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Clinical Trial Results:
Single-dose pilot study of oral rivaroxaban in pediatric subjects with venous thromboembolism

Summary
EudraCT number	2009-017313-30
Trial protocol	AT DE IT IE FR
Global end of trial date	07 Jul 2015

Results information
Results version number	v2(current)
This version publication date	04 Sep 2016
First version publication date	03 Jul 2016
Other versions	v1
Version creation reason	New data added to full data set Correction of full data set Bayer sponsor contact information to be updated

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

BAY59-7939/12892

ISRCTN number

US NCT number

NCT01145859

WHO universal trial number (UTN)

Sponsor organisation name

Bayer AG

Sponsor organisation address

Kaiser Wilhelm Allee, D51368, Leverkusen, Germany,

Public contact

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

Scientific contact

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-000430-PIP01-08

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

07 Jul 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

07 Jul 2015

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study was to investigate pharmacokinetics and pharmacodynamics of single oral doses of rivaroxaban in pediatric subjects in order to obtain weight adjusted doses with equivalent exposure compared to 10 milligram (mg) and 20 mg doses in adults.

Protection of trial subjects

The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.

Background therapy

Evidence for comparator

Actual start date of recruitment

11 Nov 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 14

Country: Number of subjects enrolled

Australia: 4

Country: Number of subjects enrolled

Austria: 3

Country: Number of subjects enrolled

Canada: 14

Country: Number of subjects enrolled

France: 4

Country: Number of subjects enrolled

Israel: 7

Country: Number of subjects enrolled

Italy: 13

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 18 centers in 7 countries worldwide between 11 November 2010 (first subject first visit) and 7 July 2015 (last subject last visit).

Screening details

Out of 72 enrolled subjects, 59 subjects were randomized and 13 subjects were excluded due to screening failures.

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Age 12-18 Years: Tablet-Low Dose

Arm description

Subjects aged from 12 to 18 years were administered with a single oral dose of rivaroxaban tablet under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kilogram (kg) received low dose of rivaroxaban (equivalent to 10 mg in adults) ranging from 2.5 to 7.5 mg, and subjects with a body weight (comparable to adults) of 50 to 100 kg received a low dose of 10 mg.

Arm type

Experimental

Investigational medicinal product name

Rivaroxaban

Investigational medicinal product code

BAY59-7939

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects aged from 12 to 18 years were administered with a single oral dose of rivaroxaban tablet under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received low dose of rivaroxaban (equivalent to 10 mg in adults) ranging from 2.5 to 7.5 mg, and subjects with a body weight (comparable to adults) of 50 to 100 kg received a low dose of 10 mg.

Age 12-18 Years: Tablet-High Dose

Arm description

Subjects aged from 12 to 18 years were administered with a single oral dose of rivaroxaban tablet under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 5 to 15 mg, and subjects with a body weight (comparable to adults) of 50 to 100 kg received a high dose of 20 mg.

Arm type

Experimental

Investigational medicinal product name

Rivaroxaban

Investigational medicinal product code

BAY59-7939

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects aged from 12 to 18 years were administered with a single oral dose of rivaroxaban tablet under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received a high dose rivaroxaban (equivalent to 20 mg in adults) ranging from 5 to 15 mg, and subjects with a body weight (comparable to adults) of 50 to 100 kg received a high dose of 20 mg.

Age 6-12 Years: Tablet-Low Dose

Arm description

Subjects aged from 6 to 12 years were administered with a single oral dose of rivaroxaban tablet under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received low dose of rivaroxaban (equivalent to 10 mg in adults) ranging from 2.5 to 7.5 mg, and subjects with a body weight (comparable to adults) of 50 to 100 kg received a low dose of 10 mg.

Arm type

Experimental

Investigational medicinal product name

Rivaroxaban

Investigational medicinal product code

BAY59-7939

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Age 6-12 Years: Suspension-Low Dose

Arm description

Subjects aged from 6 to 12 years were administered with a single oral dose of rivaroxaban suspension under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received low dose of rivaroxaban (equivalent to 10 mg in adults) ranging from 2.5 to 5 mg.

Arm type

Experimental

Investigational medicinal product name

Rivaroxaban

Investigational medicinal product code

BAY59-7939

Other name

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Age 6-12 Years: Tablet-High Dose

Arm description

Subjects aged from 6 to 12 years were administered with a single oral dose of rivaroxaban tablet under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 5 to 15 mg, and subjects with a body weight (comparable to adults) of 50 to 100 kg received a high dose of 20 mg.

Arm type

Experimental

Investigational medicinal product name

Rivaroxaban

Investigational medicinal product code

BAY59-7939

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects aged from 6 to 12 years were administered with a single oral dose of rivaroxaban tablet under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 5 to 15 mg, and subjects with a body weight (comparable to adults) of 50 to 100 kg received a high dose of 20 mg.

Age 6-12 Years: Suspension-High Dose

Arm description

Subjects aged from 6 to 12 years were administered with a single oral dose of rivaroxaban suspension under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 5 to 10 mg.

Arm type

Experimental

Investigational medicinal product name

Rivaroxaban

Investigational medicinal product code

BAY59-7939

Other name

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Subjects aged from 6 to 12 years were administered with a single oral dose of rivaroxaban suspension under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 5 to 10 mg.

Age 2-6 Years: Suspension-Low Dose

Arm description

Subjects aged from 2 to 6 years were administered with a single oral dose of rivaroxaban suspension under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 2 to 14 kg received low dose of rivaroxaban (equivalent to 10 mg in adults) ranging from 0.4 to 2.5 mg.

Arm type

Experimental

Investigational medicinal product name

Rivaroxaban

Investigational medicinal product code

BAY59-7939

Other name

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Age 2-6 Years: Suspension-High Dose

Arm description

Subjects aged from 2 to 6 years were administered with a single oral dose of rivaroxaban suspension under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 2 to 14 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 0.8 to 5.0 mg.

Arm type

Experimental

Investigational medicinal product name

Rivaroxaban

Investigational medicinal product code

BAY59-7939

Other name

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Subjects aged from 6 to 12 years were administered with a single oral dose of rivaroxaban suspension under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 5 to 10 mg.

Age 6 months-2 years: Suspension-Low Dose

Arm description

Subjects aged from 6 months to 2 years were administered with a single oral dose of rivaroxaban suspension under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 2 to 14 kg received low dose of rivaroxaban (equivalent to 10 mg in adults) ranging from 0.4 to 2.5 mg.

Arm type

Experimental

Investigational medicinal product name

Rivaroxaban

Investigational medicinal product code

BAY59-7939

Other name

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Age 6 months-2 years: Suspension-High Dose

Arm description

Subjects aged from 6 months to 2 years were administered with a single oral dose of rivaroxaban suspension under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 2 to 14 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 0.8 to 5.0 mg.

Arm type

Experimental

Investigational medicinal product name

Rivaroxaban

Investigational medicinal product code

BAY59-7939

Other name

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Subjects aged from 6 months to 2 years were administered with a single oral dose of rivaroxaban suspension under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 2 to 14 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 0.8 to 5.0 mg.

Number of subjects in period 1	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Started	4	5	4	11	4	5	11	5	6	4
Completed	4	5	4	11	4	5	11	5	6	4

Baseline characteristics

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Reporting group title

Age 12-18 Years: Tablet-Low Dose

Reporting group description

Reporting group title

Age 12-18 Years: Tablet-High Dose

Reporting group description

Subjects aged from 12 to 18 years were administered with a single oral dose of rivaroxaban tablet under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 5 to 15 mg, and subjects with a body weight (comparable to adults) of 50 to 100 kg received a high dose of 20 mg.

Reporting group title

Age 6-12 Years: Tablet-Low Dose

Reporting group description

Reporting group title

Age 6-12 Years: Suspension-Low Dose

Reporting group description

Reporting group title

Age 6-12 Years: Tablet-High Dose

Reporting group description

Subjects aged from 6 to 12 years were administered with a single oral dose of rivaroxaban tablet under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 5 to 15 mg, and subjects with a body weight (comparable to adults) of 50 to 100 kg received a high dose of 20 mg.

Reporting group title

Age 6-12 Years: Suspension-High Dose

Reporting group description

Subjects aged from 6 to 12 years were administered with a single oral dose of rivaroxaban suspension under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 5 to 10 mg.

Reporting group title

Age 2-6 Years: Suspension-Low Dose

Reporting group description

Reporting group title

Age 2-6 Years: Suspension-High Dose

Reporting group description

Subjects aged from 2 to 6 years were administered with a single oral dose of rivaroxaban suspension under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 2 to 14 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 0.8 to 5.0 mg.

