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Clinical Trial Results:
Multicenter, open-label, active-controlled, randomized study to evaluate the efficacy and safety of an age-and body weight-adjusted rivaroxaban regimen compared to standard of care in children with acute venous thromboembolism

Summary
EudraCT number	2014-000565-47
Trial protocol	ES AT IT NL BE DE GB PL IE FR FI HU SE SK PT
Global end of trial date	30 Jan 2019

Results information
Results version number	v1(current)
This version publication date	14 Aug 2019
First version publication date	14 Aug 2019
Other versions

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

14372

ISRCTN number

US NCT number

NCT02234843

WHO universal trial number (UTN)

Sponsor organisation name

Bayer AG

Sponsor organisation address

Kaiser-Wilhelm-Allee, D-51368 Leverkusen, Germany,

Public contact

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

Scientific contact

Therapeutic Area Head, Therapeutic Area Head, 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?

Analysis stage

Final

Date of interim/final analysis

30 Jan 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

30 Jan 2019

Was the trial ended prematurely?

Main objective of the trial

The primary efficacy objective is: To assess the incidence of symptomatic recurrent venous thromboembolism The principal safety objective is: To assess the incidence of overt major and clinically relevant non-major bleeding.

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 form was read by and explained to all subjects and/or parent(s)/ legal guardian(s) as appropriate. Participating adult 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. For children all relevant study information was summarized in an integrated child information sheet, an informed consent and an informed assent form provided. Consent was asked from the parent(s)/ legal guardian(s) and, if appropriate as determined by local regulation, age and individual child capability, was asked from the child, according to country-specific regulations. The parent(s)/legal guardian(s) and the child, if applicable, would have sample time and opportunity to ask questions and would be informed about the right to withdraw from the study at any time without any disadvantage and without having to provide reasons for their decision. A child could only enter the study if the parent(s)/legal guardian(s) voluntarily agree to sign and date the informed consent and the child provided informed consent or assent, as appropriate and determined by local regulation, age and individual child capability, and had done so. 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

12 Nov 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 3

Country: Number of subjects enrolled

Australia: 10

Country: Number of subjects enrolled

Austria: 12

Country: Number of subjects enrolled

Belgium: 10

Country: Number of subjects enrolled

Brazil: 5

Country: Number of subjects enrolled

Canada: 25

Country: Number of subjects enrolled

China: 9

Country: Number of subjects enrolled

Finland: 1

Country: Number of subjects enrolled

France: 26

Country: Number of subjects enrolled

Germany: 22

Country: Number of subjects enrolled

Hong Kong: 1

Country: Number of subjects enrolled

Hungary: 7

Country: Number of subjects enrolled

Ireland: 2

Country: Number of subjects enrolled

Israel: 15

Country: Number of subjects enrolled

Italy: 22

Country: Number of subjects enrolled

Japan: 6

Country: Number of subjects enrolled

Mexico: 5

Country: Number of subjects enrolled

Netherlands: 31

Country: Number of subjects enrolled

Portugal: 1

Country: Number of subjects enrolled

Russian Federation: 46

Country: Number of subjects enrolled

Singapore: 5

Country: Number of subjects enrolled

Slovakia: 2

Country: Number of subjects enrolled

Spain: 13

Country: Number of subjects enrolled

Sweden: 1

Country: Number of subjects enrolled

Switzerland: 7

Country: Number of subjects enrolled

Turkey: 8

Country: Number of subjects enrolled

United Kingdom: 51

Country: Number of subjects enrolled

United States: 154

Worldwide total number of subjects

500

EEA total number of subjects

201

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)

170

Adolescents (12-17 years)

276

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Study was conducted at 109 study centers in 28 countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Finland, France, Germany, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Mexico, Netherlands, Portugal, Russia, Singapore, Slovakia, Spain, Sweden, Switzerland, Turkey, UK, and USA between 13 Nov 2014 and 30 Jan 2019.

Screening details

A total of 520 children were screened for this study. Twenty children did not pass the screen of inclusion/exclusion criteria. A total of 500 children were randomized 2:1 to study treatment.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Rivaroxaban, aged 12-<18

Arm description

Children aged 12-<18 years randomized to rivaroxaban received either tablet or oral suspension after at least 5 days administration of initial therapy with UFH/LMWH/fondaparinux . Children with body weight of ≥ 20 kg received rivaroxaban tablets or oral suspension.

