 1-9 will therefore potentially increase the number of children who can be 
considered for the study without changing the start day of study medication.
Affected sections:
Synopsis; Section 3  Study design, Section 6.2 Visit 1 – Randomization Visit


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16.2.1.4
Modification 4: Addition of information for switch from VKA to 
rivaroxaban
Children who were randomized to rivaroxaban and in whom VKA therapy was already 
initiated before randomization, VKA therapy should be stopped and the switch to rivaroxaban 
should be made as described in Section 5.1.1.3.
Rational:
This modification clarifies the procedure for children randomized to rivaroxaban, who have 
already started VKA therapy prior to randomization.
Affected sections:
Synopsis; Section 3  Study design
16.2.1.5
Modification 5: Update of exclusion criterion 1
In exclusion criterion 1 “high risk for bleeding contraindicating anticoagulant therapy” was 
modified to read “bleeding risk contraindicating anticoagulant therapy”.
Rational:
The modified wording specifies that patients should be excluded from the study if any 
bleeding risk contraindicates anticoagulant therapy. 
Affected section:
Synopsis, Section 4.3  Exclusion criteria
16.2.1.6
Modification 6: Clarification of exclusion criterion 5
In exclusion criterion 5 it was clarified that children with sustained uncontrolled hypertension 
should be excluded from the study.
Rational:
The modification clarifies, that children with an antihypertensive therapy leading to normal 
blood pressure values (i.e. < 95th percentile) are allowed to be enrolled in the study. In 


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addition, it is clarified, that children should only be excluded from the study, if there is a 
sustained increase of blood pressure with continued measurement of values beyond the 95th 
age percentile. Individual blood pressure value(s) beyond the 95th percentile do not require 
exclusion of a child. 
Affected section:
Synopsis; Section 4.3  Exclusion criteria
16.2.1.7
Modification 7: Clarification of concomitant medication in exclusion 
criteria 7 and 8
The modification indicates that the drugs listed are considered strong inhibitors of both 
CYP3A4 and P-gp, and of strong inducers of CYP3A4, respectively, but that the lists are not 
limited to the drugs mentioned.
Rational:
Additional drugs with these properties may become available. Therefore, it is indicated that 
the lists provided may not be exhaustive.
Affected section:
Synopsis; Section 4.3  Exclusion criteria; Section 4.4  Concomitant medication
16.2.1.8
Modification 8: Addition of body weight assessment at Visits 2 and 3
The collection of body weight was added for Visits 2 and 3.
Rationale:
The body weight will be obtained additionally at Visit 2 and 3 to assess if an adjustment of 
the rivaroxaban dose is required for the child.
Affected section:
Synopsis; Section 6.3 Visit 2 at Day 30 (± 7 days); Section 6.4  Visit 3 at Day 60 (± 7 days)


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16.2.1.9
Modification 9: Addition of post-thrombotic syndrome assessment 
The assessment of the incidence of post-thrombotic syndrome was added for children of 
≥12 years with lower or upper extremity DVT at Visit 4, 5, 6 and 7.
Rationale:
Post-thrombotic syndrome is an important sequelae of deep vein thrombosis. Therefore, the 
exploratory assessment of the incidence of post-thrombotic syndrome will be included using 
the Villalta Score in children 12 years and older with DVT of the lower or upper extremity at 
month 3, 6, 9 and 12 months.
Affected section:
Synopsis; Section 3  Study design; Section 6.5  Visit 4 at Day 90 (± 7 days); Section 6.5.1  
Visit 5, Visit 6, and Visit 7 at Day 180, Day 270, Day 360 (± 7 days); Section 7.5  Efficacy 
analysis; Section 15.  References
16.2.1.10
Modification 10: Age range for assessment of oral suspension Taste-
and- Texture
The upper range for children completing the Taste- and Texture questionnaire was changed 
from <12 to < 18 years.
Rationale:
The oral suspension will be made available to children of all age groups, including 
adolescents. Therefore, the Taste- and Texture questionnaire will need to be completed by 
children from 4 to less than 18 years.
Affected section:
Synopsis; Section 7.5  Efficacy analysis
16.2.1.11
Modification 11: Introduction of additional supplies for preparation 
and administration of oral suspension 
Additional supplies will be provided to prepare, measure and administer the rivaroxaban oral 
suspension. These supplies include a syringe for measurement of 100 mL of water and liquid 


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dosing devices for measurement of the dose volume. The use of the supplies is described in 
the Rivaroxaban Oral Suspension Handling Instructions.
Rational:
The supplies are required for precise and accurate volume measurement during preparation of 
the suspension and for dose administration. 
Affected section:
Synopsis; Section 5.9  Devices for preparation and administration of rivaroxaban oral 
suspension; Section 6.2 Visit 1 – Randomization Visit; Section 6.3 Visit 2 at Day 30 (± 7 
days); Section 6.4  Visit 3 at Day 60 (± 7 days); Section 6.5  Visit 4 at Day 90 (± 7 days); 
Section 6.5.1  Visit 5, Visit 6, and Visit 7 at Day 180, Day 270, Day 360 (± 7 days)
16.2.1.12
Modification 12: Start of enrollment in cohorts 6 months to less than 2 
years and 2 to less than 6 years
The age cohorts 6 months to less than 2 years and 2 to less than 6 years were opened. In this 
context, the structure of age cohort specific dosing and regiment instructions was resolved and 
replaced by a consistent description applicable for children aged 6 months to less than 18 
years. In addition, a single dosing table was included, that provides the body weight 
dependent dosing and regimen (o.d. vs. b.i.d) irrespective of the formulation used (tablet, oral 
suspension) applicable for all age groups.
Rationale:
Opening of the age cohorts 6 months to less than 2 years and 2 to less than 6 years was 
anticipated in the original protocol. After review of phase II data from study 14374, the DMC 
recommended opening the two age cohorts.
Amendment 8 introduces a single consistent body weight adjusted dosing schedule/regimen 
for children aged 6 months to < 18 years. Age dependency is implicitly considered in this 
table as certain body weights are connected with certain ages through standard growth charts 
(with some variability, excluding extreme obesity).
Affected sections:
Synopsis; Section 3  Study design; Section 5.1.1  Rivaroxaban group; Section 17.4  Appendix 
4: Dosing table for children from 6 months to 18 years; Section 17.5 Appendix 5: Dosing 
table for children from 6 to <12 years


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16.2.1.13
Modification 13: Introduction of oral suspension
The oral suspension formulation is now provided for VTE treatment in children of all age 
cohorts.
Rationale:
This change was anticipated in the original protocol.
 
Based on a health authority 
request, the oral suspension will be provided to children of all age cohorts.
Affected section:
Section 3  Study design; Section 5.1.1  Rivaroxaban group; Section 17.4  Appendix 4: Dosing 
table for children from 6 months to 18 years; Section 17.5 Appendix 5: Dosing table for 
children from 6 to <12 years
16.2.1.14
Modification 14: Update of phase II results
The information from the phase II studies described in the protocol was updated.
Rationale:
New information on the rivaroxaban pediatric phase II studies became available and was 
updated accordingly.
Affected section:
Section 1.  Introduction
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16.2.1.15
Modification 15: Minor clarifications for consistency
Minor, consistency and logical clarifications were made throughout the document.
Rationale:
Changes were made to ensure consistency within the protocol and with the associated 
documents (Study Booklet, Rivaroxaban Oral Suspension Handling Instructions). These 
changes do not affect the overall study concept.
Affected section:
Section 1.  Introduction; Section 3  Study design; Section 6.2 Visit 1 – Randomization Visit; 
Section 6.3 Visit 2 at Day 30 (± 7 days); Section 6.4  Visit 3 at Day 60 (± 7 days); Section 6.5  
Visit 4 at Day 90 (± 7 days); Section 6.5.1  Visit 5, Visit 6, and Visit 7 at Day 180, Day 270, 
Day 360 (± 7 days); Section 6.7  30-day post study treatment contact (30 days ±7 days after 
last visit)
16.2.1.16
Modification 16: Treatment duration for children randomized last 
into the study
It is clarified that children randomized towards the end of the planned study duration will 
have a minimal study treatment duration of 3 months.
Rationale:
The study outcome parameters focus on the 3-month study period. In order to collect the 
required information from the planned number of children, especially in the younger age 
cohorts, children included towards the end of the study period will have a minimum study 
treatment duration of 3 months, however, they may not be offered the 3-month extension 
periods, or not all of them.  
Affected section:
Section 5.3  Duration of study treatment


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16.2.1.17
Modification 17: Update of rivaroxaban oral suspension information
Information regarding the rivaroxaban oral suspension formulation, including reference to 
storage condition, is updated.
Rationale:
Originally, it was intended to introduce a rivaroxaban ready-to-use suspension, however, 
based on results from phase I studies, an improved formulation, the “granules for oral 
suspension” will be introduced in phase III. Therefore, the respective information is 
exchanged.
Affected section:
Section 5.4.1  Rivaroxaban; Section 6.2 Visit 1 – Randomization Visit; Section 6.3 Visit 2 at 
Day 30 (± 7 days); Section 6.4  Visit 3 at Day 60 (± 7 days); Section 6.5  Visit 4 at Day 90 (± 
7 days); Section 6.5.1  Visit 5, Visit 6, and Visit 7 at Day 180, Day 270, Day 360 (± 7 days)
16.2.1.18
Modification 18: Addition for statistical analysis of Taste- and 
Texture questionnaire and PTS
Details of the statistical analysis for evaluation of the Taste- and- Texture Questionnaire and 
on for evaluation of the PTS assessment were added.
Rationale:
The information was missing and had to be added.
Affected section:
Section 7.5  Efficacy analysis


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16.2.1.19
Modification 19: Reporting of device-related adverse events 
Detailed information on the reporting of device-related AEs were added.
Rationale:
Adverse events may be related to device incidents. Therefore, it will be assessed whether an 
AE is related the use of a device, e.g. the syringe used for measuring the volume of water or 
the liquid dosing device.
Affected section:
Synopsis; Section 5.9  Devices for preparation and administration of rivaroxaban oral 
suspension; Section 7.9.10  Adverse events related to devices used for preparation and 
administration of rivaroxaban oral suspension
16.2.1.20
Modification 20: Addition of calculation constants for eGFR 
calculation
Constants for calculation of the eGFR in younger children were added.
Rationale:
Due to the enrollment of children as young as 6 months of age the respective constants for 
calculation of the eGFR were added to cover the entire age range of the study.
Affected sections: 
Section 6.2 Visit 1 – Randomization Visit; Section 6.3 Visit 2 at Day 30 (± 7 days); Section 
6.4  Visit 3 at Day 60 (± 7 days); Section 6.5  Visit 4 at Day 90 (± 7 days); Section 6.5.1  Visit 
5, Visit 6, and Visit 7 at Day 180, Day 270, Day 360 (± 7 days); Section 17.2  Appendix 2: 
Estimated glomerular filtration rate
16.2.2
Changes to the protocol text
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. In the display of modifications, the “old text” refers to 
the protocol version preceding this amendment. Deletions are crossed out in the “old text”. 
Additions are underlined in the “new text”. Corrections of typing errors or omissions are not 
highlighted in this amendment.


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16.2.2.1
Title page
This section was changed based on modifications 1 and 2.
Old text:
[…]
Sponsor: 
Bayer HealthCare AG, D-51368 Leverkusen, Germany
 medical expert at Bayer
Bayer HealthCare Pharmaceuticals
Avenida Domingos Jorge 1100, prédio 9503, 2o andar
04779- 900, São Paulo, SP- Brazil
Telephone:
Email:
[…]
New text:
[…]
Sponsor: 
Non-US territory: Bayer AG, D-51368 Leverkusen, Germany
US territory: 
Bayer Healthcare Pharmaceuticals Inc., 
100 Bayer Boulevard, P.O. Box 915, 
Whippany NJ 07981-0915, USA 
Aprather Weg/Gebäude 402
42113, Wuppertal, Germany
Telephone:
Email:
 
[…]
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16.2.2.2
Study center’s principal investigator agrees to the content of the final 
clinical study protocol as presented.
This section was changed based on modification 1.
Old text:
[…]
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. 
[…]
New text:
[…]
Rivaroxaban (BAY-59-7939, JNJ-39039039) is being co-developed under a collaboration and 
license agreement between Bayer AG and Ortho McNeil Pharmaceuticals, Inc. (OMP) dated 
01 Oct 2005.
[…]


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16.2.2.3
Synopsis 
This section was changed based on modifications 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 19.
Old text:
[…]
[…]
Methodology
[…]

Randomization can be done during the first 5 days of initial 
treatment and will be in a 2 (rivaroxaban): 1 (standard of care 
[SOC]) fashion. Children randomized to rivaroxaban will start 
rivaroxaban the day following the last administration of initial 
therapy with UFH, LMWH, or fondaparinux but with a minimal 
duration of initial therapy of 5 days and a maximum duration of 9 
days.
Regardless of the duration of study treatment (3, 6, 9 or 12 months), an 
additional 1-month post-treatment observational period will be completed 
for all children. All suspected clinical study outcomes and baseline and 
repeat thrombosis imaging tests will be assessed by a central independent 
adjudication committee (CIAC) blinded to treatment allocation. An 
independent Data Monitoring Committee (DMC) will monitor the 
children’s safety and give recommendations to the steering committee.
[…]
[…]
Inclusion/exclusion criteria
[…]
Exclusion
1. Active bleeding or high risk for bleeding contraindicating
anticoagulant therapy 
[…]
5. Hypertension defined as systolic and/or diastolic blood pressure
> 95th age percentile (See Appendix 3)
[…]
7. 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) 
8. Concomitant use of strong inducers of CYP3A4, i.e. rifampicin,
rifabutin, phenobarbital, phenytoin and carbamazepine
[…]
12. Previous assignment to treatment during this study
13. Participation in a study with an investigational drug or medical
device within 30 days prior to randomization


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Table 1
Flow chart
Main Treatment period
Extended treatment period 
with blocks of 3 months
30-day post 
study 
treatment
Visit 
1
2
3
4
5
6
7
8
Days
Before 
random.
After 
random.
Day 30
7 days
Day 60
7 days
Day 90
7 days
Day 180
7 days
Day 270
7 days
Day 360 
7 days
30 7 days
After last visit
Contact
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit or phone 
[…]
Dispense study medication
●
●
●
● c
●c
●c
Instruct how to take study 
medication
●
[…]
Obtain body weight d
●d
●d
●d
If suspension, complete 
pre-dosing Taste-and-
Texture questionnaire in 
children 4 to < 12 years
●
[…]
If suspension, then 
complete post-dosing 
Taste-and-Texture 
questionnaire in children 4 
to < 12 years
●
[…]
If suspension, complete 
pre-dosing Taste-and-
Texture questionnaire in 
children 4 to < 12 years
●
[…]
If suspension, then 
complete post- dosing 
Taste-and-Texture 
questionnaire in children 4
to < 12 years
●
[…]
[…]
b
Randomization can be done during the first 5 days of 
initial therapy with UFH, LMWH or fondaparinux.
[…]
[…]


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New text:
[…]
[…]
Methodology
[…]

Randomization can be done during the first 9 days of initial 
treatment and will be in a 2 (rivaroxaban): 1 (standard of care 
[SOC]) fashion. Children randomized to rivaroxaban will start 
rivaroxaban the day following the last administration of initial 
therapy with UFH, LMWH, or fondaparinux but with a minimal 
duration of initial therapy of 5 days and a maximum duration of 
9 days.
[…]
In children randomized to rivaroxaban in whom VKA therapy was 
already initiated before randomization, VKA therapy should be stopped 
and the switch to rivaroxaban should be made as described in Section 
5.1.1.3.
[…]
Regardless of the duration of study treatment (3, 6, 9 or 12 months), an 
additional 1-month post-treatment observational period will be 
completed for all children. All suspected clinical study outcomes and 
baseline and repeat thrombosis imaging tests will be assessed by a 
central independent adjudication committee (CIAC) blinded to treatment 
allocation. An independent Data Monitoring Committee (DMC) will 
monitor the children’s safety and give recommendations to the steering 
committee.
[…]
Inclusion/exclusion criteria
[…]
Exclusion
1. Active bleeding or bleeding risk contraindicating anticoagulant
therapy 
[…]
5. Sustained uncontrolled hypertension defined as systolic and/or
diastolic blood pressure > 95th age percentile (See Appendix 3) 
[…]
7. Concomitant use of strong inhibitors of both cytochrome P450
isoenzyme 3A4 (CYP3A4) and P-glycoprotein (P-gp), including but not 
limited to all human immunodeficiency virus protease inhibitors and the 
following azole-antimycotics agents: ketoconazole, itraconazole, 
voriconazole, posaconazole, if used systemically (fluconazole is 
allowed) 
8. Concomitant use of strong inducers of CYP3A4, including but
not limited to rifampicin, rifabutin, phenobarbital, phenytoin and
carbamazepine
[…]
12. Previous assignment to treatment during this study
13. Participation in a study with an investigational drug or medical
device within 30 days prior to randomization
[…]


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Table 1
Flow chart
Main Treatment period
Extended treatment period 
with blocks of 3 months
30-day post 
study 
treatment
Visit 
1
2
3
4
5
6
7
8
Days
Before 
random.
After 
random.
Day 30
7 days
Day 60
7 days
Day 90
7 days
Day 180
7 days
Day 270
7 days
Day 360 
7 days
30 7 days
After last visit
Contact
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit or phone 
[…]
Dispense study medication
●
●
●
● c
●c
●c
Dispense additional 
supplies (devices for oral 
suspension)
●
●
●
● c
●c
●c
Instruct how to take study 
medication n
●

[…]
Check for device-related 
adverse events o
●
●
●
●
●
●
●
Obtain body weight 


●d
●d
●d
●d
●d
[…]
Perform post-thrombotic 
syndrome assessment m
●
●
●
●
[…]
If suspension, complete pre-
dosing Taste-and-Texture 
questionnaire in children 4 
to < 18 years
●
[…]
If suspension, complete 
post-dosing Taste-and-
Texture questionnaire in 
children 4 to < 18 years
●
[…]
If suspension, complete pre-
dosing Taste-and-Texture 
questionnaire in children 4 
to < 18 years
●
[…]
If suspension, then 
complete post- dosing 
Taste-and-Texture 
questionnaire in children 
4 to < 18 years
●
[…]
[…]
b
Randomization can be done during the first 9 days of 
initial therapy with UFH, LMWH or fondaparinux.
m
Only in children ≥12 years with lower or upper extremity 
DVT 
n
In addition, provide Rivaroxaban Oral Suspension 
Handling Instructions, if applicable, and Study Booklet
o
Only applicable for children treated with oral suspension
[…]
IxRS = interactive voice/ web response system
PTS = post-thrombotic syndrome
[…]


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[…]
16.2.2.4
Section 1.  Introduction
This section was changed based on modifications 14 and 15.
Old text:
[…]
Enrollment for children from 12 to less than 18 years has been completed. Rivaroxaban was 
well tolerated, compliance with rivaroxaban was optimal, no recurrent venous 
thromboembolism and/or major bleeding were observed and PK/PD results confirmed a 
similar exposure as in adults receiving 20 mg of rivaroxaban once daily. Therefore, as in 
adults, there is no need for monitoring the anticoagulant activity of rivaroxaban in children
from 12 to less than 18 years.
[…]
New text:
[…]
In phase II, enrollment of children from 2 to less than 18 years has been completed. 
Rivaroxaban was well tolerated, compliance with rivaroxaban was optimal, no recurrent 
venous thromboembolism and/or major bleeding were observed and PK/PD results confirmed 
a similar exposure as in adults receiving 20 mg of rivaroxaban once daily. Therefore, as in 
adults, there is no need for monitoring the anticoagulant activity of rivaroxaban in children.
[…]
16.2.2.5
Section 3  Study design
This section was changed based on modifications 3, 4, 9, 12, 13 and 15.
Old text:
[…]
The study will be initiated with children in the age group between 12 and less than 18 years 
since the age-and body weight adjusted dosing regimen has been confirmed for this age group 
in the phase II study 14373 and was approved by the data monitoring committee and steering 
committee. The dosing schedule/regimen for this age group is available in Appendix 4.


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Once the age-and body weight adjusted dosing regimen has been confirmed for the age group 
between 6 and less than 12 years in the phase II study 14373 and approved by the data 
monitoring committee and steering committee, the dosing schedule/regimen for this age group 
will be made available through an administrative amendment (For tablet, this was 
implemented through Amendment 4). The investigators and ethics committees/IRBs will 
receive the administrative amendment well in advance with an opportunity for evaluation 
before permission will be given to start enrolling children in this age group. 
Once the age-and body weight adjusted dosing regimen has been confirmed for the age group 
between 2 and less than 6 years in the phase II study 14374 and approved by the data 
monitoring committee and steering committee, the dosing schedule/regimen for this age group 
will be made available through an administrative amendment. The investigators and ethics 
committees/IRBs will receive the administrative amendment well in advance with an 
opportunity for evaluation before permission will be given to start enrolling children in this 
age group.
Once the age-and body weight adjusted dosing regimen has been confirmed for the age group 
between 6 months and less than 2 years in the phase II study 14374 and approved by the data 
monitoring committee and steering committee, the dosing schedule/regimen for this age group 
will be made available through an administrative amendment. The investigators and ethics 
committees/IRBs will receive the administrative amendment well in advance with an 
opportunity for evaluation before permission will be given to start enrolling children in this 
age group. 
[…]
Study description
[…]
Randomization can be done during the first 5 days of initial treatment and will be in a 2
(rivaroxaban): 1 (standard of care [SOC]) fashion. Children randomized to rivaroxaban will 
start rivaroxaban the day following the last administration of initial therapy with UFH, 
LMWH, or fondaparinux but with a minimal duration of initial therapy of 5 days and a 
maximum duration of 9 days.
[…]
New text:
[…]
The study will be initiated with children in the age group between 12 and less than 18 years 
since the age-and body weight adjusted dosing regimen has been confirmed for this age group 
in the phase II study 14373 and was approved by the data monitoring committee and steering 
committee. The dosing schedule/regimen for this age group is available in Appendix 4
(update: for oral suspension this is implemented through Amendment 8).


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Once the age-and body weight adjusted dosing regimen has been confirmed for the age group 
between 6 and less than 12 years in the phase II study 14373 and approved by the data 
monitoring committee and steering committee, the dosing schedule/regimen for this age group 
will be made available through an administrative amendment (For tablet, this was 
implemented through Amendment 4; update: for oral suspension this is implemented through 
Amendment 8). The investigators and ethics committees/IRBs will receive the administrative 
amendment well in advance with an opportunity for evaluation before permission will be 
given to start enrolling children in this age group. 
Once the age-and body weight adjusted dosing regimen has been confirmed for the age group 
between 2 and less than 6 years in the phase II study 14374 and approved by the data 
monitoring committee and steering committee, the dosing schedule/regimen for this age group 
will be made available through an administrative amendment (update: implemented through 
Amendment 8). The investigators and ethics committees/IRBs will receive the administrative 
amendment well in advance with an opportunity for evaluation before permission will be 
given to start enrolling children in this age group.
Once the age-and body weight adjusted dosing regimen has been confirmed for the age group 
between 6 months and less than 2 years in the phase II study 14374 and approved by the data 
monitoring committee and steering committee, the dosing schedule/regimen for this age group 
will be made available through an administrative amendment (update: implemented through 
Amendment 8). The investigators and ethics committees/IRBs will receive the administrative 
amendment well in advance with an opportunity for evaluation before permission will be 
given to start enrolling children in this age group. 
Amendment 8 introduced a single consistent body weight adjusted dosing schedule/regimen 
for children aged 6 months to < 18 years (see Table 4; dosing table available for children with 
a body weight of ≥ 12 kg). Age dependency is implicitly considered in this table as certain 
body weights are connected (through standard growth charts) with certain ages (with some 
variability, excluding extreme obesity) as well as with anatomical and physiological 
differences that affect the absorption, distribution, metabolism, and excretion (ADME)
processes at different ages.
[…]
Study description
[…]
Randomization can be done during the first 9 days of initial treatment and will be in a 
2 (rivaroxaban): 1 (standard of care [SOC]) fashion. Children randomized to rivaroxaban will 
start rivaroxaban the day following the last administration of initial therapy with UFH, 
LMWH, or fondaparinux but with a minimal duration of initial therapy of 5 days and a 
maximum duration of 9 days.
[…]


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In children randomized to rivaroxaban in whom VKA therapy was already initiated before 
randomization, VKA therapy should be stopped and the switch to rivaroxaban should be 
made as described in Section 5.1.1.3. 
[…]
In children 12 years or older with DVT of the lower or upper extremity, the incidence of the 
post-thrombotic syndrome will be assessed at month 3, 6, 9 and 12 months, if applicable, 
using the Villalta Score. [17] 
[…]
16.2.2.6
Section 4.3  Exclusion criteria
This section was changed based on modifications 5, 6 and 7.
Old text:
[…]
1. Active bleeding or high risk for bleeding contraindicating anticoagulant therapy
5. Hypertension defined as systolic and/or diastolic blood pressure > 95th age percentile 
7. 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). For exceptions, see section 4.4. 
8. Concomitant use of strong inducers of CYP3A4, i.e. rifampicin, rifabutin, phenobarbital, 
phenytoin and carbamazepine
[…]
New text:
[…]
1. Active bleeding or bleeding risk contraindicating anticoagulant therapy
5. Sustained uncontrolled hypertension defined as systolic and/or diastolic blood pressure 
> 95th age percentile
7. Concomitant use of strong inhibitors of both CYP3A4 and P-gp, including but not 
limited to all human immunodeficiency virus protease inhibitors and the following 
azole-antimycotics agents: ketoconazole, itraconazole, voriconazole, posaconazole, if 
used systemically (fluconazole is allowed). For exceptions, see Section 4.4.
8. Concomitant use of strong inducers of CYP3A4, including but not limited to rifampicin, 
rifabutin, phenobarbital, phenytoin, and carbamazepine


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[…]
16.2.2.7
Section 4.4  Concomitant medication
This section was changed based on modification 7.
Old text:
[…]
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), if used systemically, is not allowed, as well as 
concomitant use of strong inducers of CYP3A4 (i.e. rifampicin, rifabutin, phenobarbital, 
phenytoin, carbamazepine). Concomitant treatment with fluconazole is allowed.
[…]
New text:
[…]
Concomitant use of strong inhibitors of both CYP3A4 and P-gp, i.e. all human 
immunodeficiency virus protease inhibitors and azole-antimycotics agents (including but not 
limited to ketoconazole, itraconazole, voriconazole, posaconazole), if used systemically, is not 
allowed, as well as concomitant use of strong inducers of CYP3A4 (including but not limited 
to rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine). Concomitant treatment 
with fluconazole is allowed.
[…]
16.2.2.8
Section 5.1.1  Rivaroxaban group
This section was changed based on modifications 12 and 13.
Old text:
[…]
12 to < 18 years age group
Rivaroxaban will be dosed according to the dosing schedule/regimen for the 12 to < 18 years 
age group (see Appendix 4).
Tablets will be taken once daily in the morning within 2 hours after breakfast and 
immediately followed by the intake of up to 240 mL of liquid. 