Reporting group title

Age 6 months-2 years: Suspension-Low Dose

Reporting group description

Reporting group title

Age 6 months-2 years: Suspension-High Dose

Reporting group description

Subjects aged from 6 months to 2 years were administered with a single oral dose of rivaroxaban suspension under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 2 to 14 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 0.8 to 5.0 mg.

Reporting group values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose	Total
Number of subjects	4	5	4	11	4	5	11	5	6	4	59
Age Categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	16 ( 1.4 )	14.8 ( 1.9 )	10 ( 0.8 )	7.5 ( 1.5 )	8.5 ( 1.9 )	9.2 ( 1.8 )	3.4 ( 1.2 )	3.6 ( 1.5 )	0.5 ( 0.5 )	0.5 ( 0.6 )	-
Gender Categorical
Units: Subjects
Female	1	4	1	6	2	0	5	3	3	1	26
Male	3	1	3	5	2	5	6	2	3	3	33

End points

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Reporting group title

Age 12-18 Years: Tablet-Low Dose

Reporting group description

Reporting group title

Age 12-18 Years: Tablet-High Dose

Reporting group description

Subjects aged from 12 to 18 years were administered with a single oral dose of rivaroxaban tablet under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 5 to 15 mg, and subjects with a body weight (comparable to adults) of 50 to 100 kg received a high dose of 20 mg.

Reporting group title

Age 6-12 Years: Tablet-Low Dose

Reporting group description

Reporting group title

Age 6-12 Years: Suspension-Low Dose

Reporting group description

Reporting group title

Age 6-12 Years: Tablet-High Dose

Reporting group description

Subjects aged from 6 to 12 years were administered with a single oral dose of rivaroxaban tablet under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 5 to 15 mg, and subjects with a body weight (comparable to adults) of 50 to 100 kg received a high dose of 20 mg.

Reporting group title

Age 6-12 Years: Suspension-High Dose

Reporting group description

Subjects aged from 6 to 12 years were administered with a single oral dose of rivaroxaban suspension under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 5 to 10 mg.

Reporting group title

Age 2-6 Years: Suspension-Low Dose

Reporting group description

Reporting group title

Age 2-6 Years: Suspension-High Dose

Reporting group description

Subjects aged from 2 to 6 years were administered with a single oral dose of rivaroxaban suspension under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 2 to 14 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 0.8 to 5.0 mg.

Reporting group title

Age 6 months-2 years: Suspension-Low Dose

Reporting group description

Reporting group title

Age 6 months-2 years: Suspension-High Dose

Reporting group description

Subjects aged from 6 months to 2 years were administered with a single oral dose of rivaroxaban suspension under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 2 to 14 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 0.8 to 5.0 mg.

Subject analysis set title

Safety analysis set (SAF)

Subject analysis set type

Safety analysis

Subject analysis set description

SAF (n=59) included all subjects who received at least one dose of study drug.

Subject analysis set title

Per protocol set (PPS)

Subject analysis set type

Per protocol

Subject analysis set description

PPS (n=59) included all subjects who received at least one dose of study drug with no relevant protocol deviations affecting pharmacokinetics or pharmacodynamics

Primary: Model Independent Pharmacokinetic: Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC) of Rivaroxaban in Plasma

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End point title

Model Independent Pharmacokinetic: Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC) of Rivaroxaban in Plasma ^[1] ^[2]

End point description

Area under the concentration versus time curve from zero to infinity after single dose. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

End point type

Primary

End point timeframe

0 hours (h) (pre-dose) to 24 h post-dose

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Inferential statistical analysis was planned for the overall data and not as per the reporting groups.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistics were reported only for the reporting groups specific to this endpoint.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose
Number of subjects analysed	4 ^[3]	5 ^[4]	4 ^[5]	11 ^[6]	4 ^[7]	5 ^[8]
Units: microgramhour per liter (mcgh/L)
geometric mean (geometric coefficient of variation)	1340 ( 37.7 )	1660 ( 39 )	866 ( 36 )	719 ( 42.4 )	1650 ( 38.9 )	1060 ( 48 )

Notes
[3] - PPS
[4] - PPS
[5] - PPS
[6] - PPS
[7] - PPS
[8] - PPS

No statistical analyses for this end point

Primary: Model Derived Pharmacokinetic: Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC) of Rivaroxaban in Plasma

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End point title

Model Derived Pharmacokinetic: Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC) of Rivaroxaban in Plasma ^[9]

End point description

Area under the concentration versus time curve from zero to infinity after single dose. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

End point type

Primary

End point timeframe

0 h (pre-dose) to 24 h post-dose

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Inferential statistical analysis was planned for the overall data and not as per the reporting groups.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Number of subjects analysed	4 ^[10]	5 ^[11]	4 ^[12]	11 ^[13]	4 ^[14]	5 ^[15]	11 ^[16]	5 ^[17]	6 ^[18]	4 ^[19]
Units: microgramhour per liter (mcgh/L)
geometric mean (geometric coefficient of variation)	1320 ( 13.1 )	1760 ( 20.7 )	902 ( 31.2 )	720 ( 24.1 )	1540 ( 52 )	1070 ( 37.5 )	674 ( 25.5 )	755 ( 39 )	503 ( 20.6 )	672 ( 29.4 )

Notes
[10] - PPS
[11] - PPS
[12] - PPS
[13] - PPS
[14] - PPS
[15] - PPS
[16] - PPS
[17] - PPS
[18] - PPS
[19] - PPS

No statistical analyses for this end point

Primary: Model Independent Pharmacokinetic: Area Under the Concentration From Time Zero to the Last Data Point (AUC[0-tlast]) of Rivaroxaban in Plasma

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End point title

Model Independent Pharmacokinetic: Area Under the Concentration From Time Zero to the Last Data Point (AUC[0-tlast]) of Rivaroxaban in Plasma ^[20] ^[21]

End point description

Area under the concentration versus time curve from zero to tlast after single (first) dose. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

End point type

Primary

End point timeframe

0 h (pre-dose) to 24 h post-dose

Notes
[20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, inferential statistics were not planned.
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistics were reported only for the reporting groups specific to this endpoint.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose
Number of subjects analysed	4 ^[22]	5 ^[23]	4 ^[24]	11 ^[25]	4 ^[26]	5 ^[27]
Units: microgram*hour per liter
geometric mean (geometric coefficient of variation)	1260 ( 39.7 )	1530 ( 40.4 )	839 ( 35.6 )	689 ( 42.8 )	1510 ( 35.8 )	988 ( 44.3 )

Notes
[22] - PPS
[23] - PPS
[24] - PPS
[25] - PPS
[26] - PPS
[27] - PPS

No statistical analyses for this end point

Primary: Model Independent Pharmacokinetic: Maximum Observed Drug Concentration (Cmax) of Rivaroxaban in Plasma

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End point title

Model Independent Pharmacokinetic: Maximum Observed Drug Concentration (Cmax) of Rivaroxaban in Plasma ^[28] ^[29]

End point description

Maximum observed drug concentration, directly taken from analytical data. Geometric meanand percentage geometric coefficient of variation (%CV) were reported.

End point type

Primary

End point timeframe

0 h (pre-dose) to 24 h post-dose

Notes
[28] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, inferential statistics were not planned.
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistics were reported only for the reporting groups specific to this endpoint.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose
Number of subjects analysed	4 ^[30]	5 ^[31]	4 ^[32]	11 ^[33]	4 ^[34]	5 ^[35]
Units: microgram per liter
geometric mean (geometric coefficient of variation)	161 ( 45.6 )	206 ( 41.3 )	115 ( 72.6 )	89.2 ( 59.3 )	244 ( 21.1 )	113 ( 42.9 )

Notes
[30] - PPS
[31] - PPS
[32] - PPS
[33] - PPS
[34] - PPS
[35] - PPS

No statistical analyses for this end point

Primary: Model Derived Pharmacokinetic: Maximum Observed Drug Concentration (Cmax) of Rivaroxaban in Plasma

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End point title

Model Derived Pharmacokinetic: Maximum Observed Drug Concentration (Cmax) of Rivaroxaban in Plasma ^[36]

End point description

Maximum observed drug concentration, directly taken from analytical data. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