Arm type

Experimental

Investigational medicinal product name

Rivaroxaban

Investigational medicinal product code

BAY 59-7939

Other name

Xarelto

Pharmaceutical forms

Tablet, Oral suspension

Routes of administration

Oral use

Dosage and administration details

Children with body weight of ≥ 30 kg were treated according to a once daily (o.d.) regimen, irrespective of whether they received rivaroxaban tablets or oral suspension. For switching from heparin/fondaparinux to rivaroxaban, the pharmacological activity of unfractionated heparin (UFH), low molecular weight heparin (LMWH) and fondaparinux was taken into account. Children who switched from rivaroxaban to heparin/ fondaparinux could switch at the time of the next scheduled dose. Children who switched from rivaroxaban to vitamin K antagonist (VKA) needed to continue rivaroxaban for 48 hours after the first dose of VKA.

Rivaroxaban, aged 6-<12

Arm description

Children aged 6-<12 years randomized to rivaroxaban received either tablet or oral suspension after at least 5 days administration of initial therapy with UFH/LMWH/fondaparinux . Children with body weight of ≥ 20 kg received rivaroxaban tablets or oral suspension. Children with body weight of < 20 kg received rivaroxaban as oral suspension.

Arm type

Experimental

Investigational medicinal product name

Rivaroxaban

Investigational medicinal product code

BAY 59-7939

Other name

Xarelto

Pharmaceutical forms

Tablet, Oral suspension

Routes of administration

Oral use

Dosage and administration details

Children with body weight of ≥ 30 kg were treated according to a once daily (o.d.) regimen, irrespective of whether they received rivaroxaban tablets or oral suspension. Children with body weight between 12 and < 30 kg received rivaroxaban twice daily (b.i.d) with a dosing intervals of approximately 12 hours. For switching from heparin/fondaparinux to rivaroxaban, the pharmacological activity of unfractionated heparin (UFH), low molecular weight heparin (LMWH) and fondaparinux was taken into account. Children who switched from rivaroxaban to heparin/ fondaparinux could switch at the time of the next scheduled dose. Children who switched from rivaroxaban to vitamin K antagonist (VKA) needed to continue rivaroxaban for 48 hours after the first dose of VKA.

Rivaroxaban, aged 2-<6

Arm description

Children aged 2-<6 years randomized to rivaroxaban received oral suspension after at least 5 days administration of initial therapy with UFH/LMWH/fondaparinux . Children with body weight of ≥ 20 kg received rivaroxaban tablets or oral suspension. Children with body weight of < 20 kg received rivaroxaban as oral suspension.

Arm type

Experimental

Investigational medicinal product name

Rivaroxaban

Investigational medicinal product code

BAY 59-7939

Other name

Xarelto

Pharmaceutical forms

Oral suspension, Tablet

Routes of administration

Oral use

Dosage and administration details

Children with body weight between 12 and < 30 kg received rivaroxaban twice daily (b.i.d) with a dosing intervals of approximately 12 hours. Children with body weight below 12 kg received rivaroxaban three times daily (t.i.d.) with dosing interval of approximately 8 hours. For switching from heparin/fondaparinux to rivaroxaban, the pharmacological activity of unfractionated heparin (UFH), low molecular weight heparin (LMWH) and fondaparinux was taken into account. Children who switched from rivaroxaban to heparin/ fondaparinux could switch at the time of the next scheduled dose. Children who switched from rivaroxaban to vitamin K antagonist (VKA) needed to continue rivaroxaban for 48 hours after the first dose of VKA.

Rivaroxaban, aged 0.5-<2

Arm description

Children aged 0.5-<2 years randomized to rivaroxaban received oral suspension after at least 5 days administration of initial therapy with UFH/LMWH/fondaparinux . Children with body weight of < 20 kg received rivaroxaban as oral suspension.

Arm type

Experimental

Investigational medicinal product name

Rivaroxaban

Investigational medicinal product code

BAY 59-7939

Other name

Xarelto

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Rivaroxaban, aged birth-<0.5

Arm description

Children aged birth-<0.5 years randomized to rivaroxaban received oral suspension after at least 5 days administration of initial therapy with UFH/LMWH/fondaparinux . Children with body weight of < 20 kg received rivaroxaban as oral suspension.

Arm type

Experimental

Investigational medicinal product name

Rivaroxaban

Investigational medicinal product code

BAY 59-7939

Other name

Xarelto

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

. Children with body weight below 12 kg received rivaroxaban three times daily (t.i.d.) with dosing interval of approximately 8 hours. For switching from heparin/fondaparinux to rivaroxaban, the pharmacological activity of unfractionated heparin (UFH), low molecular weight heparin (LMWH) and fondaparinux was taken into account. Children who switched from rivaroxaban to heparin/ fondaparinux could switch at the time of the next scheduled dose. Children who switched from rivaroxaban to vitamin K antagonist (VKA) needed to continue rivaroxaban for 48 hours after the first dose of VKA.