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6 to < 12 years age group
Rivaroxaban will be provided with the option of tablets or oral suspension. 
The dosing schedule/regimen for rivaroxaban tablet is provided in Appendix 5 (implemented 
through Amendment 4). The dosing schedule/regimen for rivaroxaban oral suspension will 
become available as an administrative amendment to this protocol once it has been confirmed 
for this age group in the phase II study 14373 and approved by the data monitoring committee 
and steering committee.
With an o.d. regimen, rivaroxaban will be taken in the morning within 2 hours after breakfast. 
With a b.i.d regimen the morning dose will be taken within 2 hours after breakfast and the 
evening dose will be taken within 2 hours after dinner. Each rivaroxaban dose should be 
immediately followed by the intake of up to 240 mL of liquid. 
2 to < 6 years age group
Rivaroxaban will be provided as oral suspension. The dosing schedule/regimen will become 
available as an administrative amendment to this protocol once it has been confirmed for this 
age group in the phase II study 14374 and approved by the data monitoring committee and 
steering committee.
Oral suspension will be immediately followed by the intake of up to 240 mL of liquid.
6 months to < 2 years age group
Rivaroxaban will be provided as oral suspension. The dosing schedule/regimen will become 
available as an administrative amendment to this protocol once the age-and body weight 
adjusted dosing regimen has been confirmed for this age group in the phase II study 14374 
and approved by the data monitoring committee and steering committee.
Oral suspension will be immediately followed by the intake of up to 240 mL of liquid.
Oral suspension will not be used in the 12 to < 18 years age group. It can be used in children 
aged 6 to < 12 years, and will be used in all children aged 6 months to < 6 years. Oral 
suspension should be immediately followed by the intake of up to 240 mL of liquid.  The 
Taste and Texture Questionnaire, using a visual analog scale, will be applied to determine the 
acceptance of the oral suspension in children from 4 to < 12 years. The pre-dose part of this 
questionnaire needs to be completed before rivaroxaban suspension is taken, the post-dose 
part of this questionnaire needs to be completed after rivaroxaban suspension dose is taken 
and up to 240 mL of liquid has been taken. 
Instructions on how to handle rivaroxaban oral suspension can be found in the oral suspension 
handling instructions. 
[…]


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New text:
[…]
The body weight adjusted dosing schedule for children aged 6 months to < 18 years is 
provided in Appendix 4 (see Section 17.4).
Children with body weight of ≥ 20 kg will receive rivaroxaban tablets or oral suspension. 
Children with body weight of < 20 kg will receive rivaroxaban as oral suspension.
Children with body weight of ≥ 30 kg will be treated according to a once daily (o.d.) regimen, 
irrespective of whether they receive rivaroxaban tablets or oral suspension. Children with 
body weight < 30 kg will receive rivaroxaban twice daily (b.i.d).
With a once daily regimen, rivaroxaban will be taken in the morning during or within 2 hours 
after breakfast. With a twice daily regimen the morning dose will be taken during or within 2 
hours after breakfast and the evening dose will be taken during or within 2 hours after dinner. 
Each rivaroxaban dose should be immediately followed by the intake of one typical serving of 
up to 240 mL of liquid. This volume will depend on age and may range from for example 
20 mL in children aged 6 months up to 240 mL in adolescents
Use of oral suspension
Oral suspension is available for use in children aged 6 months to < 18 years. 
At Visit 2, the Taste-and-Texture Questionnaire, using a three point scale, will be applied to 
determine the acceptance of the oral suspension in children from 4 to < 18 years. The pre-
dose part of this questionnaire needs to be completed before rivaroxaban suspension is taken, 
the post-dose part of this questionnaire needs to be completed after rivaroxaban suspension 
dose is taken and up to 240 mL of liquid has been taken. 
Instructions on how to handle rivaroxaban oral suspension can be found in the Rivaroxaban 
Oral Suspension Handling Instructions. 
[…]
16.2.2.9
Section 5.3  Duration of study treatment
This section was changed based on modification 16.
Old text:
[…]
Specifically children who turn 18 years after randomization are allowed to continue 
participation for the entire elected study treatment duration of 3, 6, 9 or 12 months.
[…]


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[…]
Specifically children who turn 18 years after randomization are allowed to continue 
participation for the entire elected study treatment duration of 3, 6, 9 or 12 months.
Children randomized last into the study will have a minimal study treatment duration of 
3 months.
[…]
16.2.2.10
Section 5.4.1  Rivaroxaban
This section was changed based on modification 17.
Old text:
[…]
Rivaroxaban will be provided by Bayer as immediate-release film-coated tablets, and as a 
0.1% suspension (1 mg/mL), see Table 5-1. Rivaroxaban will be dosed according to age- and 
body weight groups as detailed in age-group specific dosing schedules/regimens associated 
with this protocol. Since children with an estimated glomerular filtration rate below 
30 mL/min/1.73 m2 are excluded from the study, dose reduction for impaired renal function is 
not required.
Table 2
Identity of test drug 
International non-
proprietary name (INN)
Rivaroxaban
Substance code number
BAY 59-7939
Formulation
Film-coated tablets
Oral suspension 0.1%
Composition
Film-coating:  hypromellose, macrogol, 
titanium dioxide, and ferric oxide red or 
ferric oxide yellow
Excipients:  microcrystalline 
cellulose, carmellose sodium, 
xanthan gum, citric acid 
anhydrous, sodium benzoate, 
flavor sweet and creamy, 
sucralose, and water for injection
Type of packaging and 
content
Type of packaging:  plastic bottle high 
density polyethylene (HDPE) white 
opaque, closed with white screw cap 
polypropylene (PP) with sealing inserter 
and childproof lock
Type of packaging:  brown glass 
bottle type 3 with adapter 
polyethylene for plastic dosing 
pipette closed with PP screw cap 
childproof lock
Strength of rivaroxaban
Tablets of 5.0, 7.5, 10.0, 15.0 and 20.0 
mg 
1
mg per ml


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New text:
[…]
Rivaroxaban will be provided by Bayer as immediate-release film-coated tablets, and as a 
granules for oral suspension formulation (0.1% suspension as finally administered drug 
product), see Table 2. Rivaroxaban will be dosed according to body weight groups as detailed 
in the dosing schedules/regimens associated with this protocol. Since children with an 
estimated glomerular filtration rate below 30 mL/min/1.73 m2 are excluded from the study, 
dose reduction for impaired renal function is not required.
Table 2
Identity of test drug 
International non-
proprietary name (INN)
Rivaroxaban
Substance code number
BAY 59-7939
Formulation
Film-coated tablets
Granules for oral suspension
Composition
Film-coating:  hypromellose, macrogol, 
titanium dioxide, and ferric oxide red or 
ferric oxide yellow
Excipients:  microcrystalline 
cellulose and carmellose sodium, 
xanthan gum, citric acid 
anhydrous, sodium benzoate, 
flavor sweet and creamy, 
hypromellose 5 cP, sucralose, 
mannitol
Type of packaging and 
content
Type of packaging:  plastic bottle high 
density polyethylene (HDPE) white 
opaque, closed with white screw cap 
polypropylene (PP) with sealing inserter 
and childproof lock
Type of packaging:  brown glass 
bottle type 3 closed with PP screw 
cap childproof lock
Strength of rivaroxaban
Tablets of 5.0,10.0, 15.0 and 20.0 mg 
1 mg per ml
16.2.2.11
Section 5.5
Packaging and labeling, and storage
This section was changed based on modification 17.
Old text:
[…]
All study medication need to be stored at the site according to the labeled storage advice in 
accordance with Good Clinical Practice (GCP) and GMP requirements. Rivaroxaban oral 
suspension should not be frozen and should be stored at a temperature not exceeding 25°C. 
Rivaroxaban tablets should be stored at room temperature but not above 30°C. The study drug 
is to be kept in a secure area. Complete records of batch numbers and expiry dates can be 
found in the 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.


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[…]
New text
5.5
Packaging an labeling, and storage
[…]
All study medication needs to be stored at the site according to the labeled storage advice in 
accordance with Good Clinical Practice (GCP) and GMP requirements. The study drug is to 
be kept in a secure area. Complete records of batch numbers and expiry dates can be found in 
the 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.
16.2.2.12
Section 5.8 Study treatment delivery and compliance assessment
This section was changed based on modification 17.
Old text:
[…]
All empty packaging and unused study drug will be returned at all study visits. All non-used 
study medication will be kept securely in a designated locked container.
New text
[…]
All used and unused medication and additional supplies will be returned at all study visits. All 
non-used study medication will be kept securely in a designated locked container.
16.2.2.13
Section 5.9  Devices for preparation and administration of 
rivaroxaban oral suspension
This section was added based on Modification 19.
New text:
5.9  Devices for preparation and administration of rivaroxaban oral suspension
The rivaroxaban granules for oral suspension will be suspended with water. In order to 
measure the appropriate volume of water, parents will be provided with 100 ml syringes. 
In addition, parents will be provided with Liquid Dosing Devices (LDDs; dosing pipettes) for 
precise, accurate and reproducible measuring of the rivaroxaban oral suspension dose volume 
and for administration to the child. 


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Both supplies, the syringe and the LDDs, are class 1 devices with measuring function, which 
is considered a low risk class. 
The syringes and LDDs will be provided to the parents together with the rivaroxaban oral 
suspension as additional supplies. The use of these supplies is described in the Rivaroxaban 
Oral Suspension Handling Instructions. Any device malfunction or defect, or any use error by 
site personnel or parents will be assessed during study visits (see Section 7.9.10).
16.2.2.14
Section 6.2 Visit 1 – Randomization Visit 
This section was changed based on modifications 9, 11, 17, and 19.
Old text:
[…]
The parents/legal guardians and children will be given an explanation about the study and will 
be given sufficient time to consider their participation in the study and to ask any questions. 
Afterwards, informed consent and/or assent will be obtained (see section 10.2). If the child 
passes the screen of inclusion and exclusion criteria, the child can be randomized. Then, 
[…]

Randomization can be done during the first 5 days of initial treatment and will be in a 
2 (rivaroxaban): 1 (standard of care [SOC]) fashion. Children randomized to 
rivaroxaban will start rivaroxaban the day following the last administration of initial 
therapy with UFH, LMWH, or fondaparinux but with a minimal duration of initial 
therapy of 5 days and a maximum duration of 9 days.

[…]

Provide instructions on how to take the study drug and give the study booklet

[…]

Dispense study medication 

[…]

Check for adverse events

Instruct that on the day of visit 2, rivaroxaban should not be taken at home and 
medication should be brought to the hospital

[…]

Collect images of the index venous thrombotic event, prepare the adjudication 
package and send it to the central adjudication office. Visit 2 at Day 30 (± 7 days)
[…]


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New text:
[…]
The parents/legal guardians and children will be given an explanation about the study and will 
be given sufficient time to consider their participation in the study and to ask any questions. 
Afterwards, informed consent and/or assent will be obtained (see Section 10.2). If the child 
passes the screen of inclusion and exclusion criteria, the child can be randomized. Then, 
[…]

Randomization can be done during the first 9 days of initial treatment and will be in a 
2 (rivaroxaban): 1 (standard of care [SOC]) fashion. Children randomized to 
rivaroxaban will start rivaroxaban the day following the last administration of initial 
therapy with UFH, LMWH, or fondaparinux but with a minimal duration of initial 
therapy of 5 days and a maximum duration of 9 days.

[…]

Dispense study medication and additional supplies (devices for oral suspension)

Provide instructions on how to take the study drug and give the study booklet. If child 
will take rivaroxaban oral suspension, provide the Rivaroxaban Oral Suspension 
Handling Instructions. Train parents/child on the preparation and administration of the 
oral suspension and on the use of the liquid dosing device.

[…]

Check for adverse events and device-related adverse events

Instruct that on the day of visit 2, rivaroxaban should not be taken at home and that all 
used and unused medication/supplies should be returned to the hospital

[…]

Collect images of the index venous thrombotic event, prepare the adjudication 
package and send it to the central adjudication office. 
[…]
16.2.2.15
Section 6.3 Visit 2 at Day 30 (± 7 days) 
This section was changed based on modifications 8, 9, 11, 17, and 19.
Old text:

Check for potential study outcomes. If a suspected study outcome occurred, an 
adjudication package will be compiled and sent to the adjudication office. 

Assess duration and intensity of menstruation, if applicable.
In case rivaroxaban is provided as tablet:


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
[…]

Document the volume of fluid taken

Document the exact time of rivaroxaban intake and type of meal (i.e. breakfast, 
lunch, dinner) the child took 2 hours before and after rivaroxaban.
In case rivaroxaban is provided as oral suspension: 

Complete the pre-dose part of the Taste- and Texture Questionnaire only for 
children from 4 to < 12 
[…]

Document the volume of fluid taken

Complete the post-dose part of the Taste- and Texture-Questionnaire only for 
children from 4 to < 12

Document the exact time of rivaroxaban intake and type of meal (i.e. breakfast, 
lunch, dinner) the child took 2 hours before and after rivaroxaban.

[…]

Dispense study medication 

[…]

Check for adverse events

[…]

Instruct that on the day of visit 3, rivaroxaban should not be taken at home and 
medication should be brought to the hospital
[…]
New text:
[…]

Check for potential study outcomes. If a suspected study outcome occurred, an 
adjudication package will be compiled and sent to the adjudication office.

Assess duration and intensity of menstruation, if applicable.
In case rivaroxaban is provided as tablet:
[…]

Document the volume and type of fluid taken

Document the exact time of rivaroxaban intake as well as time and type of 
meal (i.e. breakfast, lunch, dinner) the child took within 2 hours before and 2 
hours after rivaroxaban.


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
In case rivaroxaban is provided as oral suspension: 

Complete the pre-dose part of the Taste- and-Texture Questionnaire only for 
children from 4 to < 18 years
[…]

Document the volume and type of fluid taken

Complete the post-dose part of the Taste- and-Texture Questionnaire only for 
children from 4 to < 18 years

Document the exact time of rivaroxaban intake as well as the time and type of 
meal (i.e. breakfast, lunch, dinner) the child took within 2 hours before and 2 
hours after rivaroxaban.

[…]

Obtain body weight and adjust the rivaroxaban dose, if applicable.

Dispense study medication and additional supplies (devices for oral suspension) 

[…]

Check for adverse events and device-related adverse events

[…]

Instruct that on the day of visit 3, rivaroxaban should not be taken at home and that all 
used and unused medication/supplies should be returned to the hospital
[…]
16.2.2.16
Section 6.4  Visit 3 at Day 60 (± 7 days)
This section was changed based on modifications 8, 9, 11, 17, and 19.
Old text:
Check for potential study outcomes. If a suspected study outcome occurred, an 
adjudication package needs to be compiled and sent to the adjudication office. Document 
the volume of fluid taken.
Assess duration and intensity of menstruation, if applicable.
In children randomized to rivaroxaban (tablet or oral suspension): 


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[…]

Document the volume of fluid taken
Document the exact time of rivaroxaban intake and type of meal (i.e. breakfast, lunch, 
dinner) the child took 2 hours before and after rivaroxaban.
At 2-8 hours after the rivaroxaban intake (tablet or suspension):
[…]

If rivaroxaban is given using an o.d. regimen:
Take rivaroxaban on the day before visit 4 at noon immediately followed by the 
intake of up to 240ml of liquid
Document the volume of fluid taken
Document the exact time of rivaroxaban intake and type of meal (i.e. breakfast, 
lunch, dinner) the child took 2 hours before and after rivaroxaban If rivaroxaban is 
given using a b.i.d. regimen:
If rivaroxaban is given using a b.i.d regimen:
Take rivaroxaban as late as possible in the evening on the day before visit 4 
immediately followed by the intake of up to 240ml of liquid
Document the volume of fluid taken
Document the exact time of rivaroxaban intake and type of meal (i.e. breakfast, 
lunch, dinner) the child took 2 hours before and after rivaroxaban

[…]

Dispense study medication 

[…]
Check for adverse events
[…]
New text:

Check for potential study outcomes. If a suspected study outcome occurred, an 
adjudication package needs to be compiled and sent to the adjudication office. 

Assess duration and intensity of menstruation, if applicable.

In children randomized to rivaroxaban (tablet or oral suspension): 
[…]
Document the volume and type of fluid taken.
Document the exact time of rivaroxaban intake as well as the time and type of meal 
(i.e. breakfast, lunch, dinner) the child took within 2 hours before and 2 hours after 
rivaroxaban.


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
At 2-8 hours after the rivaroxaban intake (tablet or suspension):

[…]

If rivaroxaban is given using an o.d. regimen:

Take rivaroxaban on the day before visit 4 at noon immediately followed by 
the intake of up to 240ml of liquid

Document the volume and type of fluid taken

Document the exact time of rivaroxaban intake as well as the time and type of 
meal (i.e. breakfast, lunch, dinner) the child took within 2 hours before and 2 
hours after rivaroxaban.
If rivaroxaban is given using a b.i.d. regimen:

Take rivaroxaban as late as possible in the evening on the day before visit 4 
immediately followed by the intake of up to 240ml of liquid

Document the volume and type of fluid taken

Document the exact time of rivaroxaban intake as well as the time and type of 
meal (i.e. breakfast, lunch, dinner) the child took within 2 hours before and 2 
hours after rivaroxaban.
[…]
Obtain body weight and adjust the rivaroxaban dose, if applicable.
Dispense study medication and additional supplies (devices for oral suspension) 
[…]

Check for adverse events and device-related adverse events

Instruct that on the day of visit 4, all used and unused medication/supplies should be 
returned to the hospital
[…]
16.2.2.17
Section 6.5  Visit 4 at Day 90 (± 7 days)
This section was changed based on modifications 9, 11, 17 and 19.
Old text:
[…]

Check for potential study outcomes. If a suspected study outcome occurred, an 
adjudication package needs to be compiled and sent to the adjudication office. 

[…]

Document the exact time of rivaroxaban intake on the day prior to visit 4 and time 
and type of meal the child took 2 hours before and 2 hours after rivaroxaban as 
well as the volume of liquid taken .

[…]


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
Dispense study medication 

Check for adverse events
[…]
New text:
[…]

Check for potential study outcomes. If a suspected study outcome occurred, an 
adjudication package needs to be compiled and sent to the adjudication office. 

In case child continues study treatment, instruct that on the day of visit 5, all used and 
unused medication/supplies should be returned to the hospital.

Document the exact time of rivaroxaban intake on the day prior to visit 4 and 
time and type of meal the child took within 2 hours before and 2 hours after 
rivaroxaban as well as the volume and type of liquid taken.

[…]

Dispense study medication and additional supplies (devices for oral suspension)  

Check for adverse events and device-related adverse events

Perform post-thrombotic syndrome assessment (only for children ≥12 years and with 
lower or upper extremity DVT) 
[…]
16.2.2.18
Section 6.5.1  Visit 5, Visit 6, and Visit 7 at Day 180, Day 270, Day 360 
(± 7 days)
This section was changed based on modifications 9, 11, 17, and 19.
Old text:
[…]

Check for potential study outcomes. If a suspected study outcome occurred, 
adjudication package needs to be compiled and sent to the adjudication office. 

[…]

Check for adverse events.

[…]

Dispense study medication, if applicable.
[…]


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New text:
[…]

Check for potential study outcomes. If a suspected study outcome occurred, 
adjudication package needs to be compiled and sent to the adjudication office. 

[…]

Check for adverse events and device-related adverse events.

Perform post-thrombotic syndrome assessment (only for children ≥12 years and with 
lower or upper extremity DVT).

[…]

Dispense study medication and additional supplies (devices for oral suspension).

[…]

Instruct that on the day of visits (visit 6 and visit 7, if applicable), all used and unused 
medication/supplies should be returned to the hospital.
[…]
16.2.2.19
Section 6.7  30-day post study treatment contact (30 days ±7 days 
after last visit)
This section was changed based on modification 15.
Old text:
[…]

Check for adverse events. 

Document if anticoagulant treatment was continued or interrupted after stopping study 
medication. 

Update eCRF.
New text:
[…]

Check for adverse events. 

Document if anticoagulant treatment was continued or interrupted after stopping study 
medication. 


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
Update eCRF.
16.2.2.20
Section 7.5  Efficacy analysis
This section was changed based on modifications 10 and 18.
New text:
[…]
Data of post-thrombotic syndrome assessment in children ≥ 12 years with lower or upper 
extremity DVT will be presented descriptively. Duration of treatment for the main treatment 
period (up to month 3) and the overall treatment duration will be summarized descriptively by 
treatment group.
Results for the Taste-and-Texture Questionnaire in children 4 to < 18 years who receive the 
oral suspension will be presented descriptively.
[…]
16.2.2.21
Section 7.9.10  Adverse events related to devices used for preparation 
and administration of rivaroxaban oral suspension
This section was added based on modification 19.
New text:
7.9.10 Adverse events related to devices used for preparation and administration of 
rivaroxaban oral suspension
7.9.10.1 Definitions
7.9.10.1.1 Incident
An “Incident” is any malfunction or deterioration in the characteristics and / or performance 
of a device, as well as any inadequacy in the labeling or the instructions for use which, 
directly or indirectly, led, might lead to or might have led to the death of a patient, or user or 
of other persons or to a serious deterioration in their state of health.
Any event which meets all three basic reporting criteria (A, B and C) is considered an
“Incident”. The criteria are as follows:
A)
An adverse device event has occurred. Typical adverse events in the context of device 
could be among others:

Malfunction or deterioration in the characteristics or performance, or

Degradation / destruction of the device, or 


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
Inappropriate therapy (e.g., underdosing or overdosing).
B) The device is suspected to be a contributory cause of the “Incident”.
C) The event led, or might have led, to death or serious deterioration in state of
health of a patient, or user, or other person.
7.9.10.1.2 Other Reportable Incident
An “Other Reportable Incident” is any incident that did not lead to death or serious 
deterioration in health, but it might do if it occurred again under less fortunate circumstances 
or without intervention of healthcare personnel. This may include cases without any medical 
event reported. 
7.9.10.1.3 Other Event 
An “Other Event” is any device related case that does not fulfill all the three basic “Incident” 
criteria A-C listed in the definition of an “Incident” above. 
7.9.10.1.4 Product Technical Complaint (PTC)
A PTC is any report received (written, electronic or verbal communication) about a potential 
or alleged failure of a product in its quality (including the identity, durability, reliability, 
safety, efficacy or performance) or suspect counterfeit. The complaint may or may not 
represent a potential risk to the patient. 
7.9.10.2 Device Malfunction or Failure and Medical Device Reporting
Any device complaint, malfunction, or failure including use errors will be recorded by the 
clinical/investigational site, including all relevant device information using the clinical 
investigations device complaint form, and forwarded within 24 hours to the sponsor or 
sponsor’s designee for evaluation and investigation, regardless of whether or not a medical 
event was associated with the device malfunction or failure.  
There are three different situations, in which a medical device complaint form might need to 
be filled out by the investigator:
a) When an AE is recorded, the investigator needs to check if a device
malfunction or failure might be associated with the recorded AE.
b) When 
a 
device 
malfunction 
or 
device 
failure 
occurs, 
the 
investigator
needs to assess whether an AE might have occurred in relation to the
device.
c) When a device malfunction, device failure, or use error occurs, without any associated 
AE, this also needs to be captured in the form and immediately forwarded to the 
sponsor for investigation.
The details of the malfunction and medical circumstances will be captured on a Device 
Complaint Form filled out by the investigator and then returned to the sponsor or sponsor’s 
designee. The final determination of reportability is made by the sponsor and not the 
clinical/investigational site based on the medical circumstances surrounding the event.  
Investigator’s notification of the sponsor


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All investigators will be instructed and trained on all relevant aspects of the investigator’s 
reporting obligations for device incidents and serious public health threats.  This information, 
including all relevant contact details, is summarized in the investigator site file. This 
information will be updated as needed.
The manufacturer will inform the sponsor about necessary trend reports and will provide the 
required documentation after completing the respective investigation and statistical analysis. 
The sponsor will then notify the authorities of any trend reports according to all applicable 
regulations.
All devices that have malfunctioned or failed will be collected and returned to the sponsor or 
sponsor’s designee. Malfunctioned or failed devices should be:

provided with a failure description („What went wrong“), 

free of sources for contamination such as drug residues, 

clearly marked as already used at patients and shall include corresponding warning 
symbols on packaging.
16.2.2.22
Section 15.  References
A new reference was added based on modification 9.
New text:
[…]
17. Kahn SR, Partsch H, Vedantham S, et al. Subcommittee on Control of Anticoagulation of 
the Scientific and Standardization Committee of the International Society on Thrombosis 
and Haemostasis. Definition of post-thrombotic syndrome of the leg for use in clinical 
investigations: a recommendation for standardization. J Thromb Haemost 2009;7:879-83.


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16.2.2.23
Section 17.2  Appendix 2: Estimated glomerular filtration rate
This section was changed based on modification 20.
Old text:
[…]
eGFR (mL/min/1.73 m2) = k * height (cm) / SCr g/dL) where k is proportionality constant:
[…]
k = 0.55 in children up to 13 years
[…]
k = 0.70 in boys > 13 and < 18 years (not in girls; because of the presumed increase in 
male muscle mass, the constant remains 0.55 for girls)
[…]
New text:
[…]
eGFR (mL/min/1.73 m2) = k * height (cm) / SCr (mg/dL) where k is proportionality constant:
[…]
Where k is proportionality constant:
k = 0.33 in pre-term infants up to 1 year
k= 0.45 in full-term infants  up to 1 year
k = 0.55 in children 1 year to 13 years
k = 0.55 in girls > 13 and < 18 years
k = 0.70 in boys > 13 and < 18 years
[…]


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16.2.2.24
Section 17.4  Appendix 4: Dosing table for children from 6 months to 
18 years
This section was changed based on modification 12 and 13.
Old text:
17.4 Appendix 4: Dosing table for children from 12 to 18 years
Table 4
Body weight-adjusted rivaroxaban dosing schedule for children aged 
12 to < 18 years
Body weight (kg)
20 mg equivalent
Min
Max
o.d. Dose
20
<30
10 mg
30
<40
15 mg
40
<50
15 mg
50
<100
20 mg
≥ 100
20 g
New text:
17.4 Appendix 4: Dosing table for children from 6 months to 18 years
Table 4
Body weight-adjusted rivaroxaban dosing schedule for children aged 
6 months to < 18 years 
Body weight (kg)
Formulation
o.d. Dose
b.i.d. Dose
Total Daily 
Dose
Min
Max
12 *
<20
Oral suspension
5 mg
10 mg
20
<30
Tablet or oral suspension
5 mg
10 mg
30
<50
Tablet or oral suspension
15 mg
15 mg
≥ 50
Tablet or oral suspension
20 mg **
20 mg **
* At present, only children with body weight of ≥12 kg can be enrolled.
** 15 mg in Japan


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16.2.2.25
Section 17.5 Appendix 5: Dosing table for children from 6 to <12 
years
This section was removed based on modification 12 and 13.
17.5 Appendix 5: Dosing table for children from 6 to <12 years
Table 4
Body weight-adjusted rivaroxaban dosing schedule for children aged 
6 to < 12 years 
Body weight (kg)
20 mg equivalent
Min
Max
o.d. Dose
b.i.d. Dose
Total Daily Dose
12
<20 a
-
-
20
<30
5 mg
10 mg
30
<50
15 mg
15 mg
≥ 50
20 mg
20 mg
a Children with body weight below 20 kg can only receive oral suspension. 