End point type

Primary

End point timeframe

0 h (pre-dose) to 24 h post-dose

Notes
[36] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, inferential statistics were not planned.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Number of subjects analysed	4 ^[37]	5 ^[38]	4 ^[39]	11 ^[40]	4 ^[41]	5 ^[42]	11 ^[43]	5 ^[44]	6 ^[45]	4 ^[46]
Units: microgram per liter
geometric mean (geometric coefficient of variation)	129 ( 11.4 )	180 ( 12 )	118 ( 11 )	82.5 ( 37.4 )	172 ( 25.9 )	85.1 ( 15.7 )	84.2 ( 36 )	60.1 ( 33.4 )	94.9 ( 28.3 )	143 ( 14.7 )

Notes
[37] - PPS
[38] - PPS
[39] - PPS
[40] - PPS
[41] - PPS
[42] - PPS
[43] - PPS
[44] - PPS
[45] - PPS
[46] - PPS

No statistical analyses for this end point

Primary: Model Derived Pharmacokinetic: Clearance (CL) of Rivaroxaban in Plasma

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End point title

Model Derived Pharmacokinetic: Clearance (CL) of Rivaroxaban in Plasma ^[47]

End point description

Systemic Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body. The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]). Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

End point type

Primary

End point timeframe

0 h (pre-dose) to 24 h post-dose

Notes
[47] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, inferential statistics were not planned.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Number of subjects analysed	4 ^[48]	5 ^[49]	4 ^[50]	11 ^[51]	4 ^[52]	5 ^[53]	11 ^[54]	5 ^[55]	6 ^[56]	4 ^[57]
Units: liter per hour
geometric mean (geometric coefficient of variation)	7.58 ( 13.1 )	6.96 ( 22.8 )	6.79 ( 25.4 )	5.78 ( 21 )	4.79 ( 16.1 )	5.87 ( 29.4 )	4.13 ( 26.3 )	4.61 ( 30.5 )	3.96 ( 17.6 )	3.95 ( 13.8 )

Notes
[48] - PPS
[49] - PPS
[50] - PPS
[51] - PPS
[52] - PPS
[53] - PPS
[54] - PPS
[55] - PPS
[56] - PPS
[57] - PPS

No statistical analyses for this end point

Primary: Model Derived Pharmacokinetic: Volume of Distribution at Steady State (Vss) of Rivaroxaban in Plasma

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End point title

Model Derived Pharmacokinetic: Volume of Distribution at Steady State (Vss) of Rivaroxaban in Plasma ^[58]

End point description

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC[0-infinity])*(AUMC[0-infinity])/AUC[0-infinity]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

End point type

Primary

End point timeframe

0 h (pre-dose) to 24 h post-dose

Notes
[58] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, inferential statistics were not planned.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Number of subjects analysed	4 ^[59]	5 ^[60]	4 ^[61]	11 ^[62]	4 ^[63]	5 ^[64]	11 ^[65]	5 ^[66]	6 ^[67]	4 ^[68]
Units: liter
geometric mean (geometric coefficient of variation)	63 ( 8.77 )	55.2 ( 13.2 )	42.6 ( 11.3 )	35.1 ( 9.62 )	40.1 ( 21.3 )	38.8 ( 13.9 )	25.2 ( 14.3 )	25 ( 9.94 )	20 ( 6.29 )	20.5 ( 8.29 )

Notes
[59] - PPS
[60] - PPS
[61] - PPS
[62] - PPS
[63] - PPS
[64] - PPS
[65] - PPS
[66] - PPS
[67] - PPS
[68] - PPS

No statistical analyses for this end point

Primary: Model Derived Pharmacokinetic: Absorption Rate Constant (Ka) of Rivaroxaban in Plasma

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End point title

Model Derived Pharmacokinetic: Absorption Rate Constant (Ka) of Rivaroxaban in Plasma ^[69]

End point description

The rate at which a drug enters the body after administration is called the absorption rate, and is represented by the symbol ka. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

End point type

Primary

End point timeframe

0 h (pre-dose) to 24 h post-dose

Notes
[69] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, inferential statistics were not planned.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Number of subjects analysed	4 ^[70]	5 ^[71]	4 ^[72]	11 ^[73]	4 ^[74]	5 ^[75]	11 ^[76]	5 ^[77]	6 ^[78]	4 ^[79]
Units: 1/hour
geometric mean (geometric coefficient of variation)	0.711 ( 7.32 )	0.686 ( 12.3 )	0.727 ( 20.3 )	0.465 ( 79.1 )	0.794 ( 12.7 )	0.232 ( 20.7 )	0.408 ( 66.2 )	0.166 ( 53.8 )	0.545 ( 51 )	0.72 ( 3.5 )

Notes
[70] - PPS
[71] - PPS
[72] - PPS
[73] - PPS
[74] - PPS
[75] - PPS
[76] - PPS
[77] - PPS
[78] - PPS
[79] - PPS

No statistical analyses for this end point

Primary: Relative Change from Baseline in Prothrombin Time (PT)

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End point title

Relative Change from Baseline in Prothrombin Time (PT) ^[80]

End point description

Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Mean and standard deviation (SD) were reported. In the below table, "n" signifies subjects who were evaluable for the specified parameter for each arm, respectively. ‘99999’ in the posting indicates that data were not calculated as no subjects were analysed for the specified time point.

End point type

Primary

End point timeframe

0 h (Pre-dose) to 24 h post-dose

Notes
[80] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, inferential statistics were not planned.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Number of subjects analysed	4 ^[81]	5 ^[82]	4 ^[83]	11 ^[84]	4 ^[85]	5 ^[86]	11 ^[87]	5 ^[88]	6 ^[89]	4 ^[90]
Units: seconds
arithmetic mean (standard deviation)
PT-baseline (n=4, 5, 4, 11, 4, 5, 11, 5, 5, 4)	18.03 ( 1.72 )	16.02 ( 3.16 )	17.88 ( 2.05 )	15.83 ( 2.78 )	13.2 ( 0.59 )	13.74 ( 0.27 )	13.93 ( 2.19 )	14.22 ( 1.67 )	15.18 ( 2.69 )	16.98 ( 2.94 )
PT-Change at 30 min (n=4,5,4,11,4,5,0,0,0,0)	1.26 ( 0.24 )	1.12 ( 0.11 )	1.11 ( 0.25 )	1.27 ( 0.22 )	1.22 ( 0.24 )	1.1 ( 0.04 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
PT-Change at 1h 30min (n=0,0,0,0,0,0,11,5,5,4)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	1.23 ( 0.13 )	1.14 ( 0.13 )	1.36 ( 0.24 )	1.36 ( 0.17 )
PT-Change at 2h (n=3,4,4,10,4,5,0,0,0,0)	1.84 ( 0.21 )	1.62 ( 0.2 )	1.49 ( 0.18 )	1.32 ( 0.19 )	1.59 ( 0.39 )	1.2 ( 0.08 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
PT- Change at 4h (n=4, 4, 0, 0, 0, 0, 0, 0, 0, 0)	1.56 ( 0.21 )	1.77 ( 0.46 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
PT-Change at 8h (n=3,5,4,11,4,5,10,5,0,0)	1.37 ( 0.12 )	1.3 ( 0.19 )	1.16 ( 0.1 )	1.14 ( 0.13 )	1.25 ( 0.2 )	1.17 ( 0.2 )	1.1 ( 0.07 )	1.07 ( 0.04 )	99999 ( 99999 )	99999 ( 99999 )
PT-Change at 20h (n=3,5,4,11,4,5,10,5,5,4)	1.13 ( 0.07 )	1.02 ( 0.06 )	1.05 ( 0.05 )	1.05 ( 0.05 )	1.03 ( 0.03 )	1.02 ( 0.07 )	1.05 ( 0.03 )	1 ( 0.05 )	1.02 ( 0.06 )	0.99 ( 0.05 )

Notes
[81] - PPS
[82] - PPS
[83] - PPS
[84] - PPS
[85] - PPS
[86] - PPS
[87] - PPS
[88] - PPS
[89] - PPS
[90] - PPS

No statistical analyses for this end point

Primary: Relative Change from Baseline in Adjusted Partial Thromboplastin Time (aPTT)

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End point title

Relative Change from Baseline in Adjusted Partial Thromboplastin Time (aPTT) ^[91]

End point description

The aPTT is a screening test for the intrinsic pathway and is sensitive for deficiencies of Factors I, II, V, VIII, IX, X, XI and XII. Higher values than the baseline indicate anticoagulant effects. In the below table, "n" signifies subjects who were evaluable for the specified parameter for each arm, respectively. ‘99999’ in the posting indicates that data were not calculated as no subjects were analysed for the specified time point.