Comparator, aged 12-<18

Arm description

Children aged 12-<18 years randomized to the comparator group continued with unfractionated heparin (UFH), low molecular weight heparin (LMWH) or fondaparinux or may switch to VKA therapy. VKA dosages were adjusted to maintain the INR within the therapeutic range (target 2.5, range 2.0 - 3.0). UFH, LMWH or fondaparinux could be discontinued once the INR was above 2.0 on two separate occasions, 24 hours apart.

Arm type

Active comparator

Investigational medicinal product name

Unfractionated Heparin (UFH)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

As per standard of care

Investigational medicinal product name

Low molecular weight Heparin (LMWH)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

As per standard of care

Investigational medicinal product name

Fondaparinux

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

As per standard of care

Investigational medicinal product name

Vitamin K Antagonist (VKA)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

As per standard of care

Comparator, aged 6-<12

Arm description

Children aged 6-<12 years randomized to the comparator group continued with unfractionated heparin (UFH), low molecular weight heparin (LMWH) or fondaparinux or may switch to VKA therapy. VKA dosages were adjusted to maintain the INR within the therapeutic range (target 2.5, range 2.0 - 3.0). UFH, LMWH or fondaparinux could be discontinued once the INR was above 2.0 on two separate occasions, 24 hours apart.

Arm type

Active comparator

Investigational medicinal product name

Unfractionated Heparin (UFH)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

As per standard of care

Investigational medicinal product name

Low molecular weight Heparin (LMWH)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

As per standard of care

Investigational medicinal product name

Fondaparinux

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

As per standard of care

Investigational medicinal product name

Vitamin K Antagonist (VKA)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

As per standard of care

Comparator, aged 2-<6

Arm description

Children aged 2-<6 years randomized to the comparator group continued with unfractionated heparin (UFH), low molecular weight heparin (LMWH) or fondaparinux or may switch to VKA therapy. VKA dosages were adjusted to maintain the INR within the therapeutic range (target 2.5, range 2.0 - 3.0). UFH, LMWH or fondaparinux could be discontinued once the INR was above 2.0 on two separate occasions, 24 hours apart.

Arm type

Active comparator

Investigational medicinal product name

Unfractionated Heparin (UFH)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

As per standard of care

Investigational medicinal product name

Low molecular weight Heparin (LMWH)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

As per standard of care

Investigational medicinal product name

Fondaparinux

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

As per standard of care

Investigational medicinal product name

Vitamin K Antagonist (VKA)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

As per standard of care

Comparator, aged 0.5-<2

Arm description

Children aged 0.5-<2 years randomized to the comparator group continued with unfractionated heparin (UFH), low molecular weight heparin (LMWH) or fondaparinux or may switch to VKA therapy. VKA dosages were adjusted to maintain the INR within the therapeutic range (target 2.5, range 2.0 - 3.0). UFH, LMWH or fondaparinux could be discontinued once the INR was above 2.0 on two separate occasions, 24 hours apart.

Arm type

Active comparator

Investigational medicinal product name

Unfractionated Heparin (UFH)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

As per standard of care

Investigational medicinal product name

Low molecular weight Heparin (LMWH)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

As per standard of care

Investigational medicinal product name

Fondaparinux

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

As per standard of care

Investigational medicinal product name

Vitamin K Antagonist (VKA)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

As per standard of care

Comparator, aged birth-<0.5

Arm description

Children aged birth-<0.5 years randomized to the comparator group continued with unfractionated heparin (UFH), low molecular weight heparin (LMWH) or fondaparinux or may switch to VKA therapy. VKA dosages were adjusted to maintain the INR within the therapeutic range (target 2.5, range 2.0 - 3.0). UFH, LMWH or fondaparinux could be discontinued once the INR was above 2.0 on two separate occasions, 24 hours apart.

Arm type

Active comparator

Investigational medicinal product name

Unfractionated Heparin (UFH)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

As per standard of care

Investigational medicinal product name

Low molecular weight Heparin (LMWH)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

As per standard of care

Investigational medicinal product name

Fondaparinux

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

As per standard of care

Investigational medicinal product name

Vitamin K Antagonist (VKA)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

As per standard of care

Number of subjects in period 1	Rivaroxaban, aged 12-<18	Rivaroxaban, aged 6-<12	Rivaroxaban, aged 2-<6	Rivaroxaban, aged 0.5-<2	Rivaroxaban, aged birth-<0.5	Comparator, aged 12-<18	Comparator, aged 6-<12	Comparator, aged 2-<6	Comparator, aged 0.5-<2	Comparator, aged birth-<0.5
Started	184	67	47	21	16	92	34	22	9	8
Completed	162	61	44	16	14	79	32	20	8	8
Not completed	22	6	3	5	2	13	2	2	1	0
Physician decision	4	1	-	1	-	-	-	1	-	-
Recovery	1	-	-	-	-	-	-	-	-	-
Consent withdrawn by subject	5	1	1	-	-	7	-	-	-	-
Death	1	-	-	-	-	-	-	-	-	-
Other	-	2	-	1	-	1	-	1	-	-
Adverse event	5	1	1	3	2	1	-	-	1	-
Non-compliance with study drug	1	-	-	-	-	1	1	-	-	-
Efficacy outcome reached	2	-	-	-	-	2	-	-	-	-
Lost to follow-up	-	1	-	-	-	-	1	-	-	-
Patient convenience	2	-	-	-	-	1	-	-	-	-
Protocol deviation	1	-	1	-	-	-	-	-	-	-