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16.3
Amendment 10
Amendment 10 is the third global amendment dated 11 Jan 2017.
16.3.1
Overview of changes
16.3.1.1
Modification 1: Addition of Visit 1a for rivaroxaban PK assessment 
A visit was added to be scheduled 2+1 days after start of rivaroxaban treatment for children 
treated according to a t.i.d. regimen. 
Rationale: Amendment 10 introduced dosing information and a new three times daily dosing 
schedule for children with body weight between 6 and <12 kg. This new dosing regimen is 
based on an exploratory PopPK model, that considers all rivaroxaban PK data available from 
children below 2 years dosed in our phase I and phase II studies. As less data are available for 
younger children (e.g., due to sparse sampling), the model predictions have a higher level of 
uncertainty for children with lower body weight. The Steering Committee therefore 
recommended to evaluate PK around the expected Cmax and at Ctrough as soon as the steady 
state is achieved (day 2+1 after start of rivaroxaban treatment; Visit 1a). 
The PK samples obtained at Visit 1a will be shipped and analyzed for each child individually 
and will allow to determine whether the plasma concentrations are in the adult reference 
range. The results will be provided to the investigator/site and discussed in a timely manner, 
i.e. within approximately 1 to 2 weeks after sample collection. 
Affected sections: Synopsis; Section 6.2 Visit 1 - Randomization Visit; Section 6.3 Visit 1a 
(2+1 days after start t.i.d. rivaroxaban)
16.3.1.2
Modification 2: Addition of dosing regimen for children with body 
weight between 6 and less than 12 kg
The dosing table was extended and now includes dosing information for children with body 
weight of 6 kg to 12 kg. Children with body weight between 6 and less than 12 kg will be 
treated according to a three times daily (t.i.d.) schedule with a time interval of approximately 
8 hours between individual doses.
Rationale: The dosing in children in general is aiming to target the adult exposure. Exposure 
was investigated in phase I and phase II studies and an attempt was made to provide a better 
match from one study to the next. The result from phase I and phase II studies have 
demonstrated that in children with body weight below 12 kg, plasma concentrations after 10 
to 12 hours were lower than expected, indicating that the clearance is higher than expected in 
these children. No signals of an impaired safety or efficacy profile was obtained in phase II 
studies. 
An exploratory PopPK model was established for children below 2 years to establish the 
dosing regimen. This model suggests that children with a body weight below 12 kg require
three times daily dosing to provide Cthrough values in the adult reference range.


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The Steering Committee agreed to the extension of the dosing regimen for children with body 
weight from 6 kg and less than 12 kg based on these model predictions. 
Affected sections: Synopsis; Section 3. Study design; Section 5.1.1 Rivaroxaban group; 
Section 6.2 Visit 1 - Randomization Visit; Section 6.3 Visit 1a (2+1 days after start t.i.d. 
rivaroxaban); Section 6.4 Visit 2 at Day 30 (± 7 days); Section 6.5 Visit 3 at Day 60 (± 7 
days); Section 6.6 Visit 4 at Day 90 (± 7 days); Section 6.14 PK/PD assessments
16.3.1.3
Modification 3: Correction of erroneous description for major 
protocol deviation documentation
The document for collection of protocol deviations was corrected to “approved final list of 
important deviations, validity findings and assignment to analysis set(s)”.
Rationale: The protocol erroneously described that protocol deviations will be collected in the 
SAP. This information had to be corrected to refer to the approved final list of important 
deviations, validity findings and assignment to analysis set(s).
Affected sections: Section 7.2 Analysis sets


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16.3.2
Changes to the protocol text
16.3.2.1
Synopsis
This section was changed based on modifications 1 and 2.
New text:
[see next page]


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Table 0-1
Flow chart 
Main Treatment period
Extended treatment period 
with blocks of 3 months
30-day 
post study 
treatment
Visit 
1
1a
2
3
4
5
6
7
8
Days
Before 
random.
After 
random.
2+1 days 
after start 
t.i.d.riva-
roxaban p
Day 30
7 days
Day 60
7 days
Day 90
7 days
Day 180
7 days
Day 270
7 days
Day 360 
7 days
30 7 days
After last 
visit
Contact
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit or 
phone 
Obtain informed consent/child 
assent 
●
Check in-/exclusion criteria
●
Obtain demographic data
●
Check medical history
●
Record concomitant 
medication/anticoagulants
●
Obtain height/length/body 
weight/blood pressure
●
Check Hb, platelets, creatinine, 
ALT, total and direct bilirubin 
●a
Perform urine pregnancy test, if 
applicable
●
Randomize patient using IxRS 
b
●
Dispense study medication 
●
●
●
● c
●c
●c
Dispense additional supplies 
(devices for oral suspension)
●
●
●
● c
●c
●c
Instruct how to take study 
medication n
●
Send baseline adjudication 
package
●
Check for adverse events
●
●
●
●
●
●
●
●
●
Check for device-related 
adverse events o
●
●
●
●
●
●
●
●
Obtain body weight 
●d
●d
●d
●d
●d
Assess duration and intensity 
of menstruation, if applicable
●
●
●
●
●
●
Check for study outcomes e
●
●
●
●
●
●
●
●
Check study drug 
accountability and compliance 
●
●
●
●
●
●
Check changes in concomitant 
medication
●
●
●
●
●
●
●
●
Obtain Hb, platelets, ALT, total 
and direct bilirubin 
●
Repeat imaging and send 
adjudication package f
●
Perform post-thrombotic 
syndrome assessment m
●
●
●
●
Complete eCRF 
●
●
●
●
●
●
●
●
●
●
Comparator group only
If INR-adjusted VKA g
1 INR per 2 weeks
continued on next page


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Table 1
Flow chart (continued)
Main Treatment period
Extended treatment period with 
blocks of 3 months
30-day 
post study 
treatment
Visit 
1
1a
2
3
4
5
6
7
8
Days
Before 
random
After 
random.
2+1 days after 
start t.i.d. 
rivaroxaban p
Day 30
7 days
Day 60
7 days
Day 90
7 days
Day 180
7 days
Day 270
7 days
Day 360 
7 days
30 7 days
After last 
visit
Contact
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit or 
phone 
Pharmacokinetics (PK) and pharmacodynamics (PD) for rivaroxaban using o.d. regimen h
If suspension, complete pre-
dosing Taste-and-Texture 
questionnaire in children 4 to 
< 18 years
●
Administer rivaroxaban at 
study site
●
●
Take up to 240 mL of liquid 
immediately after dosing
●
●
If suspension, complete post-
dosing Taste-and-Texture 
questionnaire in children 4 to 
< 18 years
●
Obtain PK blood sample i
●
●
●
●
Obtain PD blood sample j, k
● 
●
●
●
Time point for PK/PD blood 
sample (hours)
0.5-
1.5hr 
post 
dose
2.5-
4hr 
post 
dose
2-8hr 
post 
dose
20-24 hr 
after dose 
on 
previous
day 
Pharmacokinetics (PK) and pharmacodynamics (PD) for rivaroxaban using b.i.d. regimen h
If suspension, complete pre-
dosing Taste-and-Texture 
questionnaire in children 4 to 
< 18 years
●
Administer rivaroxaban at 
study site
●
●
Take up to 240 mL of liquid 
immediately after dosing
●
●
If suspension, then complete 
post- dosing Taste-and-
Texture questionnaire in 
children 4 to < 18 years
●
Obtain PK blood sample i
●
●
●
●
Obtain PD blood sample j, k
● l
●
●
●
Time point for PK/PD blood 
sample (hours) if dosing 
continues beyond Day 90
0.5-
1.5hr 
post 
dose
2.5-
4hr 
post 
dose
2-8hr 
post 
dose
10-16 hr 
after last 
evening 
dose, give 
next dose 
after 
PK/PD 
samples
Time point for PK/PD blood 
sample (hours) if dosing does 
not continue beyond Day 90
0.5-
1.5hr 
post 
dose
2.5-
4hr 
post 
dose
2-8hr 
post 
dose
10-16 hr 
after last 
evening 
dose
continued on next page


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Main Treatment period
Extended treatment period with 
blocks of 3 months
30-day 
post study 
treatment
Visit 
1
1a
2
3
4
5
6
7
8
Days
Before 
random
After 
random.
2+1 days after 
start t.i.d 
rivaroxaban p
Day 30
7 days
Day 60
7 days
Day 90
7 days
Day 180
7 days
Day 270
7 days
Day 360 
7 days
30 7 days
After last 
visit
Contact
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit or 
phone 
Pharmacokinetics (PK) and pharmacodynamics (PD) for rivaroxaban using t.i.d. regimen h
Administer rivaroxaban at 
study site
●
●
●
Take up to 120 mL of liquid 
immediately after dosing
●
●
●
Obtain PK blood sample i
●
●
●
●
●
Obtain PD blood sample j, k
●
●
●
Time point for PK/PD blood 
sample (hours) if dosing 
continues beyond Day 90
0.5-
3hr 
post 
dose
7-8hr 
post 
dose
0.5-
3hr 
post 
dose
7-8hr 
post 
dose
2-6hr 
post 
dose
10-16hr 
after last 
evening 
dose, give 
next dose 
after PD 
sample
Time point for PK/PD blood 
sample (hours) if dosing does 
not continue beyond Day 90
0.5-
3hr 
post 
dose
7-8hr 
post 
dose
0.5-
3hr 
post 
dose
7-8hr 
post 
dose
2-6hr 
post 
dose
10-16hr 
after last 
evening 
dose
Table 1
Flow chart (continued)
Footnotes:
a
Blood sample should be obtained within a maximum of 5 
days prior to randomization.
b
Randomization can be done during the first 9 days of 
initial therapy with UFH, LMWH or fondaparinux.
c
If study treatment is continued, provide study medication
d
Adjust dosage of study medication, if change in body 
weight. Additional visits can be planned to accommodate 
dose adjustment of study medication, if applicable. 
e
If suspected outcome occurred, the adjudication package 
needs to be compiled and sent to the adjudication office.
f
After the main study treatment period of 3 months, the 
diagnostic imaging test which was obtained at baseline will 
be repeated, if clinically feasible
g
VKA compliance will be ensured by minimum of 1 INR 
per 2 weeks.
h
The approximate total blood volume taken per child for 
PK/PD is 12 mL if blood taken via venipuncture, and 
24 mL if blood taken via central venous line or peripheral 
catheter.
i
Blood volume per PK sample is approximately 1.2 mL; 
total blood volume for all PK samples is 4.8 mL for o.d. 
and b.i.d. regimen and 6 mL for t.i.d. regimen.
j
Blood volume per PD sample is approximately 1.8 mL; total blood 
volume for all PD samples is 7.2 mL for o.d. and b.i.d. regimen and 
5.4 for t.i.d. regimen.
k 
Always draw the pharmacodynamics sample as the last sample.
l
PD sample will not be collected at 0.5-1.5 hr after rivaroxaban 
intake for children < 6 years
m
Only in children ≥12 years with lower or upper extremity DVT 
n
In addition, provide Rivaroxaban Oral Suspension Handling 
Instructions, if applicable, and Study Booklet
o
Only applicable for children treated with oral suspension
p
Only in children treated with rivaroxaban t.i.d. regimen. If visit 1a 
falls on a weekend and cannot take place, the visit must be 
scheduled for the following Monday.
o.d. = once daily dosing
b.i.d. = twice daily dosing
t.i.d. = three times daily dosing
eCRF = electronic case report form;
IxRS = interactive voice/ web response system
PTS = post-thrombotic syndrome


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16.3.2.2
Section 3. Study design
This section was changed based on modifications 2.
Old text:
[…]
Age dependency is implicitly considered in this table as certain body weights are connected 
(through standard growth charts) with certain ages (with some variability, excluding extreme 
obesity) as well as with anatomical and physiological differences that affect the absorption, 
distribution, metabolism, and excretion (ADME) processes at different ages.
[…]
New text:
[…]
Age dependency is implicitly considered in this table as certain body weights are connected 
(through standard growth charts) with certain ages (with some variability, excluding extreme 
obesity) as well as with anatomical and physiological differences that affect the absorption, 
distribution, metabolism, and excretion (ADME) processes at different ages.
Amendment 10 introduced dosing information and a new three times daily dosing schedule 
for children with body weight between 6 and <12 kg. This new dosing regimen is based on an 
exploratory PopPK model, that considers all rivaroxaban PK data available from children 
below 2 years dosed in our phase I and phase II studies. As less data are available for younger 
children (e.g., due to sparse sampling), the model predictions have a higher level of 
uncertainty for children with lower body weight. The Steering Committee therefore 
recommended to evaluate PK around the expected Cmax and at Ctrough as soon as the steady 
state is achieved (day 2+1 after start of rivaroxaban treatment; Visit 1a). 
The PK samples obtained at Visit 1a will be shipped and analyzed for each child individually 
and will allow to determine whether the plasma concentrations are in the adult reference 
range. The results will be provided to the investigator/site and discussed in a timely manner, 
i.e. within approximately 1 to 2 weeks after sample collection.
[…]


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16.3.2.3
Section 5.1.1 Rivaroxaban group
This section was changed based on modification 2.
New text:
[…]
Children with body weight of ≥ 30 kg will be treated according to a once daily (o.d.) regimen, 
irrespective of whether they receive rivaroxaban tablets or oral suspension. Children with 
body weight between 12 and < 30 kg will receive rivaroxaban twice daily (b.i.d) with a dosing 
intervals of approximately 12 hours. Children with body weight below 12 kg will receive 
rivaroxaban three times daily (t.i.d.) with dosing interval of approximately 8 hours.
Dosing regimen, including dosing frequency, will be adjusted if the child’s body weight 
changes during the study (Table 4). 
With a once daily regimen, rivaroxaban will be taken in the morning during or within 2 hours 
after breakfast. With a twice daily regimen the morning dose will be taken during or within 2 
hours after breakfast and the evening dose will be taken during or within 2 hours after dinner. 
With a three times daily regimen, the morning, afternoon and night doses should be taken 
during or within 2 hours after feeding.
Each rivaroxaban dose should be immediately followed by the intake of one typical serving of 
up to 240 mL of liquid (o.d. or b.i.d regimen) or 120mL (t.i.d. regimen). This volume will 
depend on age and may range from for example 20 mL in children aged 6 months up to 240 
mL in adolescents.
[…]
If rivaroxaban is taken with a t.i.d. regimen, the t.i.d. administration schedule with 
approximately 8-hour intervals should be resumed at the next scheduled dose without 
compensating for the missed dose.
On the following day, the child should continue with the regular o.d., b.i.d. or t.i.d. regimen. 
16.3.2.4
Section 6.2 Visit 1 - Randomization Visit 
This section was changed based on modifications 1 and 2.
Old text:
[…]

Instruct that on the day of visit 2, rivaroxaban should not be taken at home and that all 
used and unused medication/supplies should be returned to the hospital
[…]


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New text:
[…]

Instruct that on the day of the next scheduled visit (visit 1a for t.i.d. regimen or visit 2 
for o.d. or b.i.d. regimen), rivaroxaban should not be taken at home and that all used 
and unused medication/supplies should be returned to the hospital
[…]
16.3.2.5
Section 6.3 Visit 1a (2+1 days after start t.i.d. rivaroxaban) 
This section was introduced based on modification 1 and 2.
New text:
This visit will only be performed for children in the rivaroxaban t.i.d. group. If this visit falls 
on a weekend and cannot take place, the visit must be scheduled for the following Monday.

Check for potential study outcomes. If a suspected study outcome occurred, an 
adjudication package will be compiled and sent to the adjudication office.

Administer the next rivaroxaban dose immediately followed by the intake of up to 
120 mL of liquid.

Document the volume and type of liquid taken.

Document the exact time of rivaroxaban intake as well as the time and type of meal 
(i.e. breakfast, lunch, dinner) the child took within 2 hours before and 2 hours after 
rivaroxaban.

At 0.5-3 hours and at 7-8 hours after the rivaroxaban intake:

Collect a PK blood sample

Document the exact time of blood sampling for PK.

Check for changes in concomitant medications

Check for adverse events and device-related adverse events

Instruct that on the day of visit 2, rivaroxaban should not be taken at home and that all 
used and unused medication/supplies should be returned to the hospital

Update eCRF


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16.3.2.6
Section 6.4 Visit 2 at Day 30 (± 7 days) 
This section was changed based on modification 2.
Old text:
[…]

In case rivaroxaban is provided as tablet:

Administer the next rivaroxaban dose immediately followed by up to 240 ml of 
liquid.

Document the volume and type of fluid taken

Document the exact time of rivaroxaban intake as well as time and type of 
meal (i.e. breakfast, lunch, dinner) the child took within 2 hours before and 2 
hours after rivaroxaban.

In case rivaroxaban is provided as oral suspension: 

Complete the pre-dose part of the Taste- and-Texture Questionnaire only for 
children from 4 to < 18 years

Administer the next rivaroxaban dose immediately followed by up to 240 ml of 
liquid.

Document the volume and type of fluid taken

Complete the post-dose part of the Taste- and-Texture Questionnaire only for 
children from 4 to < 18 years

Document the exact time of rivaroxaban intake as well as the time and type of 
meal (i.e. breakfast, lunch, dinner) the child took within 2 hours before and 2 
hours after rivaroxaban.

At 0.5-1.5 and at 2.5-4 hours after this rivaroxaban intake (tablet or suspension):

Collect the PK blood sample in all children

In children 6 years or older, collect a PD blood sample after the PK blood 
sample at both time points

In children < 6 years, no PD sample will be collected after the PK sample at 
0.5-1.5 hr, but a PD sample will be taken after the PK sample at 2.5-4 hours

Document the exact time of blood sampling for PK/PD.
[…]


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New text:
[…]

In case rivaroxaban is provided as tablet:

Administer the next rivaroxaban dose immediately followed by up to 240 ml of 
liquid.

In case rivaroxaban is provided as oral suspension: 

Complete the pre-dose part of the Taste- and-Texture Questionnaire only for 
children from 4 to < 18 years

Administer the next rivaroxaban dose immediately followed by up to 240 ml 
(o.d. or b.i.d.) or up to 120 ml (t.i.d.) of liquid.

Complete the post-dose part of the Taste- and-Texture Questionnaire only for 
children from 4 to < 18 years

Document the volume and type of liquid taken

Document the exact time of rivaroxaban intake as well as time and type of meal 
(i.e. breakfast, lunch, dinner) the child took within 2 hours before and 2 hours after 
rivaroxaban.

Blood sampling for o.d. or b.i.d. regimen (tablet and oral suspension):

At 0.5-1.5 hours and at 2.5-4 hours after this rivaroxaban intake, collect the PK 
blood sample

In children 6 years or older, collect a PD blood sample after the PK blood 
sample at both time points

In children < 6 years, no PD sample will be collected after the PK sample at 
0.5-1.5 hours, but a PD sample will be taken after the PK sample at 2.5-4 hours

Blood sampling for t.i.d. regimen (oral suspension): 

At 0.5-3 hours after this rivaroxaban intake collect the PK sample, followed by 
the PD blood sample 

At 7-8 hours after this rivaroxaban intake collect the PK blood sample

Document the exact time of blood sampling for PK/PD
[…]


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16.3.2.7
Section 6.5 Visit 3 at Day 60 (± 7 days)
This section was changed based on modification 2.
Old text:
[…]

In children randomized to rivaroxaban (tablet or oral suspension): 

Administer the next rivaroxaban dose immediately followed by the intake of 
up to 240 mL of liquid.

Document the volume and type of fluid taken.

Document the exact time of rivaroxaban intake as well as the time and type of 
meal (i.e. breakfast, lunch, dinner) the child took within 2 hours before and 2 
hours after rivaroxaban.

At 2-8 hours after the rivaroxaban intake (tablet or suspension):

Collect a PK blood sample followed by the PD blood sample.

Document the exact time of blood sampling for PK/PD.

Give instructions how to handle rivaroxaban the day before visit 4:

If rivaroxaban is given using an o.d. regimen:

Take rivaroxaban on the day before visit 4 at noon immediately 
followed by the intake of up to 240ml of liquid

Document the volume and type of fluid taken

Document the exact time of rivaroxaban intake as well as the time and 
type of meal (i.e. breakfast, lunch, dinner) the child took within 2 hours 
before and 2 hours after rivaroxaban.

If rivaroxaban is given using a b.i.d. regimen:

Take rivaroxaban as late as possible in the evening on the day before 
visit 4 immediately followed by the intake of up to 240 ml of liquid

Document the volume and type of fluid taken

Document the exact time of rivaroxaban intake as well as the time and 
type of meal (i.e. breakfast, lunch, dinner) the child took within 2 hours 
before and 2 hours after rivaroxaban.
[…]


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New text:
[…]

In children randomized to rivaroxaban (tablet or oral suspension): 

Administer the next rivaroxaban dose immediately followed by the intake of up to 
240 mL (o.d. and b.i.d. regimen) or up to 120 mL (t.i.d. regimen) of liquid.

Document the volume and type of liquid taken.

Document the exact time of rivaroxaban intake as well as the time and type of 
meal (i.e. breakfast, lunch, dinner) the child took within 2 hours before and 2 hours 
after rivaroxaban.

If rivaroxaban is given using an o.d. or b.i.d. regimen, at 2-8 hours after the 
rivaroxaban intake, collect a PK blood sample followed by the PD blood sample.

If rivaroxaban is given using a t.i.d. regimen, at 2-6 hours after the rivaroxaban 
intake, collect a PK blood sample followed by the PD blood sample.

Document the exact time of blood sampling for PK/PD.

Provide instructions for the day before visit 4 

If rivaroxaban is given using an o.d. regimen, take rivaroxaban on the day 
before visit 4 at noon immediately followed by the intake of up to 240 ml of 
liquid

If rivaroxaban is given using a b.i.d. regimen, take rivaroxaban as late as 
possible in the evening on the day before visit 4 immediately followed by the 
intake of up to 240 ml of liquid

If rivaroxaban is given using a t.i.d. regimen, take rivaroxaban night dose 
before visit 4 as scheduled, immediately followed by the intake of up to 120 ml 
of liquid

Document the volume and type of liquid taken

Document the exact time of rivaroxaban intake as well as the time and type of 
meal (i.e. breakfast, lunch, dinner) the child took within 2 hours before and 
2 hours after rivaroxaban.
[…]


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16.3.2.8
Section 6.6 Visit 4 at Day 90 (± 7 days)
This section was changed based on modification 2.
Old text:
[…]

In children randomized to rivaroxaban:

Document the exact time of rivaroxaban intake on the day prior to visit 4 and time 
and type of meal the child took within 2 hours before and 2 hours after rivaroxaban 
as well as the volume and type of liquid taken.

If rivaroxaban is given using an o.d. regimen:

Collect the PK blood sample 20-24h after rivaroxaban was taken on the 
previous day, followed by the PD blood sample

Document the exact time of blood sampling for PK/PD.

If rivaroxaban is given using a b.i.d. regimen:

Collect the PK blood sample 10 to 16 hours after the last evening dose, 
followed by the PD blood sample

If dosing continues beyond visit 4/day 90, give next dose after PK/PD samples

Document the exact time of blood sampling for PK/PD.

Obtain hemoglobin, platelets, ALT, total and direct bilirubin
[…]
New text:
[…]

In children randomized to rivaroxaban:

Document the exact time of rivaroxaban intake on the day prior to visit 4 and time 
and type of meal the child took within 2 hours before and 2 hours after rivaroxaban 
as well as the volume and type of liquid taken.