End point type

Primary

End point timeframe

0 h (pre-dose) to 24 h post-dose

Notes
[91] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, inferential statistics were not planned.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Number of subjects analysed	4 ^[92]	5 ^[93]	4 ^[94]	11 ^[95]	4 ^[96]	5 ^[97]	11 ^[98]	5 ^[99]	6 ^[100]	4 ^[101]
Units: seconds
arithmetic mean (standard deviation)
aPTT-baseline (n=4,5,4,11,4,5,11,5,5,4)	42.975 ( 9.689 )	35.16 ( 7.832 )	47.25 ( 11.709 )	37.373 ( 8.173 )	32 ( 1.407 )	28.96 ( 2.266 )	32.764 ( 6.469 )	31.86 ( 5.018 )	37.64 ( 13.924 )	42.425 ( 8.742 )
aPTT-Change at 30 min (n=4,5,4,11,4,5,0,0,0,0)	1.148 ( 0.16 )	1.009 ( 0.064 )	1.055 ( 0.276 )	1.255 ( 0.23 )	1.18 ( 0.187 )	1.057 ( 0.104 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
aPTT-Change at 1h30min (n=0,0,0,0,0,0,11,5,5,4)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	1.554 ( 1.129 )	1.13 ( 0.206 )	1.248 ( 0.303 )	1.244 ( 0.18 )
aPTT-Change at 2h (n=3,4,4,10,4,5,0,0,0,0)	1.586 ( 0.17 )	1.366 ( 0.096 )	1.333 ( 0.174 )	1.315 ( 0.117 )	1.433 ( 0.25 )	1.159 ( 0.115 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
aPTT-Change at 4h (n=4,4,0,0,0,0,0,0,0,0)	1.448 ( 0.184 )	1.432 ( 0.193 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
aPTT-Change at 8h (n=3,5,4,11,4,5,10,5,0,0)	1.334 ( 0.042 )	1.21 ( 0.127 )	1.116 ( 0.143 )	1.19 ( 0.159 )	1.247 ( 0.154 )	1.216 ( 0.153 )	1.123 ( 0.055 )	1.113 ( 0.106 )	99999 ( 99999 )	99999 ( 99999 )
aPTT-Change at 20h (n=3,5,4,11,4,5,10,5,5,4)	1.117 ( 0.122 )	1.01 ( 0.074 )	1.043 ( 0.124 )	1.05 ( 0.087 )	1.035 ( 0.03 )	1.056 ( 0.076 )	0.98 ( 0.117 )	0.989 ( 0.092 )	0.986 ( 0.087 )	0.909 ( 0.12 )

Notes
[92] - PPS
[93] - PPS
[94] - PPS
[95] - PPS
[96] - PPS
[97] - PPS
[98] - PPS
[99] - PPS
[100] - PPS
[101] - PPS

No statistical analyses for this end point

Primary: Absolute Change from Baseline in Anti-factor Xa activity (anti-Xa)

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End point title

Absolute Change from Baseline in Anti-factor Xa activity (anti-Xa) ^[102]

End point description

This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. Higher Values than the baseline indicate a more pronounced inhibition. "n" signifies subjects who were evaluable for the specified parameter for each arm, respectively. ‘99999’ in the posting indicates that data were not calculated.

End point type

Primary

End point timeframe

0 h (pre-dose) to 24 h post-dose

Notes
[102] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, inferential statistics were not planned.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Number of subjects analysed	4 ^[103]	5 ^[104]	4 ^[105]	11 ^[106]	4 ^[107]	5 ^[108]	11 ^[109]	5 ^[110]	6 ^[111]	4 ^[112]
Units: microgram per liter (mcg/L)
arithmetic mean (standard deviation)
Baseline(n=4, 5, 4, 11, 4, 5, 11, 5, 6, 4)	0 ( 0 )	0 ( 0 )	17.12 ( 34.24 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )
Change at 30 min(n=3, 2, 4, 8, 2, 3, 0, 0, 0, 0)	99.454 ( 34.7872 )	84.8155 ( 87.7725 )	46.4458 ( 53.8409 )	67.9855 ( 43.3122 )	156.995 ( 26.5519 )	24.4307 ( 5.9235 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Change at 1h30min(n=0, 0, 0, 0, 0, 0, 10, 3, 4, 2)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	77.1636 ( 54.3735 )	56.924 ( 42.6556 )	106.3098 ( 78.7218 )	144.66 ( 63.4558 )
Change at 2 h(n=2, 5, 3, 10, 4, 3, 0, 0, 0, 0)	155.07 ( 17.211 )	175.3064 ( 73.6695 )	92.15 ( 111.9477 )	74.2293 ( 53.298 )	132.8078 ( 86.8632 )	62.0813 ( 21.3843 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Change at 4 h(n=3, 4, 0, 0, 0, 0, 0, 0, 0, 0)	91.756 ( 42.8758 )	234.0675 ( 80.8278 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Change at 8 h(n=4, 5, 3, 10, 4, 4, 9, 3, 0, 0)	53.6625 ( 29.0532 )	76.8676 ( 46.0017 )	10.9533 ( 43.6964 )	31.0553 ( 15.2461 )	52.8778 ( 31.0733 )	74.3968 ( 75.865 )	30.6717 ( 13.9351 )	25.0467 ( 7.6683 )	99999 ( 99999 )	99999 ( 99999 )
Change at 20 h(n=0, 1, 1, 0, 2, 1, 0, 1, 0, 0)	99999 ( 99999 )	16.236 ( 99999 )	-35.621 ( 99999 )	99999 ( 99999 )	24.5795 ( 4.7284 )	15.446 ( 99999 )	99999 ( 99999 )	23.28 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )

Notes
[103] - PPS
[104] - PPS
[105] - PPS
[106] - PPS
[107] - PPS
[108] - PPS
[109] - PPS
[110] - PPS
[111] - PPS
[112] - PPS

No statistical analyses for this end point

Primary: Baseline Adjusted Maximum Effect (Emax) and Effect at Expected Time of Minimum Drug Concentration in Plasma (Etrough) of PT and aPTT

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End point title

Baseline Adjusted Maximum Effect (Emax) and Effect at Expected Time of Minimum Drug Concentration in Plasma (Etrough) of PT and aPTT ^[113]

End point description

Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Higher values than the baseline indicate anticoagulant effects. Baseline adjusted maximum Effect (Emax) on PT was measured as maximum PT (measured in seconds) minus PT (measured in seconds) at baseline. Emax on aPTT was measured as the ratio of maximum aPTT (measured in seconds) divided by aPTT (measured in seconds) at baseline.

End point type

Primary

End point timeframe

0 h (pre-dose) to 24 h post-dose

Notes
[113] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, inferential statistics were not planned.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Number of subjects analysed	4 ^[114]	5 ^[115]	4 ^[116]	11 ^[117]	4 ^[118]	5 ^[119]	11 ^[120]	5 ^[121]	6 ^[122]	4 ^[123]
Units: seconds
arithmetic mean (standard deviation)
baseline adjusted Emax - PT	13.2 ( 4.45 )	11.5 ( 7.73 )	8.93 ( 3.83 )	5.7 ( 3.8 )	8.73 ( 4.74 )	3.96 ( 1.97 )	3.49 ( 2.05 )	2.16 ( 1.31 )	5.44 ( 3.82 )	6.13 ( 2.99 )
baseline adjusted Etrough - aPTT	4.6 ( 4.97 )	0.02 ( 2.92 )	1.08 ( 4.64 )	1.99 ( 3.65 )	1.1 ( 0.949 )	1.74 ( 2.49 )	0.69 ( 3.68 )	-0.24 ( 3.02 )	0.44 ( 3.36 )	-4.48 ( 6.12 )

Notes
[114] - PPS
[115] - PPS
[116] - PPS
[117] - PPS
[118] - PPS
[119] - PPS
[120] - PPS
[121] - PPS
[122] - PPS
[123] - PPS

No statistical analyses for this end point

Primary: Baseline Adjusted Emax and Etrough of anti -Xa

Top of page

End point title

Baseline Adjusted Emax and Etrough of anti -Xa ^[124]

End point description

This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. Higher Values than the baseline indicate a more pronounced inhibition. Emax on anti-Factor Xa activity was measured as the ratio of maximum anti-Factor Xa activity (measured in U/L) divided by anti-Factor Xa activity (measured in U/L) at baseline. ‘99999’ in the posting indicates that data were not calculated.