Baseline characteristics

Top of page

Reporting group title

Rivaroxaban, aged 12-<18

Reporting group description

Reporting group title

Rivaroxaban, aged 6-<12

Reporting group description

Reporting group title

Rivaroxaban, aged 2-<6

Reporting group description

Reporting group title

Rivaroxaban, aged 0.5-<2

Reporting group description

Reporting group title

Rivaroxaban, aged birth-<0.5

Reporting group description

Reporting group title

Comparator, aged 12-<18

Reporting group description

Reporting group title

Comparator, aged 6-<12

Reporting group description

Reporting group title

Comparator, aged 2-<6

Reporting group description

Reporting group title

Comparator, aged 0.5-<2

Reporting group description

Reporting group title

Comparator, aged birth-<0.5

Reporting group description

Reporting group values	Rivaroxaban, aged 12-<18	Rivaroxaban, aged 6-<12	Rivaroxaban, aged 2-<6	Rivaroxaban, aged 0.5-<2	Rivaroxaban, aged birth-<0.5	Comparator, aged 12-<18	Comparator, aged 6-<12	Comparator, aged 2-<6	Comparator, aged 0.5-<2	Comparator, aged birth-<0.5	Total
Number of subjects	184	67	47	21	16	92	34	22	9	8	500
Age Categorical
Units: Subjects
12-<18 years	184	0	0	0	0	92	0	0	0	0	276
6-<12 years	0	67	0	0	0	0	34	0	0	0	101
2-<6 years	0	0	47	0	0	0	0	22	0	0	69
0.5-<2 years	0	0	0	21	0	0	0	0	9	0	30
Birth-<0.5 years	0	0	0	0	16	0	0	0	0	8	24
Gender Categorical
Units: Subjects
Female	97	24	24	10	5	55	15	9	5	1	245
Male	87	43	23	11	11	37	19	13	4	7	255

End points

Top of page

Reporting group title

Rivaroxaban, aged 12-<18

Reporting group description

Reporting group title

Rivaroxaban, aged 6-<12

Reporting group description

Reporting group title

Rivaroxaban, aged 2-<6

Reporting group description

Reporting group title

Rivaroxaban, aged 0.5-<2

Reporting group description

Reporting group title

Rivaroxaban, aged birth-<0.5

Reporting group description

Reporting group title

Comparator, aged 12-<18

Reporting group description

Reporting group title

Comparator, aged 6-<12

Reporting group description

Reporting group title

Comparator, aged 2-<6

Reporting group description

Reporting group title

Comparator, aged 0.5-<2

Reporting group description

Reporting group title

Comparator, aged birth-<0.5

Reporting group description

Subject analysis set title

Full analysis set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

This population included all randomized children

Subject analysis set title

Safety analysis set (SAF)

Subject analysis set type

Safety analysis

Subject analysis set description

This population included all randomized children who received at least one dose of study medication

Subject analysis set title

Pharmacokinetics analysis set (PKS)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Includes all children randomized to rivaroxaban with at least one PK sample.

Subject analysis set title

Pharmacodynamics analysis set (PDS)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Includes all children randomized to rivaroxaban with at least one PD sample.

Subject analysis set title

Rivaroxaban group

Subject analysis set type

Sub-group analysis

Subject analysis set description

Children randomized to rivaroxaban received either tablet or oral suspension after at least 5 days administration of initial therapy with UFH/LMWH/fondaparinux. Children with body weight of ≥ 20 kg received rivaroxaban tablets or oral suspension. Children with body weight of < 20 kg received rivaroxaban as oral suspension.

Subject analysis set title

Comparator group

Subject analysis set type

Sub-group analysis

Subject analysis set description

Children randomized to the comparator group continued with UFH/LMWH/fondaparinux or may switch to VKA therapy. VKA dosages were adjusted to maintain the INR within the therapeutic range (target 2.5, range 2.0 - 3.0). UFH, LMWH or fondaparinux could be discontinued once the INR was above 2.0 on two separate occasions, 24 hours apart.