If rivaroxaban is given using an o.d. regimen, collect the blood sample for 
hemoglobin, platelets, ALT, total and direct bilirubin, followed by PK blood 
sample and finally the PD blood sample at 20-24h after rivaroxaban was taken on 
the previous day

If rivaroxaban is given using a b.i.d. regimen, collect the blood sample for 
hemoglobin, platelets, ALT, total and direct bilirubin, followed by PK blood 
sample and finally the PD blood sample at 10 to 16 hours after the last evening 
dose


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
If rivaroxaban is given using a t.i.d. regimen, collect hemoglobin, platelets, ALT, 
total and direct bilirubin, followed by the PD blood sample 10 to 16 hours after the 
last evening dose

If dosing continues beyond visit 4/day 90, give next dose after PD sample

Document the exact time of blood sampling for PK/PD.
[…]
16.3.2.9
Section 6.14 PK/PD assessments
This section was changed based on modification 2.
New text:
[…]
Blood samples will be taken for PK and PD measurements from children randomized to 
rivaroxaban. 
The following blood samples will be taken in children with o.d. or b.i.d. regimen:

two post-dose PK/PD samples at visit 2 (no PD sample at 0.5-1.5 hours for children 
< 6 years)

one post-dose PK/PD sample at visit 3, and

one pre-dose PK/PD sample at visit 4.
The following blood samples will be taken in children with t.i.d. regimen:

two post-dose PK samples at visit 1a

two post-dose PK samples at visit 2 

one post-dose PD sample at visit 2, and

one post-dose PK/PD sample at visit 3, and

one pre-dose PD sample at visit 4.
[…]


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16.3.2.10
Section 7.2 Analysis sets
This section was changed based on modification 3.
Old text:
[…]
The detailed list of these deviations will be finalized prior to database lock and included in the 
protocol deviation document and SAP.
[…]
New text:
[…]
The detailed list of these deviations will be finalized prior to database lock and included in the 
protocol deviation document, the approved final list of important deviations, validity findings 
and assignment to analysis set(s).
[…]
16.4
Amendment 12
Amendment 12 is the fourth global amendment dated 27 SEP 2017.
16.4.1
Overview of changes
16.4.1.1
Modification 1: Introducing new dosing information for children with 
body weight between 2.6 and <6 kg, and inclusion of children aged 
birth to 6 months
Rationale: Amendment 12 introduced new dosing information for children with body weight 
between 2.6 and <6 kg. This new dosing regimen is based on data from all studies in children 
younger than 2 years, as well as an exploratory PopPK model, that considers all rivaroxaban 
PK data available from all children younger than 2 years. As the exploratory model is based 
on limited data (e.g., limited number of subjects, sparse sampling), the model predictions had 
a higher level of uncertainty for these children. However, observed data from this study 
(14372) and data from the phase I/II study (17618) that is enrolling children aged < 6 months 
(including those 2.6 and <6 kg), have confirmed the predictions from the exploratory PopPK 
model in all children dosed t.i.d thus far in both studies.  Therefore, the Steering Committee 
with concurrence from the DMC recommended dosing for children < 6 kg.  
This additional dosing information facilitates enrollment of children from birth to < 6 months. 
This age group was added to a revised cohort for children from birth to aged < 2 years.  A 
single cohort from birth to aged < 2 years generally shares common risk factors for 
thrombosis, distribution of thrombus (with catheter-related thrombosis predominating), a 
different standard of care treatment regimen (< 90 days of treatment is common) and 


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rivaroxaban treatment regimen (most will require t.i.d. dosing). Lastly, to conform to 
treatment guidelines and clinical practice, a main study treatment duration of 30 days was 
added for those < 2 years with catheter-related thrombosis.
Affected sections: Synopsis; Section 1 Introduction; Section 3 Study design; Section 4.1 
planned number of children; Section 4.2 Inclusion criteria; Section 4.3 Exclusion criteria; 
Section 5.1.1 Rivaroxaban group; Section 5.3 Duration of study treatment; Section 5.4.1 
Rivaroxaban; Section 5.8 Study treatment and compliance assessment; Section 6.1 Study 
visits; Section 6.3 Visit 1a (2+1 days after start t.i.d rivaroxaban); Section 6.4 Visit 2 at Day 
30 (± 7 days); Section 6.5 Visit 3 at Day 60 (± 7 days); Section 6.6 Visit 4 at Day 90 (± 7 
days); Section 6.8 Visit 8, 30 day post study treatment contact (30 days ± 7 days after last 
visit); Section 6.14 PK/PD assessments; Section 7.4 Bleeding analysis; Section 7.5 Efficacy 
analysis; Section 7.8 Determination of sample size; Section 15 References; Section 17.2 
Appendix 2: Estimated glomerular filtration rate; Section 17.4 Appendix 4: Dosing table for 
children from birth to 18 years
16.4.1.2
Modification 2: Minor clarifications for consistency
Minor, consistency and logical clarifications were made throughout the document.
Rationale: Changes were made to ensure correctness and consistency and to remove 
redundancy within the protocol. These changes do not affect the overall study concept.
Affected sections: Title page; Section 5.5 Packaging, labeling and storage
16.4.2
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.
16.4.2.1
Title page
The section was changed based on modification 2.
Old text:
Aprather Weg/Gebäude 402
42113, Wuppertal, Germany
Telephone:
Email:
 
PPD
PPD
PPD


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New text:
Bayer U.S. LLC
Pharmaceuticals, 
Pharmaceuticals study medical Experts
100 Bayer Boulevard
P.O. Box 915
Whippany, NJ 07981
United States
Tel: 
E-mail:
16.4.2.2
Synopsis 
The section was changed based on modification 1.
Old text:
Indication
Children aged 6 months to < 18 years 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, 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 < 18 years with acute venous 
thromboembolism confirmed by diagnostic imaging.
[…]
Methodology
Children aged 6 months to < 18 years with confirmed venous 
thromboembolism who receive initial treatment with therapeutic dosages 
of unfractionated heparin (UFH), low molecular weight heparin 
(LMWH), or fondaparinux are potentially eligible for the study.
[…]
The main study treatment period is for a total of 3 months at which time 
the diagnostic imaging test, which was obtained at baseline, will be 
repeated, if clinically feasible.
[…]
The main study treatment period is for a total of 3 months at which time 
the diagnostic imaging test, which was obtained at baseline, will be 
repeated, if clinically feasible. After the main study treatment period of 3 
months, the decision is made to stop study treatment or to continue for an 
additional 3 months. In children who completed 6 months of treatment, 
the decision is made to stop study treatment or to continue for an 
additional 3 months. Then, in children who completed 9 months of 
treatment, the decision is made to stop study treatment or to continue for 
an additional 3 months.
PPD
PPD
PPD


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[…]
Regardless of the duration of study treatment (3, 6, 9 or 12 months), an 
additional 1-month post-treatment observational period will be 
completed for all children. […]
Number of children
At least 150 children are needed for this study, of whom 80 in the age 
group 12 to < 18 years, 30 in the age group 6 to < 12 years, 20 in the age 
group 2 to < 6 years, and 20 in the age group 6 months to < 2 years.
Inclusion/exclusion criteria
Inclusion
1.
Children aged 6 months to < 18 years with confirmed venous 
thromboembolism who receive initial treatment with therapeutic 
dosages of UFH, LMWH or fondaparinux and require 
anticoagulant therapy for at least 90 days. […]
2.
Informed consent provided and, if applicable, child assent 
provided
Exclusion
[…]
2.
An estimated glomerular filtration rate (eGFR) 
< 30 mL/min/1.73 m2
[…]
[…]
Primary efficacy outcome 
analysis
Incidence proportions and cumulative incidences will be calculated for 
the primary efficacy outcome at the end of month 3.
Secondary efficacy outcome 
analysis
Incidence proportions and cumulative incidences will be calculated for 
the secondary efficacy outcome at the end of month 3. 
Other efficacy outcome 
analysis
Incidence proportions will be calculated for the primary efficacy 
outcome at 6, 9 and 12 months. 
Principal safety outcome 
analysis
Incidence proportions and cumulative incidences will be calculated for 
the principal safety outcome at the end of month 3.
Other safety outcome analysis
Incidence proportions will be calculated for the principal safety outcome 
at 6, 9 and 12 months.
[…]


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Table 0-1
Flow chart 
Main Treatment period
Extended treatment period with 
blocks of 3 months
30-day 
post study 
treatment
Visit 
1
1a
2
3
4
5
6
7
8
Days
Before 
random
After 
random.
2+1 days after 
start t.i.d 
rivaroxaban p
Day 30
7 days
Day 60
7 days
Day 90
7 days
Day 180
7 days
Day 270
7 days
Day 360 
7 days
30 7 days
After last 
visit
Contact
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit or 
phone 
Pharmacokinetics (PK) and pharmacodynamics (PD) for rivaroxaban using t.i.d. regimen h
Obtain PK blood sample i
●
●
●
●
●
Obtain PD blood sample j, k
●
●
●
Time point for PK/PD blood 
sample (hours) if dosing 
continues beyond Day 90
0.5-
3hr 
post 
dose
7-8hr 
post 
dose
0.5-
3hr 
post 
dose
7-8hr 
post 
dose
2-6hr 
post 
dose
10-16hr 
after last 
evening 
dose, give 
next dose 
after PD 
sample
Footnotes:
[…]
h
The approximate total blood volume taken per child for 
PK/PD is 12 mL if blood taken via venipuncture, and up to 
24 mL if blood taken via central venous line or peripheral 
catheter (see Section 6.14).
i
Blood volume per PK sample is approximately 1.2 mL, 
total blood volume for all PK samples is 4.8 mL for o.d. 
and b.i.d. regimen and 6 mL for t.i.d. regimen.
j
Blood volume per PD sample is approximately 1.8 mL ; total blood 
volume for all PD samples is 7.2 mL for o.d. and b.i.d. regimen and 
5.4 for t.i.d. regimen.
k 
Always draw the pharmacodynamics sample as the last sample.
l
PD sample will not be collected at 0.5-1.5 hr after rivaroxaban 
intake for children < 6 years
[…]
Not applicable as Table 0-2 was added via this Amendment (Amendment 12)
New text:
Indication
Children aged birth to < 18 years 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, 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 birth to < 18 years with acute venous thromboembolism 
confirmed by diagnostic imaging.
[…]
Methodology
Children aged birth to < 18 years with confirmed venous 
thromboembolism who receive initial treatment with therapeutic dosages 
of unfractionated heparin (UFH), low molecular weight heparin 
(LMWH), or fondaparinux are potentially eligible for the study.
[…]
The main study treatment period is for a total of 3 months at which time 
the diagnostic imaging test, which was obtained at baseline, will be 
repeated, if clinically feasible.  However, in children younger than 2 
years with catheter-related thrombosis, the main study treatment period is 


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for a total of 1 month at which time the repeat imaging will be 
performed. In all children, except those < 2 years with catheter-related 
thrombosis, the decision is made to stop study treatment at 3 months or 
to continue for an additional 3 months. In children who completed 6 
months of treatment, the decision is made to stop study treatment or to 
continue for an additional 3 months. Then, in children who completed 9 
months of treatment, the decision is made to stop study treatment or to 
continue for an additional 3 months.  In children < 2 years with catheter-
related thrombosis, the decision is made to stop study treatment at 1 
month or to continue for an additional month.  Then, in children who 
completed 2 months of treatment, the decision is made to stop study 
treatment or to continue for an additional month.
Regardless of the duration of study treatment (<3, 3, 6, 9 or 12 months), 
an additional 1-month post-treatment observational period will be 
completed for all children. […]
Number of children
At least 170 children are needed for this study, of whom 80 in the age 
group 12 to < 18 years, 30 in the age group 6 to < 12 years, 20 in the age 
group 2 to < 6 years, and 20 in the age group birth to < 2 years, with at 
least 12 aged birth to < 6 months. 
Inclusion/exclusion criteria
Inclusion
1.
Children aged birth to < 18 years with confirmed venous 
thromboembolism who receive initial treatment with therapeutic 
dosages of UFH, LMWH or fondaparinux and require 
anticoagulant therapy for at least 90 days. However, children aged 
birth to < 2 years with catheter-related thrombosis require 
anticoagulant therapy for at least 30 days. 
2.
Informed consent provided and, if applicable, child assent 
provided
3.
For children younger than 6 months: 
- Gestational age at birth of at least 37 weeks.
- Oral feeding/nasogastric/gastric feeding for at least 10 days.
- Body weight ≥2600 g.
Exclusion 
2.
An estimated glomerular filtration rate (eGFR) 
< 30 mL/min/1.73 m2 (in children younger than 1 year,  serum 
creatinine results above 97.5th percentile excludes participation, 
see Table 17–1)
[…]


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Primary efficacy outcome 
analysis
Incidence proportions and cumulative incidences will be calculated for 
the primary efficacy outcome at the end of the main study treatment 
period.
Secondary efficacy outcome 
analysis
Incidence proportions and cumulative incidences will be calculated for 
the secondary efficacy outcome at the end of the main study treatment 
period.
Other efficacy outcome 
analysis
Incidence proportions will be calculated for the primary efficacy 
outcome in the extended treatment period at 3 as well as 6, 9 and 12 
months (see study flow charts).
Principal safety outcome 
analysis
Incidence proportions and cumulative incidences will be calculated for 
the principal safety outcome at the end of the main study treatment 
period.
Other safety outcome analysis
Incidence proportions will be calculated for the principal safety outcome 
in the extended treatment period at 3 as well as 6, 9 and 12 months (see 
study flow charts). 
[…]


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Table 0-1: Flow chart for all children except children aged < 2 years with catheter 
related thrombosis (see Table 2) 
Main Treatment period
Extended treatment period with 
blocks of 3 months
30-day 
post study 
treatment
Visit 
1
1a
2
3
4
5
6
7
8
Days
Before 
random
After 
random.
2+1 days after 
start t.i.d 
rivaroxaban p
Day 30
7 days
Day 60
7 days
Day 90
7 days
Day 180
7 days
Day 270
7 days
Day 360 
7 days
30 7 days
After last 
visit
Contact
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit or 
phone 
Pharmacokinetics (PK) and pharmacodynamics (PD) for rivaroxaban using t.i.d. regimen h
Obtain PK blood sample i
●
●
●q
●q
●
Obtain PD blood sample j, k
●q
●
●
Time point for PK/PD blood 
sample (hours) if dosing 
continues beyond Day 90
0.5-
3hr 
post 
dose
7-8hr 
post 
dose
0.5-
3hr 
post 
dose
7-8hr 
post 
dose
2-6hr 
post 
dose
10-16hr 
after last 
evening 
dose, give 
next dose 
after PD 
sample
Footnotes:
[…]
h
The approximate total blood volume taken per child for 
PK/PD is 12 mL if blood taken via venipuncture (for t.i.d. 
regimen it is 7.2 mL), and up to 24 mL if blood taken via 
central venous line or peripheral catheter (see 
Section 6.14).
i
Blood volume per PK sample is approximately 1.2 mL (for 
t.i.d. regimen it is 0.6 mL); total blood volume for all PK 
samples is 4.8 mL for o.d. and b.i.d. regimen and 3 mL for 
t.i.d. regimen.
j
Blood volume per PD sample is approximately 1.8 mL (for t.i.d. 
regimen it is 1.4 mL); total blood volume for all PD samples is 
7.2 mL for o.d. and b.i.d. regimen and 4.2 mL for t.i.d. regimen.
k 
Always draw the PD sample as the last sample.
l
PD sample will not be collected at 0.5-1.5 hr after rivaroxaban 
intake for children < 6 years. Please note that this is different than in 
children <2 years with catheter related thrombosis
[…]
q        Visit 2 will be modified for children weighing < 3250 grams.  The 
PK and PD samples taken 0.5 to 3 hours post-dose will be taken on 
a dosing day within the visit window (total volume to be drawn is 
2.0 mL), and the 7-8 hour post-dose PK sample (total volume to be 
drawn is 0.6 ml) may be taken on the following dosing day within 
the visit window.  This modification may only occur in children 
weighing less than 3250 kg at the time of visit 2
[…]


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Table 0-2   Flow chart for children aged < 2 years with catheter related thrombosis
Main Treatment period
Extended 
treatment period 
with blocks of 30 
days
30-day post 
study treatment
Visit 
1
1a
2
3
4
8
Days
Before 
random.
After 
random.
2+1 days 
after start 
t.i.d.
rivaroxaban 
m
Day 30
7 days
Day 60
7 days
Day 90
7 days
30 7 days
After last visitr
Contact
Visit
Visit
Visit
Visit
Visit
Visit
Visit 
Obtain informed consent
●
Check in-/exclusion criteria
●
Obtain demographic data
●
Check medical history
●
Record concomitant 
medication/anticoagulants
●
Obtain height/length/body 
weight/blood pressure
●
Check Hb, platelets, creatinine, 
ALT, total and direct bilirubin 
●a
Randomize patient using IxRS 
b
●
Dispense study medication 
●
●
●c
●c
Dispense additional supplies 
(devices for oral suspension)
●
●
●c
●c
Instruct how to take study 
medication l
●
Send baseline adjudication 
package
●
Check for adverse events
●
●
●
●
●
●
Check for device-related 
adverse events 
●
●
●
●
●
Obtain body weight 
●d
●d
●d
Check for study outcomes e
●
●
●
●
●
Check study drug 
accountability and compliance 
●
●
●
Check changes in concomitant 
medication
●
●
●
●
●
Obtain Hb, platelets, ALT, 
total and direct bilirubin 
●
Repeat imaging and send 
adjudication package f
●
Complete eCRF 
●
●
●
●
●
●
●
Comparator group only
If INR-adjusted VKA g
1 INR per 2 weeks


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Table 0-2
Flow chart for children < 2 years of age with catheter related 
thrombosis (continued)
Main Treatment period
Extended 
treatment period 
with blocks of 30 
days
30-day post 
study treatment
Visit 
1
1a
2
3
4
8
Days
Before 
random
After 
random.
2+1 days 
after start 
t.i.d 
rivaroxaban 
m
Day 30
7 days
Day 60
7 days
Day 90
7 days
30 7 days
After last visitr
Contact
Visit
Visit
Visit
Visit
Visit
Visit
Visit 
Pharmacokinetics (PK) and pharmacodynamics (PD) for rivaroxaban using b.i.d. regimenh
Administer rivaroxaban at 
study site
●
●
Take up to 240 mL of liquid 
immediately after dosing
●
●
Obtain PK blood sample i
●
●
●
●
Obtain PD blood sample j, k
● 
●
●
● o
Time point for PK/PD blood 
sample (hours) 
10-16hr 
after 
last 
evening 
dose, 
give 
next 
dose 
after 
PK 
sample
0.5-
1.5hr 
post 
dose
2.5-4hr 
post 
dose
2-8hr 
post dose
PK and PD for rivaroxaban using t.i.d. regimenh
Administer rivaroxaban at 
study site
●
●
●
Take up to 120 mL of liquid 
immediately after dosing
●
●
●
Obtain PK blood sample i
●
●
●o
●o
●
Obtain PD blood sample j, k
●o
●
● n
Time point for PK/PD blood 
sample (hours)
0.5-
3hr 
post 
dose
7-
8hr 
post 
dose
0.5-3hr 
post dose
7-8hr post 
dose
2-6hr 
post dose


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Footnotes:
a
Blood sample should be obtained within a maximum 
of 5 days prior to randomization.
b
Randomization can be done during the first 9 days of 
initial therapy with UFH, LMWH or fondaparinux.
c
If study treatment is continued, provide study 
medication
d
Adjust dosage of study medication and treatment 
regimen, if change in body weight. Additional visits 
can be planned to accommodate dose adjustment of 
study medication, if applicable. 
e
If suspected outcome occurred, the adjudication 
package needs to be compiled and sent to the 
adjudication office.
f
After the main study treatment period of 1 month,  
the diagnostic imaging test which was obtained at 
baseline will be repeated, if clinically feasible.
g
VKA compliance will be ensured by minimum of 1 
INR per 2 weeks.
h
The approximate total blood volume taken per child 
for PK/PD is 12 mL for b.i.d.and 7.2 mL for t.i.d. if 
blood taken via venipuncture, and up to 24 mL if 
blood taken via central venous line or peripheral 
catheter (see Section 6.14).
i
Blood volume per PK sample is approximately 1.2 
mL for b.i.d. and 0.6 mL for t.i.d.; total blood volume 
for all PK samples is 4.8 mL for b.i.d. and 3 mL for 
t.i.d.
j
Blood volume per PD sample is approximately 1.8 mL for 
b.i.d. and 1.4 mL for t.i.d.; total blood volume for all PD 
samples is 7.2 mL for b.i.d. and 4.2 mL for t.i.d.
k 
Always draw the PD sample as the last sample.
l
In addition, provide Rivaroxaban Oral Suspension Handling 
Instructions, and Study Booklet
m
Only in children treated with rivaroxaban t.i.d. regimen. If 
visit 1a falls on a weekend and cannot take place, the visit 
must be scheduled for the following Monday.
n
Visit 8 cannot be conducted by phone in children who are 
aged < 2 with catheter-related thrombosis, as a PD sample 
must be collected at this visit.  If the patient is started on 
another anticoagulant during the 30 day post study treatment 
period, the PD sample needs to be taken at least 8 hours 
after last dose of rivaroxaban and before initiation of a new 
anticoagulant.
o
Visit 2 will be modified for children weighing < 3250 
grams.  The PK and PD samples taken 0.5 to 3 hours post-
dose will be taken on a dosing day within the visit window 
(total volume to be drawn is 2.0 mL), and the 7-8 hour post-
dose PK sample (total volume to be drawn is 0.6 ml) may be 
taken on the following dosing day within the visit window.  
This modification may only occur in children weighing less 
than 3250 kg at the time of visit 2. 
o.d. = once daily dosing
b.i.d. = twice daily dosing
t.i.d. = three times daily dosing
eCRF = electronic case report form;
IxRS = interactive voice/ web response system
PTS = post-thrombotic syndrome
16.4.2.3
Section 1 Introduction 
The section was changed based on modification 1.
Old text:
[…]
In phase II, enrollment of children from 2 to less than 18 years has been completed. 
Rivaroxaban was well tolerated, compliance with rivaroxaban was optimal, no recurrent 
venous thromboembolism and/or major bleeding were observed and PK/PD results confirmed 
a similar exposure as in adults receiving 20 mg of rivaroxaban once daily. Therefore, as in 
adults, there is no need for monitoring the anticoagulant activity of rivaroxaban in children. 
[…]
Once the age-and body weight adjusted dosing regimen has been confirmed for the age group 
between 6 months and less than 2 years in the phase II study 14374 and approved by the data 
monitoring committee and steering committee, the dosing schedule/regimen for this age group 
will be made available through an administrative amendment. The investigators and ethics 
committees/IRBs will receive the administrative amendment well in advance with an 


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opportunity for evaluation before permission will be given to start enrolling children in this 
age group.
New text:
In phase II, enrollment of children aged 6 months to less than 18 years has been completed. 
Rivaroxaban was well tolerated, no recurrent venous thromboembolism and/or major bleeding 
were observed and PK/PD results were in the expected range for children weighing more than 
12 kg.
[…]
The age-and body weight adjusted dosing regimen has now been established for all children 
aged birth to less than 18 years from data collected in the phase I/II studies and has been 
approved by the data monitoring committee and steering committee. Table 17-2 specifies the 
dosing regimen for each age group.
16.4.2.4
Section 3 Study design
The section was changed based on modification 1.
Old text:
[…]
Once the age-and body weight adjusted dosing regimen has been confirmed for the age group 
between 6 months and less than 2 years in the phase II study 14374 and approved by the data 
monitoring committee and steering committee, the dosing schedule/regimen for this age group 
will be made available through an administrative amendment (update: implemented through 
Amendment 8). The investigators and ethics committees/IRBs will receive the administrative 
amendment well in advance with an opportunity for evaluation before permission will be 
given to start enrolling children in this age group.
[…]
The PK samples obtained at Visit 1a will be shipped and analyzed for each child individually 
and will allow to determine whether the plasma concentrations are in the adult reference 
range. The results will be provided to the investigator/site and discussed in a timely manner, 
i.e. within approximately 1 to 2 weeks after sample collection. 
[…]
Study description
Children aged 6 months to < 18 years with confirmed acute venous thromboembolism who 
receive initial treatment with therapeutic dosages of unfractionated heparin (UFH), low 
molecular weight heparin (LMWH), or fondaparinux are potentially eligible for the study. 
Initial treatment with UFH, LMWH or fondaparinux will be administered for at least 5 days 
(day 1- 5).
[…]


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After randomization, children will receive either rivaroxaban or comparator for a main study 
treatment period of 3 months. After the main study treatment period of 3 months, the 
diagnostic imaging test which was obtained at baseline will be repeated, if clinically feasible 
and the decision is made to stop study treatment or to continue for an additional 3 months. 
In children who completed 6 months of treatment, the decision is made to stop study 
treatment or to continue for an additional 3 months. Then, in children who completed 9 
months of treatment, the decision is made to stop study treatment or to continue for an 
additional 3 months. Regardless of the duration of study treatment (3, 6, 9 or 12 months), an 
additional 1-month post-treatment observational period will be completed for all children. 
After cessation of study treatment, it is at the investigator’s discretion to continue with 
anticoagulants.
[…]
For all children, visits are scheduled at regular time points (see Table 0-1). Randomized 
children who have not received the study drug will be seen (visit or phone contact) at the end 
of the respective study treatment period at month 3. Children who prematurely discontinue 
study drug will be seen at the end of the intended study treatment period at month 3, 6, 9 or 
12. During all contacts, the treatment and clinical course of the child will be evaluated. 
Children with suspected efficacy or safety outcomes will undergo confirmatory testing as per 
standard of care. Blood samples for PK/PD will be taken at defined time points (see Table 0–
1).
[…]
New text:
[…]
Once the age-and body weight adjusted dosing regimen has been confirmed for the age group 
between 6 months and less than 2 years in the phase II study 14374 and approved by the data 
monitoring committee and steering committee, the dosing schedule/regimen for this age group 
will be made available through an administrative amendment (update: implemented through 
Amendment 8). The investigators and ethics committees/IRBs will receive the administrative 
amendment well in advance with an opportunity for evaluation before permission will be 
given to start enrolling children in this age group. 
The age-and body weight adjusted dosing regimen has now been established for all children 
aged birth to less than 18 years from data collected in the phase I/II studies and has been 
approved by the data monitoring committee and steering committee. Table 17–2specifies the 
dosing regimen for each age group.
[…]
The PK samples obtained at Visit 1a will be shipped and analyzed for each child individually 
and will allow to determine whether the plasma concentrations are in the adult reference 
range. The results will be provided to the investigator/site and discussed in a timely manner, 
i.e. within approximately 1 to 2 weeks after sample collection. Up to now, the predictions 
from the exploratory PopPK model are confirmed by the data from children enrolled in this 
weight group.


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Amendment 12 opened enrollment to children aged birth to < 6 months and introduced dosing 
information for children with a body weight between 2.6 and 6 kg. This new dosing regimen 
is based on data from all studies in children younger than 2 years, as well as an exploratory 
PopPK model, that considers all rivaroxaban PK data available from all children younger than 
2 years. As the exploratory model is based on limited data (e.g., limited number of subjects, 
sparse sampling), the model predictions had a higher level of uncertainty for these children. 
However, observed data from this study (14372) and data from the phase I/II study (17618) 
that is enrolling children of this weight category, have confirmed the predictions from the 
exploratory PopPK model in all children dosed t.i.d thus far in both studies.
Study description
Children aged birth to < 18 years with confirmed acute venous thromboembolism who receive 
initial treatment with therapeutic dosages of unfractionated heparin (UFH), low molecular 
weight heparin (LMWH), or fondaparinux are potentially eligible for the study. Initial 
treatment with UFH, LMWH or fondaparinux will be administered for at least 5 days (day 1-
5).
[…]
After randomization, children will receive either rivaroxaban or comparator for a main study 
treatment period of 3 months. After the main study treatment period of 3 months, the 
diagnostic imaging test which was obtained at baseline will be repeated, if clinically 
feasible. However, in children younger than 2 years with catheter-related thrombosis, the 
main study treatment period is for a total of 1 month at which time the repeat imaging will 
be performed. 
In all children, except those aged < 2 years with catheter-related thrombosis, the decision is 
made to stop study treatment at 3 months or to continue for an additional 3 months. In 
children who completed 6 months of treatment, the decision is made to stop study treatment 
or to continue for an additional 3 months. Then, in children who completed 9 months of 
treatment, the decision is made to stop study treatment or to continue for an additional 
3 months.  In children < 2 years with catheter-related thrombosis, the decision is made to 
stop study treatment at 1 month or to continue for an additional month.  Then, in children 
who completed 2 months of treatment, the decision is made to stop study treatment or to 
continue for an additional month.
Regardless of the duration of study treatment (<3, 3, 6, 9 or 12 months), an additional 1-
month post-treatment observational period will be completed for all children. After cessation 
of study treatment, it is at the investigator’s discretion to continue with anticoagulants.
[…]
For all children, visits are scheduled at regular time points (see Table 0–1 and Table 0–2). 
Randomized children who have not received the study drug will be seen (visit or phone 
contact) at the end of the respective main study treatment period. Children who prematurely 
discontinue study drug will be seen at the end of the intended study treatment period at month 
<3, 3, 6, 9 or 12. During all contacts, the treatment and clinical course of the child will be 
evaluated. Children with suspected efficacy or safety outcomes will undergo confirmatory 


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testing as per standard of care. Blood samples for PK/PD will be taken at defined time points 
(see Table 0–1 and Table 0–2).
[…]
16.4.2.5
Section 4.1 planned number of children
The section was changed based on modification 1.
Old text:
At least 150 children are needed for this study, of whom 80 in the age group 12 to < 18 years, 
30 in the age group 6 to < 12 years, 20 in the age group 2 to < 6 years, and 20 in the age group 
6 months to < 2 years.
New text:
At least 170 children are needed for this study, of whom 80 in the age group 12 to < 18 years, 
30 in the age group 6 to < 12 years, 20 in the age group 2 to < 6 years, and 20 in the age group 
birth to < 2 years, with at least 12 aged birth to < 6 months.
16.4.2.6
Section 4.2 Inclusion criteria
The section was changed based on modification 1.
Old text:
1. Children aged 6 months to < 18 years with confirmed venous thromboembolism who 
receive initial treatment with therapeutic dosages of UFH, LMWH or fondaparinux and 
require anticoagulant therapy for at least 90 days.
2. Informed consent provided and, if applicable, child assent provided
New text:
1. Children aged birth to < 18 years with confirmed venous thromboembolism who receive 
initial treatment with therapeutic dosages of UFH, LMWH or fondaparinux and require 
anticoagulant therapy for at least 90 days. However, children aged birth to < 2 years with 
catheter-related thrombosis require anticoagulant therapy for at least 30 days.
2. Informed consent provided and, if applicable, child assent provided
3. For children younger than 6 months: 
- Gestational age at birth of at least 37 weeks.
- Oral feeding/nasogastric/gastric feeding for at least 10 days.
- Body weight ≥2600 g
16.4.2.7
Section 4.3 Exclusion criteria
The section was changed based on modification 1.