End point type

Primary

End point timeframe

0 h (pre-dose) to 24 h post-dose

Notes
[124] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, inferential statistics were not planned.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Number of subjects analysed	0 ^[125]	0 ^[126]	0 ^[127]	0 ^[128]	0 ^[129]	0 ^[130]	0 ^[131]	0 ^[132]	0 ^[133]	0 ^[134]
Units: microgram per liter (mcg/L)

Notes
[125] - Data were not available to report as it was presented graphically, as per planned analysis
[126] - Data were not available to report as it was presented graphically, as per planned analysis
[127] - Data were not available to report as it was presented graphically, as per planned analysis
[128] - Data were not available to report as it was presented graphically, as per planned analysis
[129] - Data were not available to report as it was presented graphically, as per planned analysis
[130] - Data were not available to report as it was presented graphically, as per planned analysis
[131] - Data were not available to report as it was presented graphically, as per planned analysis
[132] - Data were not available to report as it was presented graphically, as per planned analysis
[133] - Data were not available to report as it was presented graphically, as per planned analysis
[134] - Data were not available to report as it was presented graphically, as per planned analysis

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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End point title

Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

End point description

An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; lifethreatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent adverse events were defined as adverse events/serious adverse events that started or worsened after the study drug treatment.

End point type

Secondary

End point timeframe

From the start of study treatment up to 11 days

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Number of subjects analysed	4 ^[135]	5 ^[136]	4 ^[137]	11 ^[138]	4 ^[139]	5 ^[140]	11 ^[141]	5 ^[142]	6 ^[143]	4 ^[144]
Units: subjects
TEAEs	2	1	1	4	3	0	2	1	2	0
TESAEs	1	0	0	0	0	0	0	0	0	0

Notes
[135] - SAF
[136] - SAF
[137] - SAF
[138] - SAF
[139] - SAF
[140] - SAF
[141] - SAF
[142] - SAF
[143] - SAF
[144] - SAF

No statistical analyses for this end point

Secondary: Model Independent Pharmacokinetic: Area Under the Concentration Versus Time Curve From Zero to Infinity Divided by Dose (AUC/D) of Rivaroxaban in Plasma

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End point title

Model Independent Pharmacokinetic: Area Under the Concentration Versus Time Curve From Zero to Infinity Divided by Dose (AUC/D) of Rivaroxaban in Plasma ^[145]

End point description

Area under the concentration versus time curve from zero to infinity after single (first) dose divided by dose. AUC/D of Rivaroxaban was reported. Geometric mean and percentagegeometric coefficient of variation (%CV) were reported. In the below categories of the table, “n” signifies the number of subjects evaluable for the corresponding analyte.

End point type

Secondary

End point timeframe

0 h (pre-dose) to 24 h post-dose

Notes
[145] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistics were reported only for the reporting groups specific to this endpoint.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose
Number of subjects analysed	4 ^[146]	5 ^[147]	4 ^[148]	11 ^[149]	4 ^[150]	5 ^[151]
Units: hours per liter (h/L)
geometric mean (geometric coefficient of variation)	0.134 ( 37.7 )	0.0878 ( 40 )	0.141 ( 26.8 )	0.173 ( 39.6 )	0.145 ( 18.9 )	0.11 ( 46.7 )

Notes
[146] - PPS
[147] - PPS
[148] - PPS
[149] - PPS
[150] - PPS
[151] - PPS

No statistical analyses for this end point

Secondary: Model Derived Pharmacokinetic: Area Under the Concentration Versus Time Curve From Zero to Infinity Divided by Dose (AUC/D) of Rivaroxaban in Plasma

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End point title

Model Derived Pharmacokinetic: Area Under the Concentration Versus Time Curve From Zero to Infinity Divided by Dose (AUC/D) of Rivaroxaban in Plasma

End point description

End point type

Secondary

End point timeframe

0 h (pre-dose) to 24 h post-dose

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Number of subjects analysed	4 ^[152]	5 ^[153]	4 ^[154]	11 ^[155]	4 ^[156]	5 ^[157]	11 ^[158]	5 ^[159]	6 ^[160]	4 ^[161]
Units: hours per liter (h/L)
geometric mean (geometric coefficient of variation)	0.132 ( 13.1 )	0.0931 ( 22.8 )	0.147 ( 25.4 )	0.173 ( 21 )	0.135 ( 16.1 )	0.11 ( 29.4 )	0.242 ( 26.3 )	0.14 ( 30.5 )	0.253 ( 17.6 )	0.164 ( 13.8 )

Notes
[152] - PPS
[153] - PPS
[154] - PPS
[155] - PPS
[156] - PPS
[157] - PPS
[158] - PPS
[159] - PPS
[160] - PPS
[161] - PPS

No statistical analyses for this end point

Secondary: Model Independent Pharmacokinetic: Area Under the Concentration divided by dose (mg) per kg body weight (AUCnorm) of Rivaroxaban in Plasma

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End point title

Model Independent Pharmacokinetic: Area Under the Concentration divided by dose (mg) per kg body weight (AUCnorm) of Rivaroxaban in Plasma ^[162]

End point description

Area under the concentration versus time from zero to infinity after single (first) dose, divided by dose per kilogram body weight. Geometric and percentage geometric coefficient of variation (%CV) were reported.

End point type

Secondary

End point timeframe

0 h (pre-dose) to 24 h post-dose

Notes
[162] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistics were reported only for the reporting groups specific to this endpoint.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose
Number of subjects analysed	4 ^[163]	5 ^[164]	4 ^[165]	11 ^[166]	4 ^[167]	5 ^[168]
Units: kilogramhour per liter (kgh/L)
geometric mean (geometric coefficient of variation)	9.12 ( 37.3 )	5.02 ( 37.9 )	5.63 ( 32.9 )	5.11 ( 41.7 )	6.37 ( 60.1 )	3.8 ( 39.4 )

Notes
[163] - PPS
[164] - PPS
[165] - PPS
[166] - PPS
[167] - PPS
[168] - PPS

No statistical analyses for this end point

Secondary: Model Derived Pharmacokinetic: Area Under the Concentration divided by dose (mg) per kg body weight (AUCnorm) of Rivaroxaban in Plasma

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End point title

Model Derived Pharmacokinetic: Area Under the Concentration divided by dose (mg) per kg body weight (AUCnorm) of Rivaroxaban in Plasma

End point description

End point type

Secondary

End point timeframe

0 h (pre-dose) to 24 h post-dose

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Number of subjects analysed	4 ^[169]	5 ^[170]	4 ^[171]	11 ^[172]	4 ^[173]	5 ^[174]	11 ^[175]	5 ^[176]	6 ^[177]	4 ^[178]
Units: kilogramhour per liter (kgh/L)
geometric mean (geometric coefficient of variation)	8.99 ( 15.1 )	5.32 ( 20.5 )	5.87 ( 21.3 )	5.11 ( 22.7 )	4.89 ( 31.5 )	3.82 ( 27 )	3.81 ( 31.3 )	2.2 ( 51 )	2.22 ( 16.9 )	1.54 ( 26.4 )

Notes
[169] - PPS
[170] - PPS
[171] - PPS
[172] - PPS
[173] - PPS
[174] - PPS
[175] - PPS
[176] - PPS
[177] - PPS
[178] - PPS

No statistical analyses for this end point

Secondary: Model Independent Pharmacokinetic: Maximum Observed Drug Concentration Divided by Dose (Cmax/D) of Rivaroxaban in Plasma

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End point title

Model Independent Pharmacokinetic: Maximum Observed Drug Concentration Divided by Dose (Cmax/D) of Rivaroxaban in Plasma ^[179]

End point description

Maximum observed drug concentration, directly taken from analytical data, divided by dose. Cmax/D of Rivaroxaban wasreported. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

End point type

Secondary

End point timeframe

0 h (pre-dose) to 24 h post-dose

Notes
[179] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistics were reported only for the reporting groups specific to this endpoint.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose
Number of subjects analysed	4 ^[180]	5 ^[181]	4 ^[182]	11 ^[183]	4 ^[184]	5 ^[185]
Units: 1/liter
geometric mean (geometric coefficient of variation)	0.0161 ( 45.7 )	0.0109 ( 45.8 )	0.0188 ( 59.9 )	0.0214 ( 58.5 )	0.0214 ( 35.9 )	0.0117 ( 58 )

Notes
[180] - PPS
[181] - PPS
[182] - PPS
[183] - PPS
[184] - PPS
[185] - PPS

No statistical analyses for this end point

Secondary: Model Derived Pharmacokinetic: Maximum Observed Drug Concentration Divided by Dose (Cmax/D) of Rivaroxaban in Plasma