Primary: Incidence rates of all symptomatic recurrent venous thromboembolism during the main treatment period

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End point title

Incidence rates of all symptomatic recurrent venous thromboembolism during the main treatment period

End point description

The Central independent adjudication committee (CIAC) classified symptomatic recurrent venous thromboembolism (VTE). Incidence = number of events / number at risk, where: number of events = number of subjects having the event in the time window. number at risk = number of subjects in reference population

End point type

Primary

End point timeframe

During the main study treatment period (i.e., 3 months, except for children with CVC-VTE aged <2 years for whom it was 1 month)

Rivaroxaban, aged 12-<18

Rivaroxaban, aged 6-<12

Rivaroxaban, aged 2-<6

Rivaroxaban, aged 0.5-<2

Rivaroxaban, aged birth-<0.5

Comparator, aged 12-<18

Comparator, aged 6-<12

Comparator, aged 2-<6

Comparator, aged 0.5-<2

Comparator, aged birth-<0.5

Rivaroxaban group

Comparator group

Number of subjects analysed

184

335

165

Units: Incidence

number (confidence interval 95%)

2.2 (0.7 to 5.3)

0.0 (0.0 to 5.3)

0.0 (0.0 to 6.8)

0.0 (0.0 to 8.3)

0.0 (0.0 to 14.6)

3.3 (0.9 to 8.6)

2.9 (0.2 to 15.1)

4.5 (0.2 to 20.7)

0.0 (0.0 to 18.4)

0.0 (0.0 to 29.9)

1.2 (0.4 to 3.0)

3.0 (1.2 to 6.6)

Efficacy up to the end of main treatment period

Comparison groups

Rivaroxaban group v Comparator group

Number of subjects included in analysis

500

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1509

Method

Expl. Cox Proportional Hazards Model

Parameter type

Hazard ratio (HR)

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.11

upper limit

1.41

Primary: Incidence rates of all symptomatic recurrent venous thromboembolism during extended treatment period

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End point title

Incidence rates of all symptomatic recurrent venous thromboembolism during extended treatment period ^[1]

End point description

Incidence rates for all children except those aged < 2 years with catheter-related thrombosis. The Central independent adjudication committee (CIAC) classified symptomatic recurrent venous thromboembolism (VTE). Incidence = number of events / number at risk, where: number of events = number of subjects having the event in the time window. number at risk = number of subjects in reference Population. '99999' denotes data that cannot be calculated.

End point type

Primary

End point timeframe

During extended treatment period: up to month 12.

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: Descriptive statistics were done, no inferential statistical analyses were performed.

End point values	Rivaroxaban, aged 12-<18	Rivaroxaban, aged 6-<12	Rivaroxaban, aged 2-<6	Rivaroxaban, aged 0.5-<2	Rivaroxaban, aged birth-<0.5	Comparator, aged 12-<18	Comparator, aged 6-<12	Comparator, aged 2-<6	Comparator, aged 0.5-<2	Comparator, aged birth-<0.5
Number of subjects analysed	93 ^[2]	21 ^[3]	19 ^[4]	0 ^[5]	2 ^[6]	46 ^[7]	8 ^[8]	7 ^[9]	1 ^[10]	1 ^[11]
Units: Incidence
number (confidence interval 95%)
Extension 1 (month 3 to 6)	0.0 (0.0 to 3.8)	0.0 (0.0 to 14.6)	0.0 (0.0 to 16.3)	( to )	0.0 (0.0 to 77.6)	2.2 (0.1 to 10.9)	0.0 (0.0 to 14.6)	0.0 (0.0 to 37.7)	0.0 (0.0 to 95.0)	0.0 (0.0 to 95.0)
Extension 2 (month 6 to 9)	2.6 (0.1 to 13.4)	0.0 (0.0 to 29.9)	0.0 (0.0 to 40.2)	( to )	99999 (99999 to 99999)	5.3 (0.3 to 24.4)	0.0 (0.0 to 63.2)	0.0 (0.0 to 77.6)	99999 (99999 to 99999)	99999 (99999 to 99999)
Extension 3 (month 9 to 12)	0.0 (0.0 to 11.6)	0.0 (0.0 to 63.2)	0.0 (0.0 to 77.6)	( to )	99999 (99999 to 99999)	0.0 (0.0 to 23.0)	0.0 (0.0 to 95.2)	0.0 (0.0 to 77.6)	99999 (99999 to 99999)	99999 (99999 to 99999)