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Old text:
2. An estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2
New text:
2. An estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (in children 
younger than 1 year,  serum creatinine results above 97.5th percentile excludes 
participation, see Table 17–1).
16.4.2.8
Section 5.1.1 Rivaroxaban group
The section was changed based on modification 1.
Old text:
The body weight adjusted dosing schedule for children aged 6 months to < 18 years is 
provided in Appendix 4 (see Section 17.4).
[…]
Dosing regimen, including dosing frequency, will be adjusted if the child’s body weight 
changes during the study (Table 17–1). 
With a once daily regimen, rivaroxaban will be taken in the morning during or within 2 hours 
after breakfast. With a twice daily regimen the morning dose will be taken during or within 2 
hours after breakfast and the evening dose will be taken during or within 2 hours after dinner. 
With a three times daily regimen, the morning, afternoon and night doses should be taken 
during or within 2 hours after feeding.
[…]
Use of oral suspension
Oral suspension is available for use in children aged 6 months to < 18 years. 
New text:
The body weight adjusted dosing schedule for children aged birth to < 18 years is provided in 
Appendix 4 (see Section 17.4). 
22
[…]
Dosing regimen, including dosing frequency, will be adjusted if the child’s body weight 
changes during the study (Table 17–2). 
With a once daily regimen, rivaroxaban will be taken in the morning during or within 2 hours 
after breakfast. With a twice daily regimen the morning dose will be taken during or within 1 
hour after breakfast and the evening dose will be taken during or within 1 hour after dinner. 
With a three times daily regimen, the morning, afternoon and night doses should be taken 
during or within 30 minutes after feeding.
[…]


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Use of oral suspension
Oral suspension is available for use in children aged birth to < 18 years.
[…]
16.4.2.9
Section 5.3 Duration of study treatment
The section was changed based on modification 1.
Old text:
The main study treatment period is 3 months. After that, it is up to the discretion of the 
treating physician to stop study treatment or to continue for an additional 3 months. 
In children who completed 6 months of treatment, the decision can be made to stop study 
treatment or to continue for an additional 3 months. Then, in children who completed 9 
months of treatment, the decision can be made to stop study treatment or to continue for an 
additional 3 months. Thereafter, no prolongation of study treatment can take place. 
Children who turn 2, 6, 12 or 18 years after randomization can continue their treatment 
regimen. 92 Specifically children who turn 18 years after randomization are allowed to 
continue participation for the entire elected study treatment duration of 3, 6, 9 or 12 months.
Children randomized last into the study will have a minimal study treatment duration of 
3 months.
New text:
In all children, except those aged < 2 years with catheter-related thrombosis, the main study 
treatment period is 3 months. After that, it is up to the discretion of the treating physician to 
stop study treatment or to continue for an additional 3 months. 
In children who completed 6 months of treatment, the decision can be made to stop study 
treatment or to continue for an additional 3 months. Then, in children who completed 9 
months of treatment, the decision can be made to stop study treatment or to continue for an 
additional 3 months. Thereafter, no prolongation of study treatment can take place. 
In children aged < 2 years with catheter-related thrombosis, the main study treatment period is 
1 month. After that, it is up to the discretion of the treating physician to stop study treatment 
or to continue for an additional 1 month. 
In children who completed 2 months of treatment, the decision can be made to stop study 
treatment or to continue for an additional 1 months. Thereafter, no prolongation of study 
treatment can take place.
Children who turn 2, 6, 12 or 18 years after randomization can continue their treatment 
regimen. Specifically children who turn 18 years after randomization are allowed to continue 
participation for the entire elected study treatment duration of 3, 6, 9 or 12 months.
Children randomized last into the study will have a minimal study treatment duration of 
3 months, except children aged < 2 years with catheter-related thrombosis, who will have a 
minimal study treatment duration of 1 month.


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16.4.2.10
Section 5.4.1 Rivaroxaban
The section was changed based on modification 1.
Old text:
Rivaroxaban will be provided by Bayer as immediate-release film-coated tablets, and as a 
granules for oral suspension formulation (0.1% suspension as finally administered drug 
product), see Table 5–1. Rivaroxaban will be dosed according to body weight groups as 
detailed in the dosing schedules/regimens associated with this protocol Since children with an 
estimated glomerular filtration rate below 30 mL/min/1.73 m2 are excluded from the study, 
dose reduction for impaired renal function is not required.
[…]
New text:
Rivaroxaban will be provided by Bayer as immediate-release film-coated tablets, and as a 
granules for oral suspension formulation (0.1% suspension as finally administered drug 
product), see Table 5–1. Rivaroxaban will be dosed according to body weight groups as 
detailed in the dosing schedules/regimens associated with this protocol Since children with an 
estimated glomerular filtration rate below 30 mL/min/1.73 m2 (in children younger than 1 
year,  serum creatinine results above 97.5th percentile, see Table 17–1) are excluded from the 
study, dose reduction for impaired renal function is not required.
16.4.2.11
Section 5.5 Packaging, labeling and storage
The section was changed based on modification 2.
Old text:
[…]
All study medication needs to be stored at the site according to the labeled storage advice in 
accordance with Good Clinical Practice (GCP) and GMP requirements. The study drug is to 
be kept in a secure area. Complete records of batch numbers and expiry dates can be found in 
the study file.
[…]
New text:
[…]
All study medication needs to be stored at the site according to the labeled storage advice in 
accordance with Good Clinical Practice (GCP) and GMP requirements. The study drug is to 
be kept in a secure area.
[…]
16.4.2.12
Section 5.8 Study treatment and compliance assessment
Old text:


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A 1-month supply of drug will be given at visits 1, 2, and 3, if applicable. In children who 
continue study treatment for an additional 3 months, study drug will be supplied at visit 4 
covering a 3-month period. In children who continue the study for a third and a fourth cycle 
of 3 months; study drug will be supplied at visits 5 and 6.
[…]
New text:
A 1-month supply of drug will be given at visits 1, 2, and 3, if applicable. In children who 
continue study treatment for an additional 3 months, (not applicable to children aged < 2 years 
with catheter-related thrombosis) study drug will be supplied at visit 4 covering a 3-month 
period. In children who continue the study for a third and a fourth cycle of 3 months; study 
drug will be supplied at visits 5 and 6.
[…]
16.4.2.13
Section 6.1 Study visits
The section was changed based on modification 1.
Old text:
The study has 5 to 8 planned visits, depending on the elected study duration.
New text:
The study has 4 to 9 planned visits, depending on the elected study duration and dosing.
16.4.2.14
Section 6.3 Visit 1a (2+1 days after start t.i.d rivaroxaban)
The section was changed based on modification 1.
Old text:
[…]

Document the exact time of rivaroxaban intake as well as the time and type of meal 
(i.e. breakfast, lunch, dinner) the child took within 2 hours before and 2 hours after 
rivaroxaban.
[…]
New text:
[…]

Document the exact time of rivaroxaban intake as well as the time and type of meal 
(i.e. breakfast, lunch, dinner) the child took during or within 30 minutes after 
rivaroxaban.
[…]


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16.4.2.15
Section 6.4 Visit 2 at Day 30 (± 7 days)
The section was changed based on modification 1.
Old text:
[…]

Document the exact time of rivaroxaban intake as well as time and type of meal (i.e. 
breakfast, lunch, dinner) the child took within 2 hours before and 2 hours after
rivaroxaban.
[…]

In children < 6 years, no PD sample will be collected after the PK sample at 0.5-1.5 
hours, but a PD sample will be taken after the PK sample at 2.5-4 hours
[…]

Blood sampling for t.i.d. regimen (oral suspension): 
[…]

Document the exact time of blood sampling for PK/PD
[…]
New text:

Document the exact time of rivaroxaban intake as well as time and type of meal 
(i.e. breakfast, lunch, dinner) the child took in relation to rivaroxaban.
[…]

In children < 2years with catheter related thrombosis receiving the b.i.d. 
regimen, a PK sample will also be collected at 10-16h after last evening dose 
of rivaroxaban, but before the first morning dose.

In children < 6 years receiving rivaroxaban b.i.d, no PD sample will be 
collected after the PK sample at 0.5-1.5 hours, but a PD sample will be taken 
after the PK sample at 2.5-4 hours
[…]
Blood sampling for t.i.d. regimen (oral suspension):
[…]

Visit 2 will be modified for children weighing < 3250 grams.  The PK and PD 
samples taken 0.5 to 3 hours post-dose will be taken on a dosing day within the 
visit window (total volume to be drawn is 2.0 mL), and the 7-8 hour post-dose 
PK sample (total volume to be drawn is 0.6 ml) may be taken on the following 
dosing day within the visit window.  This modification may only occur in 
children weighing less than 3250 kg at the time of visit 2.
[…]


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Document the exact time of rivaroxaban dosing and blood sampling for PK/PD
[…]
Following procedures are applicable only to children <2 years of age with catheter 
related thrombosis:

Obtain safety blood sample for hemoglobin, platelets, ALT, total and direct bilirubin. 

Repeat imaging with ultrasound, if applicable. If repeat imaging can be done with 
magnetic resonance imaging (MRI) or MR angiography, this should be done only if 
sedation and/or general anesthesia are not required. Other modalities of imaging, e.g. 
computed tomography (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.

After the main 30 day study treatment period in children aged < 2 years with catheter 
related thrombosis, the decision is made to stop study treatment or to continue for an 
additional 30 days. If study treatment is stopped, the 30-day post study treatment visit 
(Visit 8) will be scheduled. If study treatment is continued for 30 days, a visit (Visit 3) 
will be schedule at day 60 ± 7 days.
16.4.2.16
Section 6.5 Visit 3 at Day 60 (± 7 days)
The section was changed based on modification 1.
Old text:
[…]
Document the exact time of rivaroxaban intake as well as the time and type of 
meal (i.e. breakfast, lunch, dinner) the child took within 2 hours before and 2 
hours after rivaroxaban.
[…]

Provide instructions for the day before visit 4 
[…]
Document the exact time of rivaroxaban intake as well as the time and type of 
meal (i.e. breakfast, lunch, dinner) the child took within 2 hours before and 
2 hours after rivaroxaban.
[…]
New text:

Document the exact time of rivaroxaban intake as well as the time and type of 
meal (i.e. breakfast, lunch, dinner) the child took in relation to rivaroxaban
[…]


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
Provide instructions for the day before visit 4 
[…]
Document the exact time of rivaroxaban intake as well as the time and type of 
meal (i.e. breakfast, lunch, dinner) the child took in relation to rivaroxaban.
[…]
Following procedures are applicable only to children <2 years of age with catheter 
related thrombosis:

If study treatment is stopped, the 30-day post study treatment visit will be scheduled. 
If study treatment is continued for an additional 30 days, a visit (Visit 4) will be 
schedule at day 90 ± 7 days. If study treatment is stopped, the 30-day post study 
treatment visit will be scheduled
16.4.2.17
Section 6.6 Visit 4 at Day 90 (± 7 days)
The section was changed based on modification 1.
Old text:

In children randomized to rivaroxaban:

Document the exact time of rivaroxaban intake on the day prior to visit 4 and time 
and type of meal the child took within 2 hours before and 2 hours after rivaroxaban 
as well as the volume and type of liquid taken.
[…]

If rivaroxaban is given using a b.i.d. regimen, collect the blood sample for 
hemoglobin, platelets, ALT, total and direct bilirubin, followed by PK blood 
sample and finally the PD blood sample at 10 to 16 hours after the last evening 
dose

If rivaroxaban is given using a t.i.d. regimen, collect hemoglobin, platelets, ALT, 
total and direct bilirubin, followed by the PD blood sample 10 to 16 hours after the 
last evening dose

If dosing continues beyond visit 4/day 90, give next dose after PD sample
[…]
After the main 3-month study treatment period, the decision is made to stop study treatment 
or to continue for an additional 3 months. If study treatment is stopped, the 30-day post study 
treatment visit will be scheduled.
[…]


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New text:

In children randomized to rivaroxaban:

Document the exact time of rivaroxaban intake on the day prior to visit 4 and time 
and type of meal the child took in relation to rivaroxaban as well as the volume 
and type of liquid taken.
[…]

If rivaroxaban is given using a b.i.d. regimen, collect the blood sample for 
hemoglobin, platelets, ALT, total and direct bilirubin, followed by PK blood 
sample and finally the PD blood sample at 10 to 16 hours after the last evening 
dose (in all children except those aged < 2 years with catheter related thrombosis).

If rivaroxaban is given using a t.i.d. regimen, collect hemoglobin, platelets, ALT, 
total and direct bilirubin, followed by the PD blood sample 10 to 16 hours after the 
last evening dose (in all children except those aged < 2 years with catheter related 
thrombosis).

If dosing continues beyond visit 4/day 90, give next dose after PD sample (in all 
children except those aged < 2 years with catheter related thrombosis)
[…]
After the main 3-month study treatment period in all children except those aged < 2 years 
with catheter related thrombosis, the decision is made to stop study treatment or to continue 
for an additional 3 months.
16.4.2.18
Section 6.8 Visit 8, 30 day post study treatment contact (30 days ± 7 
days after last visit)
The section was changed based on modification 1.
Old text:
Section 6.8 30 day post study treatment contact (30 days ± 7 days after last visit)
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 30 days 
± 7 after the last visit of the patient. 
New text:
Section 6.8 Visit 8, 30 day post study treatment contact (30 days ± 7 days after last visit)
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 (telephone contact 
cannot be conducted in children who are aged < 2 with catheter-related thrombosis) will take 
place 30 days ± 7 after the last visit of the patient. 
[…]


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Following procedures are applicable only to children <2 years of age with catheter 
related thrombosis:

This visit cannot occur by telephone

Check changes in concomitant medications

Obtain PD blood sample
o If the patient is started on another anticoagulant during the 30 day post study 
treatment period, the PD sample needs to be taken at least 8 hours after last 
dose of rivaroxaban and before initiation of a new anticoagulant.
16.4.2.19
Section 6.14 PK/PD assessments
The section was changed based on modification 1.
Old text:
The prothrombin time, aPTT and anti-factor Xa activity (anti-Xa) will be used to assess the 
pharmacodynamic effects after administration of the study drug.
Blood samples will be taken for PK and PD measurements from children randomized to 
rivaroxaban. 

The following blood samples will be taken in children with o.d.or b.i.d. regimen:
o
[…]

The following blood samples will be taken in children with t.i.d. regimen:
o
[…]
[…]
If a blood sample is taken from a central line, 3 mL of blood should be discarded.
[…]
New text:
The prothrombin time, aPTT and anti-factor Xa activity (anti-Xa) will be used to assess the 
pharmacodynamic effects after administration of the study drug.
Blood samples will be taken for PK and PD measurements from children randomized to 
rivaroxaban. 
The following blood samples will be taken in children without catheter related thrombosis and 
with

o.d. (children with body-weight > 30 kg) or b.i.d. (children with body weight 12-
30 kg) regimen:
o
[…]

t.i.d. regimen (children with body-weight < 12 kg) :


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o
[…]
The following blood samples will be taken in children aged < 2 years with catheter related 
thrombosis and

b.i.d regimen (children with body weight ≥12 kg):
o
one pre-dose PK sample at visit 2
o
two post-dose PK/PD samples at visit 2, and 
o
one post-dose PK/PD sample at visit 3, if occurs, and  
o
one PD sample at visit 8

t.i.d regimen (children with body weight <12 kg)
o
two post-dose PK sample at visit 1a, and 
o
two post-dose PK sample at visit 2
o
one post-dose PD sample at visit 2, and 
o
one post-dose PK/PD sample at visit 3, if occurs, and 
o
one PD sample at visit 8
[…]
If a blood sample is taken from a central line, it is recommended to discard 3 mL of blood. 
For small children a smaller blood volume can be discarded and sites can follow their own 
practical standard.
16.4.2.20
Section 7.4 Bleeding analysis
The section was changed based on modification 1.
Old text:
[…]
Incidence proportions (number of children with outcome during the period divided by number 
of children at risk at the beginning of the period) and cumulative incidences (time to first 
event; Kaplan-Meier) will be calculated for the primary safety outcome by treatment group at 
3 months for pooled data. Incidence proportions will be calculated for each age stratum at 
3 months as well. In addition, incidence proportions will be calculated by treatment group and
overall at 6, 9 and 12 months. Denominators in this case will be the number of patients at risk 
at the start of the respective period. Incidences will be calculated for 3 to 6-month study 
period, 6 to 9-month study period, and 9 to 12-month period, separately.
[…]
New text
[…]


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Incidence proportions (number of children with outcome during the period divided by number 
of children at risk at the beginning of the period) and cumulative incidences (time to first 
event; Kaplan-Meier) will be calculated for the primary safety outcome by treatment group at 
the end of the main study treatment period for pooled data. Incidence proportions will be 
calculated for each age stratum at the end of the main study treatment period as well. In 
addition, incidence proportions will be calculated by treatment group for each age stratum and 
pooled data overall in the extended study treatment period at 2 and 3 months (for the children 
<2 years with catheter related thrombosis) and at 6, 9 and 12 months (for the other groups).
Denominators in this case will be the number of patients at risk at the start of the respective 
period. 
[…]
16.4.2.21
Section 7.5 Efficacy analysis
The section was changed based on modification 1.
Old text:
All efficacy analyses will be performed on the full analysis set population based on the 
outcomes confirmed by the CIAC. Incidence proportions and cumulative incidences (time to 
first event; Kaplan-Meier) will be calculated for the primary and secondary efficacy outcomes 
by treatment group at 3 months for pooled data. In addition, incidence proportions will be 
calculated for each age stratum at 3 months. Incidence proportions will be calculated for the 
primary outcomes by treatment group and overall at 6, 9 and 12 months. Denominators will 
be the number of patients at risk at the start of the respective period. Incidences will be 
calculated for the 3 to 6-month study period, 6 to 9-month study period, and 9 to 12-month 
study period, separately.
[…]
New text:
All efficacy analyses will be performed on the full analysis set population based on the 
outcomes confirmed by the CIAC. Incidence proportions and cumulative incidences (time to 
first event; Kaplan-Meier) will be calculated for the primary and secondary efficacy outcomes 
by treatment group at the end of the main study treatment period for pooled data. In addition, 
incidence proportions will be calculated for each age stratum at the end of the main study 
treatment period. Incidence proportions will be calculated for the primary outcomes by 
treatment group for each age stratum and pooled data overall in the extended study treatment 
period at 2 and 3 months (for the children <2 years with catheter related thrombosis) and, at 6, 
9 and 12 months (for the other groups). Denominators will be the number of patients at risk at 
the start of the respective period.
[…]


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Subgroup analysis
Demographic and other baseline characteristics, as well as efficacy, safety and PK/PD data 
will be summarized for the main treatment period (up to the month 3 visit) for each age group 
and for combinations of age groups.
16.4.2.22
Section 7.8 Determination of sample size
The section was changed based on modification 1.
Old text:
At least 150 children 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.
New text:
At least 170 children 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.
16.4.2.23
Section 15 References
The section was changed based on modification 1.
Old text:
Not applicable.
New text:
18.
Boer DP, Rijke YB, Hop WC et al. Reference values for serum creatinine in children 
younger than 1 year of age. Pediatr Nephrol 2010;25:2107-2113.
16.4.2.24
Section 17.2 Appendix 2: Estimated glomerular filtration rate
The section was changed based on modification 1.
Old text:
Not applicable.
New text:
[…]
For children younger than 1 year, the serum creatinine levels provided in Table 17-1 are used 
instead of eGFR < 30 mL/min/1.73m2 to evaluate the eligibility regarding to the exclusion 
criterion 2 in Section 4.3. A serum creatinine above the 97.5th percentile excludes 
participation in the study.


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Table 17–1: Serum creatinine 97.5th percentile in children aged < 1 [18]
Age Group
Serum creatinine (micromol/L)
Week 2
46
Week 3
41
Week 4
37
Month 2
33
Month 3
30
Month 4-6
30
Month 7-9
30
Month 10-12
32
16.4.2.25
Section 17.4 Appendix 4: Dosing table for children from birth to 18 
years
The section was changed based on modification 1.
Old text:
Section 17.4 Appendix 4: Dosing table for children from 6 to 18 years
[…]
Table 17–2: Body weight-adjusted rivaroxaban dosing schedule for children aged 
6 months to < 18 years
Body weight (kg)
Formulation
o.d. Dose
b.i.d. Dose
t.i.d. Dose
Total Daily 
Dose
Min
Max
5
<6
Oral suspension
1.8 mg
5.4 mg
6*
<7
Oral suspension
1.6 mg
4.8 mg
[…]
New text:
Section 17.4 Appendix 4: Dosing table for children from birth to 18 years
[…]


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Table 17–2: Body weight-adjusted rivaroxaban dosing schedule for children aged 
birth to < 18 years
Body weight (kg)
Formulation
o.d. Dose
b.i.d. Dose
t.i.d. Dose
Total Daily 
Dose
Min
Max
2.6
<3
Oral suspension
0.8 mg
2.4 mg
3
<4
Oral suspension
0.9 mg
2.7 mg
4
<5
Oral suspension
1.4 mg
4.2 mg
5
<6
Oral suspension
1.6 mg
4.8 mg
6*
<7
Oral suspension
1.6 mg
4.8 mg
[…]


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17.
Appendices
17.1
Appendix 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
Appendix 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:
92
Where k is proportionality constant:
k = 0.33 in pre-term infants up to 1 year
k= 0.45 in full-term infants up to 1 year
k = 0.55 in children 1 year to 13 years
k = 0.55 in girls > 13 and < 18 years
k = 0.70 in boys > 13 and < 18 years 
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. SCr 
in micromoles per liter, the value should be multiplied by 88.4 (1 mg/dL = 88.4 umol/L).
                                                                                                                                      
92 eGFR calculation was updated via Amendment 8 (see Section 16.2.2.23)


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For children younger than 1 year, the serum creatinine levels provided in Table 17–1are used 
instead of eGFR < 30 mL/min/1.73m2 to evaluate the eligibility regarding to the exclusion 
criterion 2 in Section 4.3. A serum creatinine above the 97.5th percentile excludes 
participation in the study.
93
Table 17–1
Serum creatinine 97.5th percentile in children aged < 1 [18] 94
Age Group
Serum creatinine (micromol/L)
Week 2
46
Week 3
41
Week 4
37
Month 2
33
Month 3
30
Month 4-6
30
Month 7-9
30
Month 10-12
32
                                                                                                                                      
93 Text added via Amendment 12 (see Section 16.4.2.24)
94 Table 17-1 and guidance that serum creatinine level should be used instead of eGFR for children <1 year when evaluating 
eligibility and were added via Amendment 12 (see Section 16.4.2.24)


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17.3
Appendix 3: Reference values for blood pressure in children
Figure 1
Age-specific percentiles of blood pressure in children from birth to 12 
months
Source: Report of the Second Task Force on Blood Pressure Control in Children .Pediatrics 1987; 
79(1):1 25. 15


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Figure 2
95th blood pressure percentiles by age and height percentiles 
in children from 1 to 17 years
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
7
110
111
113
115
117
118
119
74
74
75
76
77
78
78
8
111
112
114
116
118
119
120
75
76
77
78
79
79
80
9
113
114
116
118
119
121
121
76
77
78
79
80
81
81
10
115
116
117
119
121
122
123
77
78
79
80
81
81
82
11
117
118
119
121
123
124
125
78
78
79
80
81
82
82
12
119
120
122
123
125
127
127
78
79
80
81
82
82
83
13
121
122
124
126
128
129
130
79
79
80
81
82
83
83
14
124
125
127
128
130
132
133
80
80
81
82
83
84
84
15
126
127
129
131
133
134
135
81
81
82
83
84
85
85
16
129
130
132
134
135
137
137
82
83
83
84
85
86
87
17
131
132
134
136
138
139
140
84
85
86
87
87
88
89
(continued)


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Figure 2
95th blood pressure percentiles by age and height percentiles 
in children from 1 to 17 years
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
7
110
111
112
113
115
116
116
73
74
74
75
76
76
77
8
112
112
114
115
116
118
118
75
75
75
76
77
78
78
9
114
114
115
117
120
121
122
77
77
77
78
79
80
80
10
116
116
117
119
120
121
122
77
77
77
78
79
80
80
11
118
118
119
121
122
123
124
78
78
78
79
80
81
81
12
119
120
121
123
124
125
126
79
79
79
80
81
82
82
13
121
122
123
124
126
127
128
80
80
80
81
82
83
83
14
123
123
125
126
127
129
129
81
81
81
82
83
84
84
15
124
125
126
127
129
130
131
82
82
82
83
84
85
85
16
125
126
127
129
130
131
132
82
82
83
84
85
85
86
17
125
126
127
129
130
131
132
82
83
83
84
85
85
86
Shown are 95th percentiles for blood pressure 14