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End point title

Model Derived Pharmacokinetic: Maximum Observed Drug Concentration Divided by Dose (Cmax/D) of Rivaroxaban in Plasma

End point description

Maximum observed drug concentration, directly taken from analytical data, divided by dose. Cmax/D of Rivaroxaban was reported. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

End point type

Secondary

End point timeframe

0 h (pre-dose) to 24 h post-dose

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Number of subjects analysed	4 ^[186]	5 ^[187]	4 ^[188]	11 ^[189]	4 ^[190]	5 ^[191]	11 ^[192]	5 ^[193]	6 ^[194]	4 ^[195]
Units: microgram per liter
geometric mean (geometric coefficient of variation)	0.0129 ( 11.4 )	0.00952 ( 18.7 )	0.0193 ( 15.7 )	0.0198 ( 40.7 )	0.0151 ( 27.1 )	0.0088 ( 23.8 )	0.0303 ( 42 )	0.0112 ( 24.5 )	0.0476 ( 40.3 )	0.035 ( 15.8 )

Notes
[186] - PPS
[187] - PPS
[188] - PPS
[189] - PPS
[190] - PPS
[191] - PPS
[192] - PPS
[193] - PPS
[194] - PPS
[195] - PPS

No statistical analyses for this end point

Secondary: Model Independent Pharmacokinetic: Maximum Observed Drug Concentration Divided by Dose per Kilogram Body Weight (Cmax,norm) of Rivaroxaban in Plasma

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End point title

Model Independent Pharmacokinetic: Maximum Observed Drug Concentration Divided by Dose per Kilogram Body Weight (Cmax,norm) of Rivaroxaban in Plasma ^[196]

End point description

Maximum observed drug concentration, directly taken from analytical data, divided by dose per kilogram body weight. Geometric and percentage geometric coefficient of variation (%CV) were reported. 0 h (pre-dose) to 24 h post-dose

End point type

Secondary

End point timeframe

0 h (pre-dose) to 24 h post-dose

Notes
[196] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistics were reported only for the reporting groups specific to this endpoint.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose
Number of subjects analysed	4 ^[197]	5 ^[198]	4 ^[199]	11 ^[200]	4 ^[201]	5 ^[202]
Units: kilogram per liter (kg/L)
geometric mean (geometric coefficient of variation)	1.09 ( 43.5 )	0.623 ( 38.2 )	0.747 ( 74.4 )	0.633 ( 57.6 )	0.942 ( 51.2 )	0.405 ( 41.1 )

Notes
[197] - PPS
[198] - PPS
[199] - PPS
[200] - PPS
[201] - PPS
[202] - PPS

No statistical analyses for this end point

Secondary: Model Derived Pharmacokinetic: Maximum Observed Drug Concentration Divided by Dose per Kilogram Body Weight (Cmax,norm) of Rivaroxaban in Plasma

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End point title

Model Derived Pharmacokinetic: Maximum Observed Drug Concentration Divided by Dose per Kilogram Body Weight (Cmax,norm) of Rivaroxaban in Plasma

End point description

Maximum observed drug concentration, directly taken from analytical data, divided by dose per kilogram body weight. Geometric and percentage geometric coefficient of variation (%CV) were reported.

End point type

Secondary

End point timeframe

0 h (pre-dose) to 24 h post-dose

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Number of subjects analysed	4 ^[203]	5 ^[204]	4 ^[205]	11 ^[206]	4 ^[207]	5 ^[208]	11 ^[209]	5 ^[210]	6 ^[211]	4 ^[212]
Units: kilogram per liter (kg/L)
geometric mean (geometric coefficient of variation)	0.876 ( 3.52 )	0.544 ( 8.09 )	0.77 ( 4.66 )	0.586 ( 35.8 )	0.546 ( 7.49 )	0.305 ( 7.53 )	0.476 ( 31.5 )	0.175 ( 20.7 )	0.418 ( 29.9 )	0.329 ( 12 )

Notes
[203] - PPS
[204] - PPS
[205] - PPS
[206] - PPS
[207] - PPS
[208] - PPS
[209] - PPS
[210] - PPS
[211] - PPS
[212] - PPS

No statistical analyses for this end point

Secondary: Model Independent Pharmacokinetic: Drug Concentration at 24 Hours (C24h) Post-dose of Rivaroxaban in Plasma

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End point title

Model Independent Pharmacokinetic: Drug Concentration at 24 Hours (C24h) Post-dose of Rivaroxaban in Plasma ^[213]

End point description

Geometric and percentage geometric coefficient of variation (%CV) were reported.

End point type

Secondary

End point timeframe

0 h (pre-dose) to 24 h post-dose

Notes
[213] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistics were reported only for the reporting groups specific to this endpoint.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose
Number of subjects analysed	4 ^[214]	5 ^[215]	4 ^[216]	11 ^[217]	4 ^[218]	5 ^[219]
Units: microgram per liter (mcg/L)
geometric mean (geometric coefficient of variation)	9.55 ( 30 )	11.9 ( 77 )	3.43 ( 127 )	4.18 ( 64 )	12.5 ( 128 )	7.44 ( 123 )

Notes
[214] - PPS
[215] - PPS
[216] - PPS
[217] - PPS
[218] - PPS
[219] - PPS

No statistical analyses for this end point

Secondary: Model Derived Pharmacokinetic: Drug Concentration at 24 Hours (C24h) Post-dose of Rivaroxaban in Plasma

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End point title

Model Derived Pharmacokinetic: Drug Concentration at 24 Hours (C24h) Post-dose of Rivaroxaban in Plasma

End point description

Geometric and percentage geometric coefficient of variation (%CV) were reported.

End point type

Secondary

End point timeframe

0 h (pre-dose) to 24 h post-dose

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Number of subjects analysed	4 ^[220]	5 ^[221]	4 ^[222]	11 ^[223]	4 ^[224]	5 ^[225]	11 ^[226]	5 ^[227]	6 ^[228]	4 ^[229]
Units: microgram per liter (mcg/L)
geometric mean (geometric coefficient of variation)	7.94 ( 35.4 )	9.46 ( 55.6 )	3.18 ( 73.9 )	3.35 ( 57.6 )	8.46 ( 98.5 )	7.18 ( 96.1 )	3.27 ( 65 )	5.71 ( 129 )	1.94 ( 33.5 )	2.39 ( 39.9 )

Notes
[220] - PPS
[221] - PPS
[222] - PPS
[223] - PPS
[224] - PPS
[225] - PPS
[226] - PPS
[227] - PPS
[228] - PPS
[229] - PPS

No statistical analyses for this end point

Secondary: Model Independent Pharmacokinetic: Time to Reach Maximum Drug Concentration (tmax) of Rivaroxaban in Plasma

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End point title

Model Independent Pharmacokinetic: Time to Reach Maximum Drug Concentration (tmax) of Rivaroxaban in Plasma ^[230]

End point description

Time to reach maximum drug concentration in the measured matrix, directly taken from analytical data. Median and range were reported.

End point type

Secondary

End point timeframe

0 h (pre-dose) to 24 h post-dose

Notes
[230] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistics were reported only for the reporting groups specific to this endpoint.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose
Number of subjects analysed	4 ^[231]	5 ^[232]	4 ^[233]	11 ^[234]	4 ^[235]	5 ^[236]
Units: hour
median (full range (min-max))	2.45 (0.933 to 3.37)	4.05 (0.583 to 4.73)	2.93 (2 to 8.27)	2.17 (1.02 to 8.25)	1.74 (1 to 2.5)	4.62 (3.12 to 8)

Notes
[231] - PPS
[232] - PPS
[233] - PPS
[234] - PPS
[235] - PPS
[236] - PPS

No statistical analyses for this end point

Secondary: Model Derived Pharmacokinetic: Time to Reach Maximum Drug Concentration (tmax) of Rivaroxaban in Plasma

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End point title

Model Derived Pharmacokinetic: Time to Reach Maximum Drug Concentration (tmax) of Rivaroxaban in Plasma

End point description

Time to reach maximum drug concentration in the measured matrix, directly taken from analytical data. Median and range were reported.