Notes
[2] - Extension 1 (n=93); extension 2 (n=38); extension 3 (n=26)
[3] - Extension 1 (n=21); extension 2 (n=9); extension 3 (n=3)
[4] - Extension 1 (n=19); extension 2 (n=6); extension 3 (n=2)
[5] - Extension 1 (n=0); extension 2 (n=0); extension 3 (n=0)
[6] - Extension 1 (n=2); extension 2 (n=0); extension 3 (n=0)
[7] - Extension 1 (n=46); extension 2 (n=19); extension 3 (n=14)
[8] - Extension 1 (n=8); extension 2 (n=3); extension 3 (n=1)
[9] - Extension 1 (n=7); extension 2 (n=3); extension 3 (n=2)
[10] - Extension 1 (n=1); extension 2 (n=0); extension 3 (n=0)
[11] - Extension 1 (n=1); extension 2 (n=0); extension 3 (n=0)

No statistical analyses for this end point

Primary: Number of subjects with the composite of all symptomatic recurrent venous thromboembolism during the 30 days post-study treatment period (i.e. >2 and ≤ 30 days after stop of study medication)

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End point title

Number of subjects with the composite of all symptomatic recurrent venous thromboembolism during the 30 days post-study treatment period (i.e. >2 and ≤ 30 days after stop of study medication) ^[12]

End point description

The Central independent adjudication committee (CIAC) classified symptomatic recurrent venous thromboembolism (VTE). Age group with primary efficacy outcome was reported.

End point type

Primary

End point timeframe

More than 2 and up to 30 days after stop of study medication

Notes
[12] - 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, no inferential statistical analyses were performed.

End point values	Rivaroxaban, aged 12-<18	Rivaroxaban, aged 6-<12	Rivaroxaban, aged 2-<6	Rivaroxaban, aged 0.5-<2	Rivaroxaban, aged birth-<0.5	Comparator, aged 12-<18	Comparator, aged 6-<12	Comparator, aged 2-<6	Comparator, aged 0.5-<2	Comparator, aged birth-<0.5
Number of subjects analysed	184 ^[13]	67 ^[14]	47 ^[15]	21 ^[16]	16 ^[17]	92	34 ^[18]	22 ^[19]	9 ^[20]	8 ^[21]
Units: Number of subjects	0	0	0	0	0	2	0	0	0	0

Notes
[13] - FAS
[14] - FAS
[15] - FAS
[16] - FAS
[17] - FAS
[18] - FAS
[19] - FAS
[20] - FAS
[21] - FAS

No statistical analyses for this end point

Primary: Incidence rates of the composite of treatment emergent overt major bleeding and clinically relevant non-major (CRNM) bleeding during main treatment period

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End point title

Incidence rates of the composite of treatment emergent overt major bleeding and clinically relevant non-major (CRNM) bleeding during main treatment period ^[22]

End point description

The Central independent adjudication committee (CIAC) classified bleeding as: Major bleeding defined as overt bleeding and: · associated with a fall in hemoglobin of 2 g/dL or more, or leading to a transfusion of the equivalent of 2 or more units of packed red blood cells or whole blood in adults, or occurring in a critical site, e.g. intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, retroperitoneal, or contributing to death. Clinically relevant non-major bleeding defined as overt bleeding not meeting the criteriafor major bleeding, but associated with: medical intervention, or unscheduled contact (visit or telephone call) with a physician, or (temporary) cessation of study treatment, or discomfort for the child such as pain or impairment of activities of daily life (such as loss of school days or hospitalization).

End point type

Primary

End point timeframe

During the main study treatment period (i.e., 3 months, except for children with CVC-VTE aged <2 years for whom it was 1 month)

Notes
[22] - 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, no inferential statistical analyses were performed.

Rivaroxaban, aged 12-<18

Rivaroxaban, aged 6-<12

Rivaroxaban, aged 2-<6

Rivaroxaban, aged 0.5-<2

Rivaroxaban, aged birth-<0.5

Comparator, aged 12-<18

Comparator, aged 6-<12

Comparator, aged 2-<6

Comparator, aged 0.5-<2

Comparator, aged birth-<0.5

Rivaroxaban group

Comparator group

Number of subjects analysed

180 ^[23]

67 ^[24]

46 ^[25]

21 ^[26]

15 ^[27]

89 ^[28]

34 ^[29]

22 ^[30]

9 ^[31]

8 ^[32]

329 ^[33]

162 ^[34]

Units: Incidence

number (confidence interval 95%)

1.7 (0.5 to 4.7)

3.0 (0.5 to 9.6)

6.5 (1.8 to 17.7)

4.8 (0.2 to 21.8)

6.7 (0.3 to 30.2)

2.2 (0.4 to 7.3)

0.0 (0.0 to 9.0)

0.0 (0.0 to 13.9)

11.1 (0.6 to 44.3)

0.0 (0.0 to 34.9)

3 (1.6 to 5.5)

1.9 (0.5 to 3.3)