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17.4
Appendix 4: Dosing table for children from birth to 18 years
Table 17–2
Body weight-adjusted rivaroxaban dosing schedule for children aged birth
to < 18 years
95    96
Body weight (kg)
Formulation
o.d. Dose
b.i.d. Dose
t.i.d. Dose
Total Daily 
Dose
Min
Max
2.6
<3
Oral suspension
0.8 mg
2.4 mg
3
<4
Oral suspension
0.9 mg
2.7 mg
4
<5
Oral suspension
1.4 mg
4.2 mg
5
<6
Oral suspension
1.6 mg
4.8 mg
6
<7
Oral suspension
1.6 mg
4.8 mg
7
<8
Oral suspension
1.8 mg
5.4 mg
8
<9
Oral suspension
2.4 mg
7.2 mg
9
<10
Oral suspension
2.8 mg
8.4 mg
10
<12
Oral suspension
3.0 mg
9 mg
12
<20
Oral suspension
5 mg
10 mg
20
<30
Tablet or oral 
suspension
5 mg
10 mg
30
<50
Tablet or oral 
suspension
15 mg
15 mg
≥ 50
Tablet or oral 
suspension
20 mg **
20 mg **
** 15 mg in Japan
Note: 
Dosing regimen, including dosing frequency, will be adjusted if the child’s body weight 
changes during the study.
                                                                                                                                      
95 The dosing table was updated via Amendment 8 (see Sections 16.2.2.23 and 16.2.2.24)
96 The dosing table was updated via Amendment 12 ( see Section 16.4.2.25)

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
Multicenter, open-label, active-controlled, randomized study to 
evaluate the efficacy and safety of body weight-adjusted rivaroxaban 
regimen compared to standard of care in children with acute venous 
thromboembolism 
NCT Number: 
NCT02234843 
Document Date: 
01-Mar-2019 
 


Statistical Analysis Plan
Protocol No.: BAY 59-7939/14372
Page: 1 of 35
Multicenter, open-label, active-controlled, randomized study to evaluate the 
efficacy and safety of body weight-adjusted rivaroxaban regimens 
compared to standard of care in children with acute venous 
thromboembolism
EINSTEIN Junior Phase III: oral rivaroxaban in children with venous thrombosis
Bayer study drug
BAY 59-7939/rivaroxaban/Xarelto
Clinical study 
phase:
III
Date:
01 Mar 2019
Study No.:
14372
Version:
3.0
Authors:
 (Versions 1.0, 2.0, 3.0)
 (Versions 2.0, 3.0)
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD
PPD


Statistical Analysis Plan
Protocol No.: BAY 59-7939/14372
Page: 2 of 35
Table of Contents
Table of Contents ..................................................................................................................... 2
Table of Tables ......................................................................................................................... 3
Abbreviations............................................................................................................................ 4
1.
Introduction....................................................................................................................... 5
2.
Study Objectives................................................................................................................ 6
3.
Study Design ...................................................................................................................... 6
3.1
Study population.............................................................................................................. 7
3.2
Treatment groups and regimens....................................................................................... 7
3.3
Outcomes ......................................................................................................................... 8
4.
General Statistical Considerations .................................................................................. 9
4.1
General Principles............................................................................................................ 9
4.2
Handling of Dropouts ...................................................................................................... 9
4.3
Handling of Missing Data................................................................................................ 9
4.3.1
General Rules ............................................................................................................... 9
4.3.2
Descriptive analyses for premature discontinuations................................................. 10
4.3.3
Imputing partial and completely missing dates.......................................................... 10
4.3.4
Imputation rules for thrombus burden assessment if repeated imaging was not 
performed or done outside of time window ............................................................... 11
4.3.5
Imputation rules for missing baseline body weight.................................................... 13
4.4
Interim Analyses and Data Monitoring ......................................................................... 13
4.5
Data Rules...................................................................................................................... 13
4.5.1
Baseline laboratory values.......................................................................................... 13
4.5.2
Compliance................................................................................................................. 14
4.5.2.1
Rivaroxaban ............................................................................................................ 14
4.5.2.2
LMWH or Fondaparinux......................................................................................... 14
4.5.2.3
Vitamin K antagonists............................................................................................. 14
4.5.3
Time definitions for the time to event analyses.......................................................... 15
4.6
Validity Review ............................................................................................................. 16
5.
Analysis Sets .................................................................................................................... 16
6.
Statistical Methodology .................................................................................................. 17
6.1
Population characteristics .............................................................................................. 17
6.1.1
Demographic and Baseline Characteristics................................................................ 17
6.1.2
Summaries of kidney function.................................................................................... 18
6.1.3
Description of the index venous thrombosis .............................................................. 19
6.1.4
Concomitant medication............................................................................................. 19
6.1.4.1
Anticoagulants that were prolonged or started after the main treatment period ..... 19
6.2
Study drug exposure and compliance ............................................................................ 20
6.2.1
Summary of treatment duration.................................................................................. 20
6.2.2
Summary of compliance............................................................................................. 20


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6.2.3
Summary of INR measurements for the VKA treatment ........................................... 20
6.3
Efficacy.......................................................................................................................... 20
6.3.1
Statistical models........................................................................................................ 21
6.3.2
Sensitivity analysis to account for dropouts............................................................... 22
6.4
Pharmacokinetics / pharmacodynamics......................................................................... 23
6.5
Safety ............................................................................................................................. 25
6.5.1
Adverse events............................................................................................................ 25
6.5.2
Adverse events of special interest .............................................................................. 25
6.5.3
Laboratory .................................................................................................................. 25
6.5.4
Bleeding analysis........................................................................................................ 26
6.5.4.1
Statistical models..................................................................................................... 27
6.6
Taste-and-texture questionnaire..................................................................................... 27
6.7
Pre-specified subgroup analysis..................................................................................... 28
6.8
Extrapolation of data obtained in adult patients with VTE treated with rivaroxaban to 
the setting of treatment of VTE with rivaroxaban in children....................................... 28
7.
Document history and changes in the planned statistical analysis............................. 29
8.
References ........................................................................................................................ 30
9.
Appendix.......................................................................................................................... 32
9.1
Sample size and power considerations .......................................................................... 32
9.2
Example OpenBUGS code for sensitivity analysis of the primary efficacy outcome to 
account for Dropout....................................................................................................... 33
9.3
Adverse events of special interest.................................................................................. 33
9.3.1
Potential treatment-emergent AESIs .......................................................................... 33
9.3.2
Suspected or confirmed AESIs................................................................................... 34
9.4
Reference values for kidney function classification...................................................... 34
9.5
Bleeding site categorization........................................................................................... 35
Table of Tables
Table 4–1. Overview of repeated imaging categories from the CIAC and the imputation rules 
for if repeated imaging was not performed or done out of time window.............. 12
Table 4–2. Categorization of the thrombus burden assessment at the repeated imaging after 
imputation.............................................................................................................. 13
Table 4–3. Time to event and time to censoring...................................................................... 16
Table 9–1. Number of subjects to be randomized depending on the hazard rate of the 
recurrent VTE........................................................................................................ 32
Table 9–2. Reference values for serum creatinine in different subgroups............................... 34
Table 9–3. Bleeding site grouping of confirmed bleedings ..................................................... 35


Statistical Analysis Plan
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Abbreviations
ADS
Analysis dataset
AE
adverse event
AESI
adverse event of special interest
AG
Aktiengesellschaft, joint stock company
ALT
alanine aminotransferase
BAY
sponsor’s reference number for drugs
b.i.d.
twice daily
CIAC
central independent adjudication committee 
CKD
chronic kidney disease
Cmax
maximum drug concentration in measured matrix,
Cmax,ss
maximum drug concentration at steady state during a dosage interval
CSR
Clinical Study Report
CT
Ctrough
CVC
CVST
computed tomography
drug concentration in measured matrix at the end of the dosing interval,
central venous catheter
cerebral vein and sinus thrombosis
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
IEC
Independent Ethics Committee
INR
international normalized ratio 
IRB
Institutional Review Board
ITT
Intent-to-treat
IxRS
interactive voice/web response system
LMWH
low molecular weight heparin
LOS
listing only set
MCMC
Monte Carlo Markov Chain
MedDRA
Medical Dictionary for Regulatory Activities


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mg
Milligram
min
Minute
ml
Milliliter
mmHg
millimeter of mercury
MR(I)
magnetic resonance (imaging)
NI
non-inferiority
o.d.
once daily
PD
Pharmacodynamics
PE
pulmonary embolism
PK
pharmacokinetic(s)
SAE
serious adverse event
SAP
statistical analysis plan
SOC
standard of care 
tmax
time to reach Cmax,ss
UFH
unfractionated heparin
VKA
vitamin K antagonist
VTE
venous thromboembolism
1.
Introduction
This SAP is based on the following study protocol versions:

Original protocol, Version 1.0, dated 12 Mar 2014

Amendment 1 (local amendment Japan), dated 21 Oct 2014

Amendment 2 (local amendment Canada), dated 28 Oct 2014

Amendment 3 (local amendment Germany), dated 02 Dec 2014

Amendment 4 forming integrated protocol Version 2.0, dated 21 Jul 2015

Amendment 5 (local amendment Canada), dated 21 Jul 2015

Amendment 6 (local amendment Japan), dated 28 Jul 2015

Amendment 7 (local amendment Canada), dated 20 Oct 2015

Amendment 8 forming integrated protocol Version 3.0, dated 20 Sep 2016

Amendment 9 (local amendment Canada), dated 20 Dec 2016

Amendment 10 forming integrated protocol Version 4.0, dated 11 Jan 2017

Amendment 11 (local amendment Japan), dated 07 Mar 2017

Amendment 12 forming integrated protocol version 5.0, dated 27 Sep 2017.

Amendment 13 (local amendment Japan), dated 14 Nov 2017

Amendment 14 (local amendment Turkey), dated 19 Dec 2017

Amendment 15 (local amendment Japan), dated 10 Jan 2018

Amendment 16 (local amendment Spain), dated 03 Apr 2018


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
Amendment 17 (local amendment Germany), dated 04 May 2018
“The goal of the rivaroxaban pediatric program is to make rivaroxaban available to children 
for treatment and secondary prevention of venous thromboembolism (VTE). It is anticipated 
that similar exposure in children, as compared to adults, will result in a similar safety and 
efficacy profile in children.” (study protocol, Section 1).
For more details see study protocol, Section 1. 
2.
Study Objectives
According to the study protocol version 5.0, Section 2:
The efficacy objectives are:

To assess the incidence of symptomatic recurrent VTE

To assess the incidence of symptomatic recurrent VTE and asymptomatic 
deterioration on repeat imaging at the end of main treatment period 
The safety objective is:

To assess the incidence of overt major and clinically relevant non-major bleeding.
Other objectives are:

To characterize the pharmacokinetic (PK) / pharmacodynamics (PD) profile of 
rivaroxaban
Note that the main treatment period is Month 1, Day 30 ± 7, for children from birth to <2 
years with CVC-VTE (central venous catheter venous thromboembolism), for other children 
Month 3, Day 90 ± 7.
3.
Study Design
This is a multicenter, open-label, active-controlled, randomized study to evaluate the efficacy 
and safety of body weight-adjusted rivaroxaban regimens in children with acute VTE.
Children aged birth to <18 years with confirmed acute VTE who received initial treatment 
with therapeutic dosages of unfractionated heparin (UFH), low molecular weight heparin 
(LMWH), or fondaparinux are potentially eligible for the study. Initial treatment with UFH, 
LMWH or fondaparinux will be administered for at least 5 days. Randomization can be done 
during the first 9 days of initial treatment and will be in a 2 (rivaroxaban): 1 (comparator) 
fashion. Note that comparator can also mean comparator administered with standard of care.
After randomization, all children, except those aged < 2 years with CVC-VTE, will receive 
either study medication with rivaroxaban or comparator for a (main study treatment) period of 
3 months. After the main study treatment period of 3 months, the diagnostic imaging test 
which was obtained at baseline will be repeated, if clinically feasible, and the decision will be
made by the investigator to stop study treatment or to continue for an additional 3 months. In 
children who completed 6 months of treatment, the decision will be made to stop study 


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treatment or to continue for an additional 3 months. Then, in children who completed 9 
months of treatment, the decision will be made to stop study treatment or to continue for an 
additional 3 months. Regardless of the duration of study treatment (3, 6, 9 or 12 months), an 
additional 1-month post-treatment observational period will be completed for all children. 
After cessation of study treatment, it will be at the investigator’s discretion to continue with 
anticoagulants.
In children aged < 2 years with CVC-VTE, the main study treatment period is 1 month. After 
that, it is at the discretion of the investigator to stop study treatment or to continue for an 
additional 1 month. In children who completed 2 months of treatment, the decision can be 
made to stop study treatment or to continue for an additional 1 month. 
All suspected clinical study outcomes and baseline and repeat thrombosis imaging tests will 
be assessed by a central independent adjudication committee (CIAC) blinded to treatment 
allocation. An independent data monitoring committee (DMC) will monitor the children’s 
safety and give recommendations to the steering committee.
For further details see study protocol version 5.0, Section 3.
3.1
Study population
At least 170 children are needed for this study, 80 in the age group 12 to < 18 years, 30 in the 
age group 6 to < 12 years, 20 in the age group 2 to < 6 years, and 20 in the age group birth 
to < 2 years, with at least 12 aged birth to < 0.5 years.
Children aged birth to < 18 years with confirmed VTE who receive initial treatment with 
therapeutic dosages of UFH, LMWH or fondaparinux and require anticoagulant therapy for at 
least 90 days will be included. However, for children with CVC-VTE who are younger than 2 
years, the required minimum duration of anticoagulant therapy is at least 30 days.
For further details, see study protocol version 5.0, Section 4.
For further sample size and power consideration, see Appendix, section 9.1.
3.2
Treatment groups and regimens
Allocation to treatment will be done centrally by an interactive voice /web response system 
(IxRS). Allocation will be done in a 2 (rivaroxaban) to 1 (comparator) fashion and it will be 
stratified by two types of baseline presentation of venous thrombosis as diagnosed by the 
investigator and entered in the IxRS (for more details see section 5.1 of the study protocol) for 
each age group, separately.
All children randomized to the rivaroxaban group before implementation of protocol 
amendment 10 received tablets in the 12 to < 18 years age group. Rivaroxaban was provided 
with the option of tablets or oral suspension for the 6 to < 12 years age group, and as oral 
suspension for children younger than 6 years.
According to protocol amendment 10, children with body weight of ≥ 30 kg will be treated 
according to a once daily (o.d.) regimen, irrespective of whether they receive rivaroxaban 
tablets or oral suspension. Children with body weight between 12 and < 30 kg will receive 
rivaroxaban twice daily (b.i.d) with a dosing intervals of approximately 12 hours, although 


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children with body weight between 20 and <30 kg enrolled prior to protocol amendment 8 
will receive rivaroxaban o.d. Children with body weight below 12 kg will receive rivaroxaban 
three times daily (t.i.d.) with dosing interval of approximately 8 hours. Dosing regimen, 
including dosing frequency, will be adjusted if the child’s body weight changes during the 
study. For further details regarding dosing, see section 5.1.1 and Appendix 4 of the study 
protocol version 5.0. Children randomized to the comparator group will continue with UFH, 
LMWH or fondaparinux or may switch to VKA therapy.
For further details, see study protocol version 5.0, Section 5.
3.3
Outcomes

The primary efficacy outcome is composite of symptomatic recurrent VTE;

The secondary efficacy outcome is the composite of symptomatic recurrent VTE and 
asymptomatic deterioration in thrombotic burden on repeat imaging at the end of the 
main treatment period

Further efficacy outcomes:
o
Composite of symptomatic recurrent VTE and major bleeding 
o
Composite of symptomatic recurrent VTE and asymptomatic deterioration and 
no change in thrombotic burden assessment on repeat imaging at the end of the 
main treatment period 
o
Composite of symptomatic recurrent VTE and thrombotic burden assessment 
at repeated imaging at the end of the main treatment period (symptomatic 
recurrent VTE, asymptomatic deterioration, no relevant change, uncertain, 
improved, normalized).
o
Normalization of thrombotic burden assessment on repeat imaging at the end 
of the main treatment period without confirmed symptomatic recurrent VTE 
o
Fatal or non-fatal pulmonary embolism 
o
Composite of symptomatic recurrent VTE and other clinically significant 
thrombosis

The principal safety outcome is the composite of overt major and clinically relevant 
non-major bleeding. 

Further safety outcomes
o
Death
o
Other vascular events (arterial thrombotic complications i.e. myocardial 
infarction, ischemic stroke, cerebrovascular accident, non-CNS systemic 
embolism)
o
Major bleeding
o
Clinically relevant non-major bleeding


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o
Trivial bleeding
For further details, see sections 6.10 and 6.13 of the study protocol version 5.0
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 using other statistical software as applicable.
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.
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 (for all children except children 
aged < 2 years with CVC-VTE, see study flow chart on Table 0-1 of the study protocol
version 5.0, for children aged < 2 years with CVC-VTE, see study flow chart on Table 0-2 ). 
Randomized children who have not received the study drug will be seen (visit or phone 
contact) at the end of the respective study treatment period. Children who prematurely 
discontinue study drug will be seen at the end of the intended study treatment period (for 
children from birth to < 2 years with CVC-VTE at Month 1, for other children at Month 3, 6, 
9 or 12). 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 (for all 
children except children aged < 2 years with CVC-VTE see study flow chart on Table 0-1 of 
the study protocol, for children aged < 2 years with CVC-VTE see study flow chart on Table 
0-2 of the study protocol).
For further details about collecting data from children who prematurely discontinue study 
medication see study protocol version 5.0 section 7.10.
4.3
Handling of Missing Data
4.3.1 General Rules
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 missing values including laboratory values at baseline and post-baseline visits, 
number of missing weight values and missing values in other relevant variables will be 
displayed by means of descriptive statistics by treatment group to explore potential missing 
data imbalance in these variables.


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For PK/PD data, individual listings of the subjects with missing data will be provided by age 
groups, regimen and formulation. All subjects with unscheduled visits will be also be listed 
for all visits separately for PK and PD data. Duplicate records identified by PCTRTV will not 
be analyzed.
4.3.2 Descriptive analyses for premature discontinuations
The number of subjects who prematurely discontinue study treatment and/or the study for any 
reason, as well as the reasons for premature discontinuation of study treatment and study by 
treatment group will be reported for the main treatment period, extended treatment period and 
intended treatment period. The denominators will be number of patients in the Safety set for 
the main treatment period and number of patients who entered the extended treatment period 
respectively for calculating the percentages of subjects who discontinue.
Baseline characteristics will be summarized descriptively by completers (defined in Section 
4.5.3) versus non-completers. For details on baseline characteristics, please see Section 6.1.1.
4.3.3 Imputing partial and completely missing dates
If appropriate, the following rules will be implemented so as not to exclude subjects from 
statistical analyses due to missing or incomplete data:

Efficacy and Safety outcomes
If there is no evidence from the incomplete event date that the event occurred 
definitely earlier than start of study medication/randomization then for cases where 
start month and year are reported but day is missing, impute the maximum of (date of 
randomization, first date of study medication, 01.month.year). For cases where only 
start year is reported, impute the maximum of (date of randomization, first date of 
study medication, 01.01.year). For events with complete missing date impute the 
maximum of (date of randomization, first date of study medication).

Adverse events
A missing or partial start date for an adverse event will be imputed with the same rules 
as above for efficacy and safety outcomes

Start and stop date of study medication from the exposure dataset for subjects
who took study medication
Start date
If the start day of study medication is missing in the rivaroxaban arm, then the start 
date will be imputed as the maximum of (date of randomization, 01.month.year). 
Otherwise, if start month is also missing, then the start date will be imputed with the 
date of randomization.
In the comparator arm, the start date will simply be the randomization date.
Stop date
If stop date is missing or partial and there is an adverse event with action taken ‘drug 
withdrawn’, then the stop date of study medication will be imputed by the start date of 
that adverse event. Otherwise the stop date will be imputed with the latest of (date of 
last study medication dispense, start date of the study medication period, 1st day of the 


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stop month if month and year are available, 1st June if stop year is available only), but 
not later than the death date if the patient died.

Stop date of initial treatment 
If the stop date of initial treatment is missing due to subject withdrawal, then the stop 
date will not be imputed and simply be indeterminate. 

Stop date of any anticoagulant therapy including those started within 7 days after 
the actual stop of main study treatment period
For anticoagulants that started within 7 days after the actual stop of main study 
treatment period, a missing stop date will be imputed with the start date of the 
subsequent anticoagulant, if administered. Otherwise, if other anticoagulant was not 
administered subsequently, the stop date will be imputed with the latest of (stop date 
of study medication + 1, start date of the anticoagulant+1, 1st day of the stop month, if 
month and year are available, 1st June, if stop year is available only), but not later than 
the death date, if the patient died. Anticoagulants that started within 7 days after the 
actual stop of main study treatment period and reported by the investigator as 
“continued after study” do not have a stop date. In such cases, the stop date will be 
imputed with the last contact date for calculations.
4.3.4 Imputation rules for thrombus burden assessment if repeated imaging was 
not performed or done outside of time window
Table 4–1shows thrombus burden assessment categories from the CIAC and categorization, if 
repeated imaging was not performed or done out of time window. Table 4–2summarizes the 
categorization after imputation. The analysis will be performed based on that order of the 
categories. The CIAC will select the relevant repeated imaging by patient in case of multiple 
imaging at the end of the main treatment period.


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Table 4–1. 
Overview of repeated imaging categories from the CIAC and the imputation rules 
for if repeated imaging was not performed or done out of time window
Repeat imaging
Status of anticoagulant therapy
Thrombus burden assessment 
categories
Performed in time window, 
assessment is either
normalized, improved,
unchanged or deteriorated*
Not applicable
Accept adjudication outcome
Performed before time 
window, assessment is 
either normalized,
improved, unchanged or 
deteriorated*
If any anticoagulation** stopped at 
the time of imaging (+ 7 days)
Accept adjudication outcome 
Performed before time 
window, assessment is 
either normalized,
improved, unchanged or 
deteriorated*
If any anticoagulation** continued 
for >7 days after repeat imaging 
Classify outcome as “uncertain”
Performed after time 
window, assessment is 
either normalized,
improved, unchanged or 
deteriorated*
Not applicable
Classify as “uncertain”
Not performed or 
assessment is not 
evaluable
If any anticoagulation** stopped 
before main treatment time 
window&
Classify as “uncertain”
Not performed or 
assessment is not 
evaluable
If any anticoagulation** stopped 
during main treatment time window&
Classify as “improved”
Not performed or 
assessment is not 
evaluable
If any anticoagulation** is continued 
after main treatment time window&
Classify as “uncertain”
Confirmed symptomatic 
recurrent venous 
thromboembolism+ 
Not applicable
Classify as “recurrent VTE”
*Time window for repeat imaging relative to randomization: Day 90±21 (or Day 30±7 for children with 
CVC-VTE younger than 2 years).
**Any anticoagulation defined as anticoagulant therapy with either study medication or non-study 
anticoagulation with either direct factor Xa inhibitors, direct thrombin inhibitors, unfractionated or 
low molecular weight heparin (except mucopolysaccharide polysulfuric acid ester), fondaparinux, 
or a vitamin K antagonist. Non-study anticoagulant therapy counted if started within 7 days after 
stop of study medication with a duration of at least 7 days (subsequent therapies will also be 
considered).
&Time window for stop of study medication relative to randomization: Day 83-97 (or Day 23-37 for 
children with CVC-VTE younger than 2 years).
+regardless of availability of repeat imaging, up to the upper limit of the end of main treatment time 
window, see section 4.5.3.


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Table 4–2. 
Categorization of the thrombus burden assessment at the repeated imaging after 
imputation
Category
Source
Normalized
Adjudication by the CIAC
Improved
Adjudication by the CIAC or derived by algorithm
Uncertain
Derived by algorithm
Unchanged
Adjudication by the CIAC
Deteriorated including recurrent VTE
Adjudication by the CIAC
Note: The analysis will be performed based on the above order of the categories.
4.3.5 Imputation rules for missing baseline body weight
For subjects whose weights have not been recorded at baseline, the following imputation 
strategy will be implemented:

If available, the weight recorded in the study drug exposure form will be used

For subjects with any recorded dose of enoxaparin, the baseline weight will be 
calculated based on the total daily enoxaparin dose divided by 1.5 if a once daily 
regimen was used and divided by 2.0 if a twice-daily regimen was used

For all other subjects, the weight recorded at any other visit will be used.
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 VTEs and 
bleedings. Organizational aspects, responsibilities, and processes will be described in the 
DMC charter. 
4.5
Data Rules
4.5.1 Baseline laboratory values
Hemoglobin (Hb), platelets, creatinine, alanine aminotransferase (ALT), total and direct 
bilirubin taken for the screening visit (visit 1) will be considered for the baseline. If a blood 
creatinine value is not available up to randomization, the value from the sample taken no later 
than 14 days after randomization will be considered. In case of more than one available lab
value the non-missing value closest to randomization will be taken. If the estimated 
glomerular filtration rate (eGFR) was not calculated, 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 study protocol version 5.0 Appendix 17.2, if all other 
required measurements (gender, age, height) are available. In children younger than 1 year, 
serum creatinine levels will be considered instead of eGFR.


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4.5.2 Compliance
4.5.2.1
Rivaroxaban 
For the tablet formulation, the visit compliance will be calculated as number of tablets taken 
divided by number of tablets to be taken between the two visits considering b.i.d. or o.d. 
regimen. In addition, overall compliance will be calculated for the main treatment period as
total number of tablets taken divided by the total number of tablets to be taken between the 
first intake and last intake dates in the main treatment period.
For the suspension formulation, the visit compliance will be calculated as volume of 
suspension taken divided by volume of suspension to be taken between the two visits 
considering required dose (volume) given the weight of the child and o.d., b.i.d. or t.i.d
regimen. In addition, overall compliance will be calculated for the main treatment period as 
total volume of suspension taken divided by the total volume of suspension to be taken 
between the first intake and last intake dates in the main treatment period.
4.5.2.2
LMWH or Fondaparinux
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 main 
treatment period as total number of syringes administered divided by the total number of 
syringes to be administered between the first intake and last intake dates in the main treatment 
period for those countries where study medication provided centrally 
(France, Italy, Poland, Belgium, Spain, Japan, Austria, Russia, Turkey). In all other 
countries, LMWH or fondaparinux study medication is supplied locally, i.e. no drug 
accountability will be available, but the parents’ statement about compliance will be entered 
as comment.
4.5.2.3
Vitamin K antagonists
The study protocol states that at least one international normalized ratio (INR) measurement is 
required per two weeks, if the INR is stable in therapeutic range (INR 2 to 3). If the INR is 
out of therapeutic range, INR monitoring should be performed more frequently per 
investigators’ discretion. 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 19 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 80, his 5th period had a relative 
length of (80-4*19)/19=0.21). 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 4.21 (i.e. less than 5 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. 