End point type

Secondary

End point timeframe

0 h (pre-dose) to 24 h post-dose

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Number of subjects analysed	4 ^[237]	5 ^[238]	4 ^[239]	11 ^[240]	4 ^[241]	5 ^[242]	11 ^[243]	5 ^[244]	6 ^[245]	4 ^[246]
Units: hour
median (full range (min-max))	2.57 (2.5 to 3)	2.53 (2.47 to 2.93)	2.22 (1.73 to 2.7)	2.2 (1.67 to 4.23)	2.32 (1.87 to 2.67)	4 (3.2 to 5.13)	2.37 (1.33 to 4.67)	3.63 (1.73 to 6.2)	1.43 (1.23 to 2.33)	1.45 (1.17 to 1.6)

Notes
[237] - PPS
[238] - PPS
[239] - PPS
[240] - PPS
[241] - PPS
[242] - PPS
[243] - PPS
[244] - PPS
[245] - PPS
[246] - PPS

No statistical analyses for this end point

Secondary: Model Independent Pharmacokinetic: Half Life Associated With the Terminal Slope (t1/2) of Rivaroxaban in Plasma

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End point title

Model Independent Pharmacokinetic: Half Life Associated With the Terminal Slope (t1/2) of Rivaroxaban in Plasma ^[247]

End point description

Half-life associated with the terminal slope. Geometric mean and percentage geometric coefficient of variation(%CV) were reported.

End point type

Secondary

End point timeframe

0 h (pre-dose) to 24 h post-dose

Notes
[247] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive statistics were reported only for the reporting groups specific to this endpoint.

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose
Number of subjects analysed	4 ^[248]	5 ^[249]	4 ^[250]	11 ^[251]	4 ^[252]	5 ^[253]
Units: hour
geometric mean (geometric coefficient of variation)	5.24 ( 15.7 )	5.22 ( 41.1 )	3.96 ( 24 )	4.44 ( 16.5 )	5.68 ( 39.6 )	5.04 ( 30.6 )

Notes
[248] - PPS
[249] - PPS
[250] - PPS
[251] - PPS
[252] - PPS
[253] - PPS

No statistical analyses for this end point

Secondary: Model Derived Pharmacokinetic: Half Life Associated With the Terminal Slope (t1/2) of Rivaroxaban in Plasma

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End point title

Model Derived Pharmacokinetic: Half Life Associated With the Terminal Slope (t1/2) of Rivaroxaban in Plasma

End point description

Half-life associated with the terminal slope. Geometric mean and percentage geometric coefficient of variation(%CV) were reported.

End point type

Secondary

End point timeframe

0 h (pre-dose) to 24 h post-dose

End point values	Age 12-18 Years: Tablet-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 6-12 Years: Tablet-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 2-6 Years: Suspension-High Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Number of subjects analysed	4 ^[254]	5 ^[255]	4 ^[256]	11 ^[257]	4 ^[258]	5 ^[259]	11 ^[260]	5 ^[261]	6 ^[262]	4 ^[263]
Units: hour
geometric mean (geometric coefficient of variation)	12.1 ( 3.09 )	12.2 ( 4.39 )	12 ( 4.54 )	12.2 ( 3.93 )	12.9 ( 4.67 )	12.3 ( 6.41 )	12.9 ( 6.32 )	12.6 ( 7.31 )	12.7 ( 3.66 )	12.7 ( 3.08 )

Notes
[254] - PPS
[255] - PPS
[256] - PPS
[257] - PPS
[258] - PPS
[259] - PPS
[260] - PPS
[261] - PPS
[262] - PPS
[263] - PPS

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From the start of study treatment up to 11 days

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Age 12-18 Years: Tablet-Low Dose

Reporting group description

Subjects aged from 12 to 18 years were administered with a single oral dose of rivaroxabantablet under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received low dose of rivaroxaban (equivalent to 10 mg in adults) ranging from 2.5 to 7.5 mg, and subjects with a body weight (comparable to adults) of 50 to 100 kg received a low dose of 10 mg.

Reporting group title

Age 6-12 Years: Tablet-Low Dose

Reporting group description

Reporting group title

Age 6-12 Years: Suspension-Low Dose

Reporting group description

Reporting group title

Age 12-18 Years: Tablet-High Dose

Reporting group description

Subjects aged from 12 to 18 years were administered with a single oral dose of rivaroxaban tablet under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 5 to 15 mg, and subjects with a body weight (comparable to adults) of 50 to 100 kg received a high dose of 20 mg.

Reporting group title

Age 6-12 Years: Tablet-High Dose

Reporting group description

Subjects aged from 6 to 12 years were administered with a single oral dose of rivaroxaban tabletunder fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 5 to 15 mg, and subjects with a body weight (comparable to adults) of 50 to 100 kg received a high dose of 20 mg.

Reporting group title

Age 2-6 Years: Suspension-High Dose

Reporting group description

Subjects aged from 2 to 6 years were administered with a single oral dose of rivaroxabansuspension under fed conditions, and the dosage was adjusted based on the individual age andbody weight. Subjects with a body weight of 2 to 14 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 0.8 to 5.0 mg.

Reporting group title

Age 6-12 Years: Suspension-High Dose

Reporting group description

Subjects aged from 6 to 12 years were administered with a single oral dose of rivaroxaban suspension under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 14 to 50 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 5 to 10 mg.

Reporting group title

Age 2-6 Years: Suspension-Low Dose

Reporting group description

Subjects aged from 2 to 6 years were administered with a single oral dose of rivaroxabansuspension under fed conditions, and the dosage was adjusted based on the individual ageand body weight. Subjects with a body weight of 2 to 14 kg received low dose of rivaroxaban (equivalent to 10 mg in adults) ranging from 0.4 to 2.5 mg.

Reporting group title

Age 6 months-2 years: Suspension-Low Dose

Reporting group description

Reporting group title

Age 6 months-2 years: Suspension-High Dose

Reporting group description

Subjects aged from 6 months to 2 years were administered with a single oral dose of rivaroxaban suspension under fed conditions, and the dosage was adjusted based on the individual age and body weight. Subjects with a body weight of 2 to 14 kg received high dose of rivaroxaban (equivalent to 20 mg in adults) ranging from 0.8 to 5.0 mg.

Serious adverse events	Age 12-18 Years: Tablet-Low Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-High Dose	Age 2-6 Years: Suspension-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0	0	0
Vascular disorders
Pelvic venous thrombosis
subjects affected / exposed	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Age 12-18 Years: Tablet-Low Dose	Age 6-12 Years: Tablet-Low Dose	Age 6-12 Years: Suspension-Low Dose	Age 12-18 Years: Tablet-High Dose	Age 6-12 Years: Tablet-High Dose	Age 2-6 Years: Suspension-High Dose	Age 6-12 Years: Suspension-High Dose	Age 2-6 Years: Suspension-Low Dose	Age 6 months-2 years: Suspension-Low Dose	Age 6 months-2 years: Suspension-High Dose
Total subjects affected by non serious adverse events
subjects affected / exposed	1 / 4 (25.00%)	1 / 4 (25.00%)	4 / 11 (36.36%)	1 / 5 (20.00%)	3 / 4 (75.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	2 / 11 (18.18%)	2 / 6 (33.33%)	0 / 4 (0.00%)
Investigations
C-reactive protein increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Contusion
subjects affected / exposed	0 / 4 (0.00%)	1 / 4 (25.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0	0
Nervous system disorders
Headache
subjects affected / exposed	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
General disorders and administration site conditions
Catheter site bruise
subjects affected / exposed	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Pyrexia
subjects affected / exposed	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	2	0	1	0	0	0	0	0
Vessel puncture site bruise
subjects affected / exposed	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	1	0	1	0	0
Vessel puncture site pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Constipation
subjects affected / exposed	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	0
Gastritis
subjects affected / exposed	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Dyspepsia
subjects affected / exposed	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Vomiting
subjects affected / exposed	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Upper respiratory tract inflammation
subjects affected / exposed	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Skin and subcutaneous tissue disorders
Dermatitis allergic
subjects affected / exposed	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Dermatitis diaper
subjects affected / exposed	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Urticaria
subjects affected / exposed	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	6	0	0	0	0	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

13 Sep 2011

A taste and texture questionnaire was introduced to assess the children’s acceptance of the oral suspension in the early development phase. Clarification of exclusion criterion “history of severe allergies, severe nonallergic drug reactions, or multiple drug allergies” where severe was also added to non-allergic drug reactions. Re-screening of the children was introduced when a repeated local lab clotting test was within the normal range. Clarification of approximate total blood volume ranges were given. Single repetition of local laboratory clotting tests before administration of study drug was done. Administrative changes were done.