Notes
[23] - SAF
[24] - SAF
[25] - SAF
[26] - SAF
[27] - SAF
[28] - SAF
[29] - SAF
[30] - SAF
[31] - SAF
[32] - SAF
[33] - SAF
[34] - SAF

No statistical analyses for this end point

Primary: Incidence rates of the composite of treatment emergent overt major bleeding and clinically relevant non-major (CRNM) bleeding during extended treatment period

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End point title

Incidence rates of the composite of treatment emergent overt major bleeding and clinically relevant non-major (CRNM) bleeding during extended treatment period ^[35]

End point description

Incidence rates for all children except those aged < 2 years with catheter-related thrombosis. The CIAC classified bleeding as: Major bleeding defined as overt bleeding and: associated with a fall in hemoglobin of 2 g/dL or more, or leading to a transfusion of the equivalent of 2 or more units of packed red blood cells or whole blood in adults, or occurring in a critical site, e.g. intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, retroperitoneal, or contributing to death. Clinically relevant non-major bleeding defined as overt bleeding not meeting the criteriafor major bleeding, but associated with: medical intervention, or unscheduled contact (visit or telephone call) with a physician, or (temporary) cessation of study treatment, or discomfort for the child such as pain or impairment of activities of daily life (such as loss of school days or hospitalization). '99999' denotes data that cannot be calculated.

End point type

Primary

End point timeframe

During extended treatment period: up to month 12.

Notes
[35] - 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, no inferential statistical analyses were performed.

End point values	Rivaroxaban, aged 12-<18	Rivaroxaban, aged 6-<12	Rivaroxaban, aged 2-<6	Rivaroxaban, aged 0.5-<2	Rivaroxaban, aged birth-<0.5	Comparator, aged 12-<18	Comparator, aged 6-<12	Comparator, aged 2-<6	Comparator, aged 0.5-<2	Comparator, aged birth-<0.5
Number of subjects analysed	93 ^[36]	21 ^[37]	19 ^[38]	12 ^[39]	4 ^[40]	46 ^[41]	8 ^[42]	7 ^[43]	3 ^[44]	5 ^[45]
Units: Incidence
number (confidence interval 95%)
Extension 1 (month 3 to 6)	1.1 (0.1 to 5.3)	0.0 (0.0 to 14.6)	0.0 (0.0 to 16.3)	0.0 (0.0 to 23.6)	0.0 (0.0 to 52.7)	0.0 (0.0 to 6.9)	0.0 (0.0 to 34.9)	0.0 (0.0 to 37.7)	0.0 (0.0 to 63.2)	0.0 (0.0 to 50.0)
Extension 2 (month 6 to 9)	2.6 (0.1 to 13.4)	0.0 (0.0 to 29.9)	0.0 (0.0 to 40.2)	11.1 (0.6 to 44.3)	99999 (99999 to 99999)	5.3 (0.3 to 24.4)	0.0 (0.0 to 63.2)	0.0 (0.0 to 77.6)	0.0 (0.0 to 77.6)	0.0 (0.0 to 63.2)
Extension 3 (month 9 to 12)	0.0 (0.0 to 11.6)	0.0 (0.0 to 63.2)	0.0 (0.0 to 77.6)	99999 (99999 to 99999)	99999 (99999 to 99999)	0.0 (0.0 to 23.0)	0.0 (0.0 to 95.0)	0.0 (0.0 to 77.6)	99999 (99999 to 99999)	99999 (99999 to 99999)

Notes
[36] - Extension 1 (n=93); extension 2 (n=38); extension 3 (n=26);
[37] - Extension 1 (n=21); extension 2 (n=9); extension 3 (n=3)
[38] - Extension 1 (n=19); extension 2 (n=6); extension 3 (n=2)
[39] - Extension 1 (n=12); extension 2 (n=9); extension 3 (n=0)
[40] - Extension 1 (n=4); extension 2 (n=0); extension 3 (n=0)
[41] - Extension 1 (n=46); extension 2 (n=19); extension 3 (n=14)
[42] - Extension 1 (n=8); extension 2 (n=3); extension 3 (n=1)
[43] - Extension 1 (n=7); extension 2 (n=2); extension 3 (n=2)
[44] - Extension 1 (n=3); extension 2 (n=2); extension 3 (n=0)
[45] - Extension 1 (n=5); extension 2 (n=3); extension 3 (n=0)

No statistical analyses for this end point

Secondary: Incidence rates of the composite of all symptomatic recurrent venous thromboembolism and asymptomatic deterioration in thrombotic burden on repeat imaging during the main treatment period

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End point title

Incidence rates of the composite of all symptomatic recurrent venous thromboembolism and asymptomatic deterioration in thrombotic burden on repeat imaging during the main treatment period