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4.5.3 Time definitions for the time to event analyses
Individual intended end of main study treatment period
According to the protocol version 5.0, the following time window limit per patient will be 
applied as follows based on predefined main treatment duration 
All children except children aged < 2 years with CVC-VTE
a) If the last treatment visit day was less than 90-7=83 then events up to Day 83 will be 
considered.
b) If the last treatment visit day was between Day 83 and Day 97, then events up to the visit 
day will be considered.
c) If the last treatment visit day was later than Day 97, then events up to Day 97 will be 
considered.
Children aged < 2 years with CVC-VTE
a) If the last treatment visit day was less than 30-7=23, then events up to Day 23 will be 
considered.
b) If the last treatment visit day was between Day 23 and Day 37, then events up to the visit 
day will be considered.
c) If the last treatment visit day was later than Day 37, then events up to Day 37 will be 
considered.
Main treatment period completer: patient who was on study medication until the lower limit 
of the scheduled main treatment period or who had the last treatment visit or last vital status 
collected not earlier than the end of main treatment, as given in under a), b) or c) in the 
respective scenarios.
For an event contributing to the following time-to-event variables, the time windows are 
defined in Table 4–3:

symptomatic recurrent VTE

composite of overt major and clinically relevant non-major bleeding. 

composite of symptomatic recurrent VTE and major bleeding 

composite of symptomatic recurrent VTE and other clinically significant thrombosis


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Table 4–3. Time to event and time to censoring
Event or censoring up to 
the end of the main 
treatment period
On Treatment 
Treatment-emergent 
event or censoring up 
to two days after last 
intake of study 
medication, but not later 
than the end of the main
treatment period
On Treatment
Treatment-emergent 
event or censoring up 
to two days after last 
intake of study 
medication
Reference date
Randomization2
Randomization2
Randomization2
Subjects with 
an event of 
interest
Events occurring until the 
end of main treatment 
period1 described above 
calculated per subject.
Events occurring up to 
two days after last intake 
of study medication, but 
not later than the end of 
main treatment limit1 per 
subject. 
Events occurring up to 
2 days after stop of 
medication
Censoring date 
for subjects 
without an 
event of 
interest
Minimum of 
- [last visit date of the 
subject]
- [end of main treatment 
limit1)]
Minimum of 
- [last visit date of the 
subject]
- [end of main treatment 
limit1)]
- [days up to last study 
treatment +2 days]
Minimum of 
- [last visit date of the 
subject]
- [days up to last study 
treatment +2 days]
1)
For end of main treatment limit, see definitions above in this section. If a subject died due to 
another reason, the censoring date cannot be later than death date.
2)
Bleeding events with onset on the day of randomization are considered only if the 
investigator stated that the event was related to study medication.
4.6
Validity Review
The results of the Validity Review Meeting will be documented in the Validity Review 
Report and may comprise decisions and details relevant for statistical evaluation. Any 
relevant changes to the statistical analysis prompted by the results of the validity review 
meeting might be documented in an amendment or, if applicable, in a supplement to this SAP.
5.
Analysis Sets
Final decisions regarding the assignment of subjects to analysis sets will be made during the 
Validity Review Meeting and documented in the Validity Review Report (see section 4.6).
Full analysis set (FAS): this population will include all randomized children. 
Safety analysis set (SAF): this population will include all randomized children who received 
at least one dose of study medication. 


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Per-protocol set (PPS): this population will include all FAS children without major protocol 
deviations. The detailed list of these deviations will be finalized prior to database lock and 
included in the protocol deviation document and SAP. 
Listing-only set (LoS): this population includes all screening failures, i.e. all children with 
valid informed consent who were not randomized.
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)
6.
Statistical Methodology
6.1
Population characteristics
Summary statistics (arithmetic mean, standard deviation, median, minimum and maximum for 
quantitative variables) will be presented in total and by treatment. Frequency tables for 
qualitative data will be provided. Medical history findings will be summarized using Medical 
Dictionary for Regulatory Activities (MedDRA) Primary System Organ Class / High Level 
Term. Concomitant medication will be displayed using WHO-DD. No statistical tests will be
performed to compare these characteristics across treatment groups. 
6.1.1 Demographic and Baseline Characteristics
The following baseline characteristics will be summarized overall and by age groups, weight 
groups (seven level grouping), formulation assignment and presentation of index event 
(subgroups are defined in Section 6.6):
Demographics
o
Sex
o
Race
o
Ethnicity
o
Weight
o
Height
o
BMI (<25 kg/m2,  25-35 kg/m2, >35 kg/m2)
o
Kidney function – for details see section 6.1.2


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Clinical characteristics
o
Classification of index event (confirmed; unconfirmed/unknown)
o
Presentation of index event by location (split by all CVST, CVC-VTE, non-
CVC-VTE) – for details see section 6.1.3
o
Was the index event a recurrent episode of venous thrombosis? (yes; no)
o
Was the index event symptomatic? (yes; no; unconfirmed/unknown)
o
Risk factors (provoked thrombosis by persistent risk factor, provoked 
thrombosis by persistent and transient risk factors, provoked thrombosis by 
transient risk factor, unprovoked, unconfirmed/unknown)
A substudy will be conducted on patients with baseline CVST. The details will be discussed 
in a separate technical document. 

Initial treatment
Type of initial treatment of the index event will be summarized by the following:
o
Overview of initial treatment with UFH, LMWH or fondaparinux and 
thrombolytic drugs and/or thrombectomy 
Initial anticoagulant or thrombolytic treatment by medication type.The duration of initial 
treatment up to the start of study medication will be summarized by descriptive statistics in 
the treatment arm only.
6.1.2 Summaries of kidney function
Descriptive statistics will be provided for serum creatinine levels in mg/dL for all data 
combined and for each age cohort. Number of patients aged  ≥1 year will be summarized by 
the following categories of kidney function based on the estimated GFR (for formulas, see the 
study protocol):
o
normal kidney function (≥ 80 mL/min/1.73m2)
o
mild kidney dysfunction (50 to <80 mL/min/1.73m2)
o
moderate kidney dysfunction (30 to <50 mL/min/1.73m2)
o
severe kidney dysfunction (< 30 mL/min/1.73m2)
In children < 1 year, since the GFR cannot be accurately calculated and comparable GFR 
categories do not exist, the following categories based on creatinine would be merged into 
those based on the estimated GFR as follows [15]:
o
the <90th percentile group for creatinine into the eGFR >80ml/min/1.73m2
(normal kidney function)
o
the 90-97.5th percentile group for creatinine into the eGFR 50-80
ml/min/1.73m2 (mild kidney dysfunction)


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o
>97.5th percentile group for creatinine into the eGFR 30-50 ml/min/1.73m2
(moderate kidney dysfunction)
The percentiles depend on the age at which creatinine was measured and are given in the 
appendix, Table 9–2, taken from [15].
6.1.3 Description of the index venous thrombosis
The CIAC will categorize the index venous thrombosis of each patient to one of the following 
location groups:

Lower extremity

Caval vein

Portal vein

Renal vein

Right side of the heart

Lung

Upper extremity

Jugular vein

Cerebral vein or sinus

Mesenteric vein
Moreover, the CIAC will specify whether the relevant index venous thrombosis was catheter-
related on non-catheter related.
Using the categorizations by CIAC and the above locations, there will be three main groups: 
- CVST, 
- CVC-VTE, 
- non-CVC-VTE.
Index event locations of subjects with unconfirmed/unknown index events will be listed.
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
Anticoagulants that were prolonged or started after the main treatment 
period
Any anticoagulant therapy with either study medication or non-study medication with either 
direct factor Xa inhibitors, direct thrombin inhibitors, UFH, or LMWH (except 
mucopolysaccharide polysulfuric acid ester), fondaparinux, or a VKA will be considered. 
Non-study anticoagulant therapy will be counted, if it started within 7 days after end of main 
treatment. Subsequent therapies will also be considered.
Number of subjects who had any anticoagulant treatment within 7 days after end of main 
treatment period with a duration of at least 7 days will be displayed by treatment group.


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Subjects for whom the investigator stopped the main study treatment up to the main treatment 
end visit and did not start any concomitant anticoagulant will not be considered as having 
extended anticoagulation, even if the main study treatment visit took place later than defined 
in the study protocol.
6.2
Study drug exposure and compliance
The descriptive statistics in this section will be done for all data combined and for each age 
group.
6.2.1 Summary of treatment duration
The overall treatment duration (date of last study medication-date of randomization+1 day) up 
to the end of the extended treatment period (mean, SD, minimum, quartiles, median, 
maximum) as well as the cumulative durations will be summarized by treatment group in the 
safety analysis set and in the per protocol analysis set.
6.2.2 Summary of compliance
The compliance calculation is based on tablet counts or on the volume of suspension taken for 
the rivaroxaban group, and on number of syringes of LMWH administered or on the 
frequency of INR measurements during VKA treatment in the comparator group. Due to this 
fundamental differences, the actual percentage compliance values are not fully comparable 
between the 2 treatment groups. Hence, only the following compliance categories will be 
compared between treatment groups in the per protocol set and safety analysis set:
Missing, Compliance <50%, Compliance ≥50% to <80%, Compliance ≥80%.
6.2.3 Summary of INR measurements for the VKA treatment
The INR values will be described (mean – SD) biweekly for the main treatment period. 
Proportion of patients with average INR<2, within 2 to 3 INR inclusive and INR>3 will be 
summarized biweekly using the observed INR values during the main treatment period (2 day 
window inclusive). Multiple INR measurements observed on the same day will be first 
averaged, and the average value for the day will contribute to the patient-specific average. 
The time intervals will be specified using the day of measurement relative to the first VKA 
dose after initial treatment. 
6.3
Efficacy
All efficacy analyses will be performed on the FAS, SAF and PPS populations based on the 
outcomes specified in section 3.3 and confirmed by the CIAC. Incidence proportions will be 
calculated for the efficacy outcomes by treatment group at the end of the main treatment 
period for the combined data over all children and by classification of index event. 
Cumulative incidences (time to first event; Kaplan-Meier, Kalbfleisch and Prentice, 7) will be 
calculated for the primary efficacy outcome and for the composite of all symptomatic 
recurrent VTE and major bleeding by treatment group at the end of the main study treatment 
period for pooled data over all children. Kaplan-Meier estimates beyond 1 month are 
applicable for those children who are planned to be treated for 3 months in the main treatment 


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period. In addition, incidence proportions will be calculated for each age stratum, weight 
group (seven level grouping), dosing formulation assignment at the end of the main treatment 
period for SAF and PPS populations and by presentation of index event (for children <2 years 
with CVC-VTE separately as well). Incidence proportions will be calculated for the primary 
outcome by treatment group for each age stratum, and pooled data excluding children <2 
years with CVC-VTE in the extended study treatment period at 6, 9 and 12 months. Counts of 
composite of symptomatic recurrent VTE and thrombotic burden assessment at repeated 
imaging at the end of the main treatment period will be reported by classification and 
presentation of index event. The counts will also be calculated for subjects with 
anticoagulants that were prolonged after the main treatment period versus subjects that 
without any anticoagulants after the main treatment period. Incidence proportions in the 
extended treatment period for children <2 years with CVC-VTE will be presented separately 
at 2 and 3 months. Denominators will be the number of patients at risk at the start of the 
respective period. 
Two-sided 95% confidence intervals for the frequency efficacy outcomes will be calculated 
by applying the method of Blyth-Still-Casella [13, 14]. For time-to-event analyses, the 
censoring mechanism will be assumed to be non-informative. The analyses described above 
will include events up to the end of study periods per subject regardless of the actual stop date 
of study medication. For details of time to event and time to censoring see section 4.5.3.
Events that occurred more than 2 days after stop of study medication up to 30 days will be 
listed.
For further subgroups and pools see section 6.7.
6.3.1 Statistical models
Although the study is not designed to test a hypothesis regarding comparing incidences of 
outcomes between rivaroxaban versus comparator with standard of care, exploratory stratified 
(strata: CVST, CVC-VTE, non-CVC-VTE) Cox proportional hazards models will be fitted for 
the primary efficacy outcome and for the composite of all symptomatic recurrent VTE and 
major bleeding. In addition, Cox proportional hazards models will be fitted separately for the 
subgroups CVST, CVC-VTE and non-CVC-VTE for the primary efficacy outcome and for 
the composite of all symptomatic recurrent VTE and major bleeding. As it is expected that in 
some strata the number of events will be low, Firth’s penalized maximum likelihood 
estimation will be used to reduce bias in the parameter estimates. Point estimates for hazard 
ratios, confidence intervals (obtained with profile-likelihood function) and p-values for the 
treatment effect will be reported. No hazard ratio will be calculated if no event occurred in a 
treatment group.
Logistic regression models will be fitted for the binary secondary and other efficacy outcomes 
(composite of symptomatic recurrent VTE and asymptomatic deterioration in thrombotic 
burden on repeat imaging, composite of symptomatic recurrent VTE and asymptomatic 
deterioration and no change in thrombotic burden assessment on repeat imaging, 
normalization of thrombotic burden assessment on repeat imaging; for more details see 
section 3.3) for the main treatment period to compare incidences between treatment groups.


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In addition, absolute risk differences (differences in incidence proportions) for the primary,
secondary and further efficacy (composite of symptomatic recurrent VTE and major bleeding; 
composite of symptomatic recurrent VTE and asymptomatic deterioration and no change in 
thrombotic burden assessment on repeat imaging at the end of the main treatment period; 
normalization of thrombotic burden assessment on repeat imaging at the end of the main 
treatment period without confirmed symptomatic recurrent VTE; composite of symptomatic 
recurrent VTE and other clinically significant thrombosis) outcomes for the main treatment 
period will be calculated between rivaroxaban minus comparator overall, by age group, 
weight group (seven level grouping), dosing formulation assignment and by presentation of 
index event (for children <2 years with CVC-VTE separately as well) with unstratified exact 
method using the standardized test statistic and inverting a two-sided test [9] as exploratory 
analysis. The software StatXact will be used for the calculation of the exact confidence 
intervals.
The ordered categories of thrombotic burden assessment at the end of main treatment period 
after imputations as described in section 4.3.4 will be compared between treatment groups 
with the nonparametric test by van Elteren [11, 12] for stratified ordinal response data (this 
test is an extension of Wilcoxon's rank-sum test). Strata will be presentation of index event 
(CVST, CVC-VTE, non-CVC-VTE). In addition, the thrombotic burden assessment at the 
end of main treatment period will be compared between treatment groups by fitting 
proportional odds models:
	
 =  

 =  + 
where 
αj are 4 intercepts comparing 4 ordered categories of thrombotic burden assessment at the end 
of the main treatment period comparing with the selected baseline;
x is the matrix for the factors treatment group, presentation of index event (3 groups) for the 
subjects;
β is the corresponding log odds ratio parameters to be estimated.
One can compare the treatment groups by calculating odds ratios using different cutpoints, for 
example normalized versus not normalized, normalized+improved versus the rest etc, see 
cutpoints in section 4.3.4. The constraint placed on the proportional odds is that the odds ratio 
for treatment groups is constant over the cutpoints [10] i.e. the model can be interpreted as 
“average up" over all possible cutpoint models to maximize the amount of information one 
can get out of the data. The result from the proportional odds model is the odds ratio of 
improving of the thrombotic burden between the rivaroxaban and comparator treatment 
groups. If the proportional odds assumption is likely violated (p<0.10), the odds ratios for 
different cutpoints will be presented. Subjects with not available, not evaluable or out of time 
window will be listed including location of the index venous thrombosis and its imaging 
method(s) together with their imputed assessment according to section 4.3.4. 
6.3.2 Sensitivity analysis to account for dropouts
Sensitivity analyses will be performed in order to evaluate the potential influence of dropouts 
on the incidence of the primary efficacy outcome for the main treatment period including 


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patients having scheduled 3 months of study treatment (i.e. except children <2 years with
CVC-VTE where the main treatment period is 1 months). In these analyses subjects with 
premature termination before the end of intended main treatment period (no follow-up until 
Month 3 defined as Day 83, until Month 1 as Day 23, see section 4.5.3) 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 each 
treatment group separately. This method is an application of methods for informative 
missigness odds ratio (IMOR) by White et al [8].

tj,i ~ exp(hnon-informative,i)
Pnon-informative, j, i = 1-e-( tj,i ∙hnon-informative,i )
hdropout,i = hnon-informative,i ∙IMHR 
Pdropout, j,i = 1-e-([83-tj,i] ∙hdropout,i)
Poverall, j, i = min(1, Pnon-informative, j, i + Pdropout, j,i)
Poverall, mean, i = mean(Poverall, j, i)i
where
tj,i: event times (or censoring) of patient j in treatment group i.
hnon-informative,i: hazard of the primary efficacy outcome assuming non-informative 
censoring using all patients’ data in treatment group i.
Pnon-informative, j, i: the cumulative event probability at Day 83 or at censoring calculated 
based on the exponential model for patient j in treatment group i.
hdropout,i: hazard of the primary efficacy outcome after dropping out in treatment group i.
Pdropout, j, i: the assumed worse case (defined in scenarios) cumulative event probability at 
from censoring up to Day 83 calculated from the exponential model for patient j in 
treatment group i.
Poverall, mean, i: mean of the cumulative event probability in treatment group i.
IMHR: informative missingness hazard ratio.

Prior for log hazard (non-informative censoring) for both treatment groups:
log(hnon-informative,i) ~ 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
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. Profiles and summary statistics for PK/PD data, by dosing 
regimen (OD, BID, TID) and by combination of dosing regimen and age groups (birth to <2 


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years, birth to < 0.5 years, 0.5 years to <2 years, 2 to <6 years, 6 to <12 years, 12 to <18 
years), by combination of dosing regimen and formulation (tablet, suspension), by 
combination of dosing regimen and weight groups (>12 kg, between 6 and 12 kg and below 6 
kg), by combination of dosing regimen, age groups, and formulation, and by combination of 
weight categories, dosing regimen and formulation will be provided. For PK parameters, 
additionally, summary statistics by age groups and by combination of age groups and 
formulation will be provided, i.e. pooling of dosing regimens. Number of subjects valid in all
three of PK, PD and PPS analysis sets will be tabulated by age groups (birth to <2 years, birth 
to <0.5 years, 0.5 years to <2 years, 2 to <6 years, 6 to <12 years, 12 to <18 years). Note that 
PK validity assessment will be performed according to the “Guidance document for PK 
validity in Phase II/III trials”.
Japanese patients will be included in the PK/PD modeling and the influence of ethnicity will 
be investigated.
Pharmacokinetic data
The concentration-times courses of rivaroxaban will be tabulated separated by regimen and 
per age group for each sampling interval. The following statistics will be calculated for each 
of the sampling intervals: arithmetic mean, standard deviation and coefficient of variation 
(CV), geometric mean, geometric standard deviation (re-transformed standard deviation of the 
logarithms) and CV, minimum, median, maximum value and the number of measurements. 
Means for any interval will only be calculated if at least 2/3 of the individual data were 
measured and were above the lower limit of quantification (LLOQ). For the calculation of the 
mean value a data point below LLOQ will be substituted by one half of this limit. In tables 
showing mean values, where values below LLOQ are included in the calculation of mean 
values, these means will be marked.
Individual and geometric mean concentration vs time curves of rivaroxaban (using the actual 
sampling times for individual plots and the planned sampling intervals for mean plots) will be 
plotted using both linear and semilogarithmic scale.
If applicable, pharmacokinetic characteristics derived via popPK modeling (tmax excluded) 
will be summarized by the statistics mentioned above. tmax will be described utilizing 
minimum, maximum and median as well as frequency counts.
Comparisons with reference data will be graphically sketched.
Pharmacodynamic data
Results for pharmacodynamic data will be displayed using appropriate summary statistics and 
figures.
In addition, the PK/PD relationship in the age groups will be investigated in an exploratory 
manner and compared to the adult reference data. Comparisons with reference data will be 
graphically sketched. The relationships between PT and anti-Xa with rivaroxaban 
concentrations will be explored by regression methods including analysis of potential effects 
of age and/or weight effects enriched by data from other pediatric trials as appropriate and 
may be reported separately.


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In case of any finding, further explorative investigations may be done.
6.5
Safety
6.5.1 Adverse events 
Individual listings of adverse events (AEs) will be provided. The incidence of treatment-
emergent AEs will be summarized by treatment, using MedDRA preferred terms, grouped by 
primary system organ class. Time window for treatment-emergent events is defined as events 
occurring after randomization until last intake of study medication plus 2 days. The 
incidences will be presented for each age cohort separately and for the following time points:

Post-randomization AEs up to the end of the main treatment period 

Treatment-emergent AEs up to the end of the main treatment period

All post-randomization AEs 

All treatment-emergent AEs 

Post-randomization AEs started after the end of main treatment period 

Treatment-emergent AEs started after the end of main treatment period 

AEs started more than 2 days after stop of study medication up to 30 days  
For the purpose of AE documentation, study drug is defined as either rivaroxaban or 
comparator, as allocated starting from randomization up to the end of study treatment visit.
6.5.2 Adverse events of special interest
The incidences of the AEs of special interest (AESI) - 1) liver-related AEs, 2)
Thrombocytopenia , 3) allergic skin reactions and allergic systemic reactions, will be flagged
by the sponsor’s medical experts as “potential” and “suspected or confirmed” AESI by
medical review. Also, subjects with concurrent elevations of ALT > 5x ULN and total 
bilirubin > 2x ULN, subjects with platelet count below 50 x 109 /L will be counted. The 
incidences will then be displayed by treatment group for the following time periods:

Post-randomization AEs up to the end of the main treatment period 

Treatment-emergent AEs up to the end of the main treatment period

All post-randomization AEs 

All treatment-emergent AEs 

Post-randomization AEs started after the end of main treatment period 

Treatment-emergent AEs started after the end of main treatment period 

AEs started more than 2 days after stop of study medication up to 30 days  
For more details, see Appendix 9.3.
6.5.3 Laboratory 
Descriptive statistics will be presented for Hb, platelets, ALT, total and direct bilirubin at 
visit 4 (at visit 2 for children with CVC-VTE) and for their changes to baseline. Unscheduled 
visits will be included for the summary statistics tables if the patient did not have end of 


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treatment visit, and the unscheduled visit was around the planned EoT visit (for example, ±3 
week). 
In addition, number of subjects with treatment-emergent high and treatment-emergent low 
laboratory abnormalities by laboratory category and treatment will be displayed. The 
numerator will be the number of subjects with at least one high laboratory assessment after 
the start of treatment who had a normal or lower than normal laboratory assessment at 
baseline in the treatment-emergent high laboratory abnormalities table. Similarly for the 
treatment-emergent low laboratory abnprmalities table. The descriptive statistics will be done 
for all data combined and for each age cohort. In addition, all laboratory data will be listed by 
patient.
6.5.4 Bleeding analysis
All bleeding analyses will be performed on the safety analysis set based on the outcomes 
confirmed by the CIAC and categorized into one of the following bleeding sites:

Gastrointestinal tract

Nasal

Oral Cavity

Skin

Injection site

Genital

Urinary tract

Conjunctival

Intra-articular

Respiratory tract

Intramuscular – without compartment syndrome

Intracranial

Other 

Unknown
For details, see Appendix 9.5.
All bleeding events that occurred during study treatment or within 2 days after stop of study 
medication (i.e. treatment-emergent) will be summarized by treatment group. 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 during the period divided by number 
of children at risk at the beginning of the period) and cumulative incidences (time to first 
event; Kaplan-Meier, Kalbfleisch and Prentice, 7) will be calculated for the primary safety 
outcome by treatment group at the end of the main study treatment period (for children <2 
years with CVC-VTE separately as well). Incidence proportions for the principal safety 
outcome will be reported overall by classification of index event. Incidence proportions will 
also be calculated for each age stratum, weight group (seven level grouping), dosing 


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formulation assignment, summaries of kidney function at the end of the main study treatment 
period and by presentation of index event as well (for children <2 years with CVC-VTE 
separately as well). For details of time to event and time to censoring see section 4.5.3.
In addition, incidence proportions will be calculated by treatment group for each age stratum, 
and overall in the extended study treatment period at 2 and 3 months (for the children 
<2 years with CVC-VTE) and, at 6, 9 and 12 months (for the other groups). Denominators in 
this case will be the number of patients at risk at the start of the respective period. Two-sided 
95% confidence intervals for the frequency of bleeding outcomes will be calculated by 
applying the method of Blyth-Still-Casella [13, 14].
Incidence proportions of other bleeding outcomes and components including duration and 
intensity of menstrual bleeding, any new action taken based on the menstrual bleeding 
questionnaire per on-treatment visit will be presented descriptively. The last menstrual 
bleeding start date, whether the menarche occurred before start of anticoagulation and new 
action taken related to menstrual bleeding (e.g., change in contraceptive therapy, blood 
transfusion, prohemostatic drug / antifibrinolytic drug, other concomitant medications or 
referral to gynecologist) will also be listed.
6.5.4.1
Statistical models
For comparing incidences of outcomes between rivaroxaban versus comparator, stratified 
(strata: CVST, CVC-VTE, non-CVC-VTE) Cox proportional hazards models models will be 
fitted for the time to principal safety outcome as an exploratory analysis as described for 
efficacy in Section 6.3.1. As with the efficacy outcomes, Cox proportional hazards models 
will be fitted separately for the subgroups CVST, CVC-VTE and non-CVC-VTE.
As it is expected that in some strata the number of events will be low, Firth’s penalized 
maximum likelihood estimation will be used to reduce bias in the parameter estimates. Point 
estimates for hazard ratios, confidence intervals (obtained with profile-likelihood function) 
and p-values for the treatment effect will be obtained. No hazard ratio will be calculated if no 
event occurred in a treatment group.
In addition, absolute risk differences (differences in incidence proportions) for the principal 
safety outcome at the end of the main treatment period will be calculated between rivaroxaban 
minus comparator with standard of care overall, by age group, weight group (seven level 
grouping), dosing formulation assignment and by presentation of index event (for children <2 
years with CVC-VTE separately as well) with unstratified exact method using the 
standardized test statistic and inverting a two-sided test [9] as exploratory analysis. The 
software StatXact will be used for the calculation of the exact confidence intervals.
6.6
Taste-and-texture questionnaire
Results for the taste-and-texture questionnaire in children 4 to < 18 years who receive the oral 
suspension will be presented descriptively as counts and proportions of responses by 
questions overall and by age groups.


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6.7
Pre-specified subgroup analysis
Analysis by baseline and clinical characteristics The efficacy, bleeding and safety outcomes, 
including appropriate confidence intervals, at the end of the main treatment period will be 
described by the following subgroups. 