19 Jun 2013

Updates on approved indications of rivaroxaban’s were given. Total number of children included were corrected. Study duration was extended due to slow enrolment. Changes to the exclusion criteria were made. Spiking experiments results to reliably predict rivaroxaban oral doses for children resulting in similar drug exposure as in adults were updated. Changes with regard to local safety lab at Visit 1, 2 and 3 were described. Changes with regard to AE reporting of adverse events (AEs) occurring between Visit 1 and Visit 2 which were not reported as AEs but recorded as medical history were made. Changes in the section on expected adverse events with reference to the most current version of the Investigators Brochure (IB) and the Company Core Data Sheet (CCDS) attached to the IB were made. Measurement of anti-Factor Xa as local lab clotting test was removed. PK sampling time windows were extended. Introduction of a new integrated flow chart compiling the information related to all age groups, from 6 months to <18 years and laboratory examinations was made. Sponsor’s medical expert and medically responsible person were changed.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Baseline adjusted Emax and Etrough of anti-Xa could not be included in basic results format as the results were presented graphically. 99999=Data not calculated, Occurrence of "±” in relation with geometric CV is auto-generated and cannot be deleted.

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Clinical trials

Clinical Trial Results: Single-dose pilot study of oral rivaroxaban in pediatric subjects with venous thromboembolism

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Model Independent Pharmacokinetic: Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC) of Rivaroxaban in Plasma

Primary: Model Independent Pharmacokinetic: Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC) of Rivaroxaban in Plasma

Primary: Model Derived Pharmacokinetic: Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC) of Rivaroxaban in Plasma

Primary: Model Derived Pharmacokinetic: Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC) of Rivaroxaban in Plasma

Primary: Model Independent Pharmacokinetic: Area Under the Concentration From Time Zero to the Last Data Point (AUC[0-tlast]) of Rivaroxaban in Plasma

Primary: Model Independent Pharmacokinetic: Area Under the Concentration From Time Zero to the Last Data Point (AUC[0-tlast]) of Rivaroxaban in Plasma

Primary: Model Independent Pharmacokinetic: Maximum Observed Drug Concentration (Cmax) of Rivaroxaban in Plasma

Primary: Model Independent Pharmacokinetic: Maximum Observed Drug Concentration (Cmax) of Rivaroxaban in Plasma

Primary: Model Derived Pharmacokinetic: Maximum Observed Drug Concentration (Cmax) of Rivaroxaban in Plasma

Primary: Model Derived Pharmacokinetic: Maximum Observed Drug Concentration (Cmax) of Rivaroxaban in Plasma

Primary: Model Derived Pharmacokinetic: Clearance (CL) of Rivaroxaban in Plasma

Primary: Model Derived Pharmacokinetic: Clearance (CL) of Rivaroxaban in Plasma

Primary: Model Derived Pharmacokinetic: Volume of Distribution at Steady State (Vss) of Rivaroxaban in Plasma

Primary: Model Derived Pharmacokinetic: Volume of Distribution at Steady State (Vss) of Rivaroxaban in Plasma

Primary: Model Derived Pharmacokinetic: Absorption Rate Constant (Ka) of Rivaroxaban in Plasma

Primary: Model Derived Pharmacokinetic: Absorption Rate Constant (Ka) of Rivaroxaban in Plasma

Primary: Relative Change from Baseline in Prothrombin Time (PT)

Primary: Relative Change from Baseline in Prothrombin Time (PT)

Primary: Relative Change from Baseline in Adjusted Partial Thromboplastin Time (aPTT)

Primary: Relative Change from Baseline in Adjusted Partial Thromboplastin Time (aPTT)

Primary: Absolute Change from Baseline in Anti-factor Xa activity (anti-Xa)

Primary: Absolute Change from Baseline in Anti-factor Xa activity (anti-Xa)

Primary: Baseline Adjusted Maximum Effect (Emax) and Effect at Expected Time of Minimum Drug Concentration in Plasma (Etrough) of PT and aPTT

Primary: Baseline Adjusted Maximum Effect (Emax) and Effect at Expected Time of Minimum Drug Concentration in Plasma (Etrough) of PT and aPTT

Primary: Baseline Adjusted Emax and Etrough of anti -Xa

Primary: Baseline Adjusted Emax and Etrough of anti -Xa

Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

Secondary: Model Independent Pharmacokinetic: Area Under the Concentration Versus Time Curve From Zero to Infinity Divided by Dose (AUC/D) of Rivaroxaban in Plasma

Secondary: Model Independent Pharmacokinetic: Area Under the Concentration Versus Time Curve From Zero to Infinity Divided by Dose (AUC/D) of Rivaroxaban in Plasma

Secondary: Model Derived Pharmacokinetic: Area Under the Concentration Versus Time Curve From Zero to Infinity Divided by Dose (AUC/D) of Rivaroxaban in Plasma

Secondary: Model Derived Pharmacokinetic: Area Under the Concentration Versus Time Curve From Zero to Infinity Divided by Dose (AUC/D) of Rivaroxaban in Plasma

Secondary: Model Independent Pharmacokinetic: Area Under the Concentration divided by dose (mg) per kg body weight (AUCnorm) of Rivaroxaban in Plasma

Secondary: Model Independent Pharmacokinetic: Area Under the Concentration divided by dose (mg) per kg body weight (AUCnorm) of Rivaroxaban in Plasma

Secondary: Model Derived Pharmacokinetic: Area Under the Concentration divided by dose (mg) per kg body weight (AUCnorm) of Rivaroxaban in Plasma

Secondary: Model Derived Pharmacokinetic: Area Under the Concentration divided by dose (mg) per kg body weight (AUCnorm) of Rivaroxaban in Plasma

Secondary: Model Independent Pharmacokinetic: Maximum Observed Drug Concentration Divided by Dose (Cmax/D) of Rivaroxaban in Plasma

Secondary: Model Independent Pharmacokinetic: Maximum Observed Drug Concentration Divided by Dose (Cmax/D) of Rivaroxaban in Plasma

Secondary: Model Derived Pharmacokinetic: Maximum Observed Drug Concentration Divided by Dose (Cmax/D) of Rivaroxaban in Plasma

Secondary: Model Derived Pharmacokinetic: Maximum Observed Drug Concentration Divided by Dose (Cmax/D) of Rivaroxaban in Plasma

Secondary: Model Independent Pharmacokinetic: Maximum Observed Drug Concentration Divided by Dose per Kilogram Body Weight (Cmax,norm) of Rivaroxaban in Plasma

Secondary: Model Independent Pharmacokinetic: Maximum Observed Drug Concentration Divided by Dose per Kilogram Body Weight (Cmax,norm) of Rivaroxaban in Plasma

Secondary: Model Derived Pharmacokinetic: Maximum Observed Drug Concentration Divided by Dose per Kilogram Body Weight (Cmax,norm) of Rivaroxaban in Plasma

Secondary: Model Derived Pharmacokinetic: Maximum Observed Drug Concentration Divided by Dose per Kilogram Body Weight (Cmax,norm) of Rivaroxaban in Plasma

Secondary: Model Independent Pharmacokinetic: Drug Concentration at 24 Hours (C24h) Post-dose of Rivaroxaban in Plasma

Secondary: Model Independent Pharmacokinetic: Drug Concentration at 24 Hours (C24h) Post-dose of Rivaroxaban in Plasma

Secondary: Model Derived Pharmacokinetic: Drug Concentration at 24 Hours (C24h) Post-dose of Rivaroxaban in Plasma

Secondary: Model Derived Pharmacokinetic: Drug Concentration at 24 Hours (C24h) Post-dose of Rivaroxaban in Plasma

Secondary: Model Independent Pharmacokinetic: Time to Reach Maximum Drug Concentration (tmax) of Rivaroxaban in Plasma

Secondary: Model Independent Pharmacokinetic: Time to Reach Maximum Drug Concentration (tmax) of Rivaroxaban in Plasma

Secondary: Model Derived Pharmacokinetic: Time to Reach Maximum Drug Concentration (tmax) of Rivaroxaban in Plasma

Secondary: Model Derived Pharmacokinetic: Time to Reach Maximum Drug Concentration (tmax) of Rivaroxaban in Plasma

Secondary: Model Independent Pharmacokinetic: Half Life Associated With the Terminal Slope (t1/2) of Rivaroxaban in Plasma

Secondary: Model Independent Pharmacokinetic: Half Life Associated With the Terminal Slope (t1/2) of Rivaroxaban in Plasma

Secondary: Model Derived Pharmacokinetic: Half Life Associated With the Terminal Slope (t1/2) of Rivaroxaban in Plasma

Secondary: Model Derived Pharmacokinetic: Half Life Associated With the Terminal Slope (t1/2) of Rivaroxaban in Plasma

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Single-dose pilot study of oral rivaroxaban in pediatric subjects with venous thromboembolism