End point description

The secondary efficacy outcome defined as the composite of all symptomatic recurrent venous thromboembolism and asymptomatic deterioration on repeat imaging as assessed by central independent adjudication committee. (CIAC) Incidence = number of events / number at risk, where: number of events = number of subjects having the event in the time window. number at risk = number of subjects in reference population

End point type

Secondary

End point timeframe

During the main study treatment period (i.e., 3 months, except for children with CVC-VTE aged <2 years for whom it was 1 month)

Rivaroxaban, aged 12-<18

Rivaroxaban, aged 6-<12

Rivaroxaban, aged 2-<6

Rivaroxaban, aged 0.5-<2

Rivaroxaban, aged birth-<0.5

Comparator, aged 12-<18

Comparator, aged 6-<12

Comparator, aged 2-<6

Comparator, aged 0.5-<2

Comparator, aged birth-<0.5

Rivaroxaban group

Comparator group

Number of subjects analysed

184 ^[46]

67 ^[47]

47 ^[48]

21 ^[49]

16 ^[50]

92 ^[51]

34 ^[52]

22 ^[53]

9 ^[54]

8 ^[55]

335 ^[56]

165 ^[57]

Units: Incidence

number (confidence interval 95%)

2.2 (0.7 to 5.3)

0.0 (0.0 to 5.3)

2.1 (0.1 to 10.7)

0.0 (0.0 to 14.6)

0.0 (0.0 to 19.8)

4.3 (1.5 to 10.3)

2.9 (0.2 to 15.1)

4.5 (0.2 to 20.7)

0.0 (0.0 to 29.9)

0.0 (0.0 to 34.9)

1.5 (0.6 to 3.4)

3.6 (1.6 to 7.6)

Notes
[46] - FAS
[47] - FAS
[48] - FAS
[49] - FAS
[50] - FAS
[51] - FAS
[52] - FAS
[53] - FAS
[54] - FAS
[55] - FAS
[56] - FAS
[57] - FAS

No statistical analyses for this end point

Secondary: AUC(0-24)ss in plasma

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End point title

AUC(0-24)ss in plasma ^[58]

End point description

AUC(0-24)ss: Area under the concentration vs. time curve from time 0 to 24 hours at steady state.

End point type

Secondary

End point timeframe

over 24 hours

Notes
[58] - 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 done, no inferential statistical analyses were performed. Only for Rivaroxaban age groups values were provided.

End point values	Rivaroxaban, aged 12-<18	Rivaroxaban, aged 6-<12	Rivaroxaban, aged 2-<6	Rivaroxaban, aged 0.5-<2	Rivaroxaban, aged birth-<0.5
Number of subjects analysed	173 ^[59]	65 ^[60]	44 ^[61]	21 ^[62]	13 ^[63]
Units: microgram*hour per liter
geometric mean (geometric coefficient of variation)	2120 ( 26.4 )	1960 ( 31.7 )	2380 ( 40.7 )	1840 ( 36.4 )	1590 ( 29.6 )

Notes
[59] - Number of observations N = 174. One child with two sets of PK parameters due to regimen switch. PKS
[60] - Number of observations N = 67.Two children with two sets of PK parameters due to regimen switch. PKS
[61] - PKS
[62] - Number of observations N = 22. One child with two sets of PK parameters due to regimen switch. PKS
[63] - PKS

No statistical analyses for this end point

Secondary: Cmax,ss in plasma

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End point title

Cmax,ss in plasma ^[64]

End point description

Maximum drug concentration in measured matrix at steady state during a dosage interval

End point type

Secondary

End point timeframe

0 hours to 24 hours, 0 hours to 12 hours or 0 hours to 8 hours (one dosing interval in steady state)

Notes
[64] - 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 done, no inferential statistical analyses were performed. Only for Rivaroxaban age groups values were provided.

End point values	Rivaroxaban, aged 12-<18	Rivaroxaban, aged 6-<12	Rivaroxaban, aged 2-<6	Rivaroxaban, aged 0.5-<2	Rivaroxaban, aged birth-<0.5
Number of subjects analysed	173 ^[65]	65 ^[66]	44 ^[67]	21 ^[68]	13 ^[69]
Units: microgram per liter
geometric mean (geometric coefficient of variation)	237 ( 20.6 )	184 ( 36.2 )	182 ( 31.2 )	136 ( 29.4 )	119 ( 24.1 )

Notes
[65] - Number of observations N = 174. One child with two sets of PK parameters due to regimen switch. PKS
[66] - Number of observations N = 67.Two children with two sets of PK parameters due to regimen switch.PKS
[67] - PKS
[68] - Number of observations N = 22. One child with two sets of PK parameters due to regimen switch. PKS
[69] - PKS

No statistical analyses for this end point

Secondary: Ctrough,ss in plasma

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End point title

Ctrough,ss in plasma