Age (birth to <2 years; (birth to <0.5 years; 0.5 to <2 years); 2 to <6 years; 6 to <12 
years; 12 to <18 years)

Body weight 
Three level grouping: <6 kg; 6 to 12 kg; >12 kg
Seven level grouping:  0<5 kg; 5 to 10 kg; 10 to 20 kg; 20 to 30 kg; 30 to 40 kg; 40 to 
50 kg; >50 kg

Gender (male; female)

Presentation of index event (CVST; CVC-VTE; non-CVC-VTE)

Was the index event a recurrent episode of venous thrombosis? (yes; no)

Risk factors (provoked thrombosis by persistent risk factor, provoked thrombosis by 
persistent and transient risk factors, provoked thrombosis by transient risk factor, 
unprovoked, unconfirmed/unknown)

Dosing formulation assignment (rivaroxaban tablets, rivaroxaban oral suspension, 
comparator) for SAF and PPS populations

Presence of catheter (only at baseline, at baseline and end of main treatment, no)
6.8
Extrapolation of data obtained in adult patients with VTE treated with 
rivaroxaban to the setting of treatment of VTE with rivaroxaban in
children
To allow extrapolation of efficacy from adults to the pediatric population [16, 17, 18], the 
following conditions are considered. First, the pediatric 20 mg-equivalent rivaroxaban dose 
regimens should result in similar achieved drug exposure in children as observed in adults 
who received the approved therapeutic dose of 20 mg once-daily. Second, the clinical course 
of VTE (i.e. incidences of symptomatic recurrent VTE, major bleeding and mortality) should 
be similar in children and adults. Finally, the response to rivaroxaban therapy as compared to 
standard anticoagulation should be similar in children and adults. 
To document the similarity between adults and children in clinical course of VTE and the 
relative efficacy and safety, the following analyses will be done for the primary efficacy 
outcome, composite of primary efficacy outcome and major bleeding, composite of major and 
clinically relevant nonmajor bleeding:
1) Assessment of the incidences and the corresponding two-sided 95% confidence 
intervals by treatment group
2) Assessment of the relative treatment effects (hazard ratio and their 95, 90, 80, 50% 
confidence intervals) 


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These analyses will be done for the FAS but also for the subgroup of children with non-CVC-
VTE (excluding those with CVC-VTE and CVST).
The upper margin of the 95% CI of the rivaroxaban versus comparator hazard ratio will be 
used for comparison with the non-inferiority margin as established for the Einstein DVT and 
PE program. In that program, a non-inferiority margin of 2.0 was accepted for the individual 
Einstein DVT and PE studies whereas a non-inferiority margin of 1.75 was accepted for the 
pooled Einstein DVT and PE data.
7.
Document history and changes in the planned statistical analysis

First draft of SAP was circulated with the Bayer team on 30 SEP 2014.

Version 1.0 was released on 03 Dec 2014.

SAP Version 2.0 dated 13 Feb 2019 was prepared to provide the following edits. None of 
them are considered to change the primary efficacy analysis and other analyses as 
described in the study protocol and its amendments and in the SAP version 1.0 dated 03 
Dec 2014.
o
Referred all study protocol versions/amendments up to date
o
Although the initial description of the program referred to treatment with “age and 
body weight” adjusted rivaroxaban regimen, in reality rivaroxaban dose 
adjustments based on age never took place. Since pediatric rivaroxaban regimens 
are entirely based on body weight, we refer in this document, including the title, to 
“body weight –adjusted” rivaroxaban regimens
o
The assessment of repeated imaging at visit contains a further category 
‘normalized’ which was added in section 3.3. Imputation rules for thrombus 
burden assessment if repeated imaging was not performed or it was done outside 
of time window was included in section 4.3.
o
Different main and extended treatment periods for children aged < 2 years with 
catheter-related thrombosis were considered.
o
The sample size was increased to at least 170 children due to the extended age 
group from birth to 0.5 years.
o
Descriptive analysis of the menstrual bleeding questionnaire was included.
o
Van Elteren test and and proportional odds model to compare change in thrombus 
burden categories at the end of main treatment period between treatment groups 
was defined.
o
Subgroup analyses and calculation of confidence intervals for frequencies were 
included.
o
Calculation of compliance for the VKA comparator treatment will be based on 19 
days periods as done in other studies.
o
Concomitant antithrombotics will be categorized based on Drug Groupings (DGs, 
both Standardized DGs and Bayer DGs, related to WHODrug Version 2018sep 
and requested updates).
o
A section with detailed time definitions for the time to event analyses was
included.

SAP Version 3.0 dated 01 Mar 2019 was prepared to provide the following edits. None of 
them are considered to change the primary efficacy analysis and other analyses as 


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described in the study protocol and its amendments and in the SAP version 1.0 dated 03 
Dec 2014 or SAP version 2.0 dated 13 Feb 2019.
o
Subgroup for index event classification
o
Bleeding site groupings
o
Reference to analysis for Japanese patients was removed, because such analysis 
will be performed separately.
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. Jung,Sin-Ho; Kang, Sun J.; McCall, Linda M.; Blumenstein, Brent. 2005. 'Sample Sizes 
Computation for Two-Sample Noninferiority Log-Rank Test', J. of Biopharmaceutical 
Statistics, Volume 15, pages 969-979.
6. Hintze, J. (2011). PASS 11. NCSS, LLC. Kaysville, Utah, USA. www.ncss.com.
7. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. Wiley Series 
in Probability and Statistics, 2. Edition – 2002.
8. 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.
9. Agresti A, MinY. On small-sample confidence intervals for parameters in discrete 
distributions. Biometrics 2001; 57: 963-971.
10. Hosmer DW, Lemeshow S. Special Topics, in Applied Logistic Regression, 2nd Edition, 
John Wiley & Sons, Inc., Hoboken, NJ, USA, 2000. doi: 10.1002/0471722146.ch8.
11. van Elteren PH. On the combination of independent two-sample tests of Wilcoxon. 
Bulletin of the International Statistical Institute. 1960, 37: 351-361.
12. Dmitrienko A, Molenberghs G, Chuang-Stein C, Offen W. Analysis of Clinical Trials 
Using SAS: A Practical Guide, Cary, NC: SAS Institute Inc, 2005.
13. Blyth C, Still H. Binomial confidence intervals. Journal of American Statistical 
Association 1983; 78:108-116.


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14. Casella G. Refining binomial confidence intervals. Canadian Journal of Statistics 1986; 
14:113-129.
15. Boer DP, de Rijke YB, Hop WC, et al.  Pediatr Nephrol. 2010; Reference values for 
serum creatinine in children younger than 1 year of age; 25:2107–2113.
16. Lensing AWA et al. Rivaroxaban versus standard anticoagulation for acute venous 
thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study. Throm J 
l2018; 16:34. Doi: 10.1186/s12959-018-0188-y.
17. Reflection paper on the use of extrapolation in the development of medicines for 
paediatrics. 7 October 2018, EMA/189724/2018.
18. Dunne J, Rodriguez WJ, Murphy MD, Beasley BN, Burckart GJ, Filie JD, et al. 
Extrapolation of adult data and other data in pediatric drug-development programs. 
Pediatrics. 2011;128:e1242–9.


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9.
Appendix 
9.1
Sample size and power considerations
The sample size of 170 children does not originate from a formal sample size calculation, but 
is based on a feasibility assessment. In order to show non-inferiority (NI) of rivaroxaban 
versus comparator regarding symptomatic recurrent VTE, one would use a non-inferiority 
margin of 2.0 on the hazard ratio scale, as it was derived for the VTE treatment studies in 
adults and one would apply similar statistical model appropriate for time to event data
(Einstein DVT and PE studies; see 1, 2, 3). A non-inferiority logrank test with an overall 
number of patients of 90 having outcome event achieves 90% power at a one-sided 0.05 
significance level to show non-inferiority with a margin of hazard ratio of 2.0 when the actual 
hazard ratio is 1.0. In the REVIVE randomized controlled clinical trial in pediatric population 
(Massicotte et al., 4) under reviparin-sodium (LMWH), 2/36 patients (5.6%) had recurrent 
VTE or death and 4/40 patients (10.0%) receiving UFH/VKA over 3 months. Based on this 
incidence data and assuming a dropout rate of only 0.01 in both treatment group Table 9-1
shows the number of subjects to be randomized to show non-inferiority (margin: 2.0) based 
on the required number of events to be observed.
Table 9–1. 
Number of subjects to be randomized depending on the hazard rate of the 
recurrent VTE.
Hazard rate (in 
both groups)
Nrivaroxaban
Nccomparator
Ntotal
0.05
613
1247
1860
0.07
442
900
1342
0.09
347
707
1054
0.10
314
639
953
Note: The calculations are based on the NI margin of 2.0 (HR), one-sided 0.05 significance level, 90% 
power, actual HR of 1.0, proportion of dropouts of 0.01 in both groups.
The calculations were performed based on methods by Jung et al. (5) with the statistical 
software PASS 11 (6). Such large sample sizes are assessed as not feasible for pediatric 
studies in this indication. However, this study with at least 150 children 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.


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9.2
Example OpenBUGS code for sensitivity analysis of the primary efficacy 
outcome to account for Dropout 
OpenBUGS model
model
{
for (i in 1 : N) {
# Survival times bounded below by censoring times:
   t[i] ~ dexp(mu)C(t.cen[i],)
   p.imhr2[i] <- min(1,(1 - exp(-(t.obs[i] * mu)) + 1 -  exp(-((t.limit - t.obs[i]) * mu * IMHR2)))) 
}
mu <- exp(alpha);
alpha ~ dnorm(-6.6, 0.4)
IMHR2 ~ dlnorm (0.693, 10)
CDF <- 1 - exp(-(t.limit * mu))
p.mean.imhr2 <- mean(p.imhr2[])
}
OpenBUGS node statistics
mean
sd
MC_error
val2.5pc
median
val97.5pc
start
sample
CDF
0.07934
0.03257
0.002
0.03089
0.07445
0.1573
30001
30000
IMHR2
2.1
0.6788
0.004
1.069
2.0
3.714
30001
30000
Alpha
-6.997
0.439
0.027
-7.88
-6.978
-6.184
30001
30000
Mu
0.001004
4.33E-04
2.656E-5
3.78E-04
9.32E-04
0.002062
30001
30000
p.mean.imhr2
0.1132
0.05039
0.003
0.04112
0.1047
0.2365
30001
30000
9.3
Adverse events of special interest
9.3.1 Potential treatment-emergent AESIs
Adverse events screened will be reviewed and flagged by the sponsor’s medical experts 
whether they fulfill the criteria of liver-related or thrombocytemia or allergic reactions AESI 
to classify for full or partial narrative.

The SMQ for liver-related AEs is: 
SMQ Drug related hepatic disorders – comprehensive search: 20000006 excluding 
sub-SMQ Liver-related coagulation and bleeding disturbances: 20000015

The SMQ for Haematopoietic thrombocytopenia (SMQ) is: 20000031

The SMQs for allergic skin reactions and allergic systemic reactions are: Anaphylactic 
reaction (2 - narrow scope only) (SMQ code='20000021'), SMQ Severe cutaneous 
adverse reactions (2 - narrow scope only) (SMQ code='20000020'), SMQ 
Hypersensitivity (2 - narrow scope only) (SMQ code='20000214), SMQ Angioedema 
(2 - narrow scope only) (SMQ code=’20000024’)


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Additional adverse event fulfilling the criteria of AESI may also be flagged during medical 
review.The incidences of these adverse events using MedDRA SOC and PT will be displayed 
by treatment group.
9.3.2 Suspected or confirmed AESIs
The incidences of the suspected or confirmed AESIs will be derived from flagging those 
identified for full narratives during medical review and which had already been flagged as a 
potential AESI requiring partial narrative. 
9.4
Reference values for kidney function classification
The reference values are from the publication of Boer et al. [15].
Table 9–2. Reference values for serum creatinine in different subgroups
Group
Creatininepredicted
a
2.5th percentileb
10th percentileb
90th percentileb
97.5th percentileb
nc
Day 1
55
37
43
70
81
5
Day 2
47
32
36
60
69
13
Day 3
42
29
33
54
62
12
Day 4
39
27
31
50
58
9
Day 5
37
25
29
48
55
8
Day 6
36
24
28
46
53
7
Day 7
34
23
27
44
51
13
Week 2
31
21
24
40
46
15
Week 3
28
19
22
36
41
15
Week 4
25
17
20
32
37
15
Month 2
22
15
17
29
33
65
Month 3
20
14
16
26
30
69
Month 4–6
20
14
16
26
30
65
Month 7–9
20
14
16
26
30
65
Month 10–12
21
15
17
27
32
65
Values are given as micromoles per litre (μmol/L). To express serum creatinine values in milligrams per declitre (mg/dL) divide by 88.4
a Creatininepredicted expresses predicted median values by our formula
b 2.5th, 10th, 90th and 97.5th percentiles are the percentiles predicted from the model
c n is the number of included patients


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9.5
Bleeding site categorization
Table 9–3. Bleeding site grouping of confirmed bleedings
Bleeding Site Grouping
Individual Bleeding Site as adjudicated
Gastrointestinal tract
Gastrointestinal tract - esophageal
Gastrointestinal tract - gastric
Gastrointestinal tract - large intestine / colon
Gastrointestinal tract - rectal - non-hemorrhoidal
Nasal
Nasal
Oral Cavity/Gingival
Gastrointestinal tract - oral cavity
Gastrointestinal tract – gingival
Skin
Skin (other than injection site) - petechiae
Skin (other than injection site) - ecchymosis
Skin (other than injection site) – hematomaSkin (other than injection 
site) - surgical site
Leg
Finger
Upper limb
Skin, other
Ear
Umbilical 
Other – ostomy bag
Other - stoma
Injection site
Injection / blood sampling site
Skin (other than injection site) - percutaneous instrumentation site
Genital
Genital - ovarian
Genital - uterine
Genital - vaginal
Urinary tract
Urinary bladder
Urethra
Kidney
Conjunctival
Eye - conjunctival
Intra-articular
Intra-articular
Respiratory tract
Respiratory tract – pleural
Respiratory tract - tracheal
Intramuscular – without
compartment syndrome
Intramuscular - without compartment syndrome
Intracranial
Intracranial - subdural
Unknown
Undetermined


Statistical Analysis Plan Supplement 2.0 
Protocol No.: BAY 59-7939/14372
Page: 1 of 8
Title page
Study Protocol Title (incl. version no. and date): Multicenter, open-label, 
active-controlled, randomized study to evaluate the efficacy and safety of 
body weight-adjusted rivaroxaban regimen compared to standard of care 
in children with acute venous thromboembolism 
EINSTEIN Junior Phase III: oral rivaroxaban in children with venous 
thrombosis
Global Protocol Amendment 12 forming integrated protocol version 5.0, dated 27 SEP 2017
SAP (incl. Version no. and date): SAP version 3.0, dated 01 MAR 2019
[Analysis 
purpose:]
Additional Analyses 
Clinical study 
phase:
III
Date:
03 MAY 2019
Study No.:
14372
Version:
2.0
Authors:
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 unless 
quotations from other documents are given.  Hence, the appearance of product names without these 
symbols does not imply that these names are not protected.
This “Additional Statistical Analysis Plan” is produced on a word-processing system and bears no signatures.
PPD
PPD


Statistical Analysis Plan Supplement 2.0
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Table of Contents
Title page................................................................................................................................... 1
Abbreviations............................................................................................................................ 3
1.
Introduction....................................................................................................................... 3
2.
Description of additional analyses and clarifications .................................................... 3
2.1
Study medication ............................................................................................................. 3
2.1.1
Treatment Duration up to the end of main treatment period ........................................ 3
2.1.2
Rivaroxaban study treatment up to the end of main treatment period.......................... 3
2.1.3
Comparator study treatment up to the end of main treatment period........................... 4
2.2
Intended duration of main treatment for subjects with CVC-VTE and <2years who 
were enrolled before Protocol Amendment 12................................................................ 4
2.3
Imputation rules for thrombus burden assessment if repeated imaging was not 
performed or done outside of time window..................................................................... 4
2.4
Compliance ...................................................................................................................... 5
2.5
Analysis sets .................................................................................................................... 6
2.5.1
Per-protocol set (PPS) .................................................................................................. 6
2.5.2
Amended population for the PK analysis..................................................................... 6
2.6
Pediatric risk factors for thrombosis................................................................................ 6
2.7
Additional Efficacy and Safety Analyses ........................................................................ 7
3.
Document history and changes in the planned statistical analysis............................... 8
4.
References .......................................................................................................................... 8


Statistical Analysis Plan Supplement 2.0
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Abbreviations
BAY
sponsor’s reference number for drugs
BMI
body mass index
CIAC
CVC
central independent adjudication committee 
central venous catheter
CVST
cerebral vein and sinus thrombosis
eGFR
estimated glomerular filtration rate
FAS
full analysis set
LMWH
low molecular weight heparin
mg
Milligram
min
Minute
ml
Milliliter
PK
pharmacokinetic(s)
SAP
statistical analysis plan
UFH
unfractionated heparin
VKA
vitamin K antagonist
VTE
venous thromboembolism
1.
Introduction
This SAP Supplement 2.0 is based on the SAP version 3.0. The purpose of this SAP 
Supplement 2.0 is to define further analyses and include clarifications or alterations of 
analyses specified on the original SAP. Sections 2.1, 2.3, 2.6, 2.7 specify further analyses 
while the rest of the sections are clarifications or alterations to the analyses specified in SAP 
version 3.0. None of the additional analyses detailed in this document are considered to 
change the primary efficacy analysis and other analyses as described in the study protocol and 
its amendments and in the SAP version 3.0 dated 01 Mar 2019. 
2.
Description of additional analyses and clarifications
2.1
Study medication
2.1.1
Treatment Duration up to the end of main treatment period
In addition to the analyses specified in Section 6.2.1 of the original SAP, the duration of the 
study treatment in the main treatment period will be summarized separately for (i) children 
aged < 2 years with CVC-VTE, (ii) all other children - overall, by treatment and age groups
by calculating number of data available and missing data, mean, standard deviation, 
minimum, quartiles, median, and maximum. 
For each subject, the main treatment period for this analysis is defined as the period starting 
on the day of randomization and stopping either on the day of the last intake of study 
medication or on Day 97 (Day 37 for children < 2 years with CVC-VTE), whichever comes 
earlier.
2.1.2
Rivaroxaban study treatment up to the end of main treatment period
Number of subjects in the rivaroxaban arm will be presented by dosing formulation 
assignment (tablet versus suspension) overall and by age group.


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2.1.3
Comparator study treatment up to the end of main treatment period
Number of subjects in the comparator arm will be presented by the following main categories 
overall and by age group:

LMWH/Fondaparinux (UFH) only

VKA
2.2
Intended duration of main treatment for subjects with CVC-VTE and 
<2years who were enrolled before Protocol Amendment 12
Subjects with CVC-VTE and <2 years who were enrolled before Protocol Amendment 12 will 
be considered similar to such subjects enrolled after Protocol Amendment 12. This means that 
the main treatment duration, for the purpose of analysis of key end points, will be 1 month. 
After that, there may be two consecutive optional  extension periods of 1 month duration each. 
Treatment beyond 3 months will be considered as part of the second extension period.
2.3
Imputation rules for thrombus burden assessment if repeated imaging 
was not performed or done outside of time window
The SAP Version 3 defined imputation rules for thrombotic burden at repeated imaging based 
on the availability of the assessment, relative time to randomization and presence/timing of 
anticoagulant treatment, see more details in Table 4-1 of section 4.3.4 of the SAP version 3.0. 
The following modifications will be applied to the status of anticoagulation therapy outlined 
in Table 4-1 of the original SAP version 3.0.


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Table 2–1. 
Overview of repeated imaging categories from the CIAC and the imputation rules 
for if repeated imaging was not performed or done out of time window
Repeat imaging
Status of anticoagulant therapy
Thrombus burden assessment 
categories
Performed in time window, 
assessment is either 
normalized, improved, 
unchanged or deteriorated*
Not applicable
Accept adjudication outcome
Performed before time 
window, assessment is 
either normalized, 
improved, unchanged or 
deteriorated*
If any anticoagulation** stopped up
to 7 days after repeat imaging 
Accept adjudication outcome 
Performed before time 
window, assessment is 
either normalized, 
improved, unchanged or 
deteriorated*
If any anticoagulation** continued 
for >7 days after repeat imaging 
Classify outcome as “uncertain”
Performed after time 
window, assessment is 
either normalized, 
improved, unchanged or 
deteriorated*
Not applicable
Classify as “uncertain”
Not performed or 
assessment is not 
evaluable
If any anticoagulation** stopped 
before main treatment time window
(or no anticoagulation recorded)&
Classify as “uncertain”
Not performed or 
assessment is not 
evaluable
If any anticoagulation** stopped 
during main treatment time window&
Classify as “improved”
Not performed or 
assessment is not 
evaluable
If any anticoagulation** is continued 
after main treatment time window&
Classify as “uncertain”
Confirmed symptomatic 
recurrent venous 
thromboembolism+ 
Not applicable
Classify as “recurrent VTE”
*Time window for repeat imaging relative to randomization: Day 90±21 (or Day 30±7 for children with CVC-VTE 
younger than 2 years).
**Any anticoagulation defined as anticoagulant therapy with either study medication or non-study 
anticoagulation with either direct factor Xa inhibitors, direct thrombin inhibitors, unfractionated or low 
molecular weight heparin (except mucopolysaccharide polysulfuric acid ester), fondaparinux, or a vitamin K 
antagonist. Non-study anticoagulant therapy counted if started within 7 days after stop of study medication 
with a duration of at least 7 days (subsequent therapies will also be considered).
&Time window for stop of anticoagulation relative to randomization: Day 83-97 (or Day 23-37 for children with 
CVC-VTE younger than 2 years).
+regardless of availability of repeat imaging, up to the upper limit of the end of main treatment time window, see 
section 4.5.3 from SAP Version 3.0.
In addition to that, the original results of the adjudication will be cross-tabulated with the 
imputed categories and counts (%) per each cross-tabulation categories will be presented.
2.4
Compliance
Overall compliance for the main treatment period will be calculated taking into account dose 
interruptions; for the total duration of exposure interruptions will be excluded. Visit 


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compliance will not be calculated as it cannot be estimated reliably and  it has no relevance.
For further details of the methods of calculation, see SAP version 3.0 Section 4.5.2. Subjects 
who took both VKA and LMWH/Fondaparinux, compliance will be calculated for both 
periods separately and the overall compliance will be a weighted average by duration of 
treatment. For subjects on LMWH/Fondaparinux treatment and did not have study medication 
dispensed by the site or dispensed but not returned, compliance will not be calculated and 
“not available” will be displayed in the tables. This category will also include subjects whose 
medication was dispensed in the main treatment period but returned in the extended treatment 
period.
The above compliance calculation will also done for the overall study period.
2.5
Analysis sets
2.5.1
Per-protocol set (PPS)
This population included all FAS (i.e. randomized) children without major protocol 
deviations. The detailed list of these deviations were finalized prior to database lock and 
included in the protocol deviation document and validity review report. Further details of the 
deviations will not be added here; please see the above documents for more details.
2.5.2
Amended population for the PK analysis
Four rivaroxaban subjects who had at least one valid rivaroxaban concentration measurement 
were excluded by error from the PK analysis set and one subject without rivaroxaban 
concentration measurement was included by error in the PK analysis set. In the PK validity 
assessment performed according to the “Guidance document for PK validity in Phase II/III 
trials” (see SAP version 3.0), all concentrations invalid for PK were individually flagged so 
that the exclusion of invalid PK data via these flags is assured. Based on this and in agreement 
with the orginal SAP, only subjects with at least 1 PK sample in accordance with the PK 
sampling strategy will be included in the PK analysis (including Population PK analysis).
This will be documented in a Note to File.
2.6
Pediatric risk factors for thrombosis
The CIAC performed a standardized assessment of the clinical characteristics of each 
individual subject with a confirmed thrombosis to determine risk categories for VTE. For 
further details see section 6.1.1 of the SAP version 3.0.
The following 12 categories, as adjudicated, will be considered as distinct risk factor for the 
calculation of the number of risk factors per patient

Active cancer

Family history of venous thrombosis

Known inherited thrombophilia

Acquired thrombophilia


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
Major congenital venous anomaly

Major organ disease

Central venous catheter

Major infectious disease

Major surgery or major trauma

Morbid Obesity

Prolonged immobilization

Use of estrogens or progestins
As per the SAP Version 3.0, the number of subjects having each of the above risk factors will 
be tabulated. In addition to that, number of subjects having one, two or more than two risk 
factors will be presented overall, by treatment and age groups. The risk factors will be 
presented overall in the full analysis set and in the safety analysis set as well as by age groups
2.7
Additional Efficacy and Safety Analyses
The stratified Cox proportional hazard models for time to event outcomes, the logistic 
regression models for binary outcomes and the proportional odds model fitted for ordered 
categorical outcome of the thrombus burden assessment at repeated imaging as specified in 
the SAP Version 3.0 are considered as generalized linear models, which allows for response 
variables that have error distribution models other than a normal distribution (1). Although the 
number of subjects with primary and secondary efficacy outcomes, principal safety outcomes 
are relatively low, according to Vittinghoff et al. (2) and Lin et al. (3) models even with 5-9 
events per predictor variable provide reasonably conservative confidence intervals and p-
values. The following analyses will be performed in addition to the efficacy and safety 
analyses specified in the SAP Version 3.0:
Efficacy Analysis:
Cox proportional hazards models will be fitted for the composite of symptomatic recurrent 
VTE and other clinically significant thrombosis overall and separately for the subgroups 
CVST, CVC-VTE and non-CVC-VTE up to the end of the main treatment period. As it is 
expected that in some strata the number of events will be low, Firth’s penalized maximum 
likelihood estimation will be used to reduce bias in the parameter estimates. Point estimates 
for hazard ratios, confidence intervals (obtained with profile-likelihood function) and p-values 
for the treatment effect will be reported. 
Safety Analysis:
Exact confidence intervals for the incidences by treatment group and absolute risk differences 
(differences in incidence proportions between treatment groups) and their exact confidence 
intervals will be calculated at the end of the main treatment period for the following safety 
outcomes:
o
Death


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o
Major bleeding
3.
Document history and changes in the planned statistical analysis

First draft of SAP Supplement was circulated with the Bayer team on 03 APR 2019.

Version 1.0 was released on 08 APR 2019.

SAP Supplement Version 2.0 dated 03 MAY 2019 was prepared to provide the following 
edits. None of them are considered to change the primary efficacy analysis and there is no 
substantial change to other analyses as described in the study protocol and its 
amendments, SAP Version 3.0 or SAP Supplement version 1.0 dated 08 APR 2019.
o
Clarifications to imputation rules for thrombus burden assessment if repeated 
imaging was not performed or done outside of time window from Section 4.3.4 of 
SAP Version 3.0
o
‘Morbid Obesity’, as adjudicated, to be considered a pediatric risk factor instead of 
‘BMI > 35 kg/m2’ calculated from the data
o
Added note to the appropriateness of the confidence intervals and p-values 
calculated from the Cox proportional hazards and logictic regression models. 
4.
References
1. McCullagh P, Nelder JA. Generalized Linear Models. 2nd Edition, Chapman and Hall, 
London, 1989.
2. Vittinghoff  E, McCulloch CE. Relaxing the Rule of Ten Events per Variable in Logistic 
and Cox Regression. Am J Epidemiol 2007;165:710-8.
3. Lin IF, Chang WP, Liao YN. Shrinkage methods enhanced the accuracy of parameter 
estimation using Cox models with small number of events. J Clin Epidemiol. 2013; 
66:743-51. doi: 10.1016/j.jclinepi.2013.02.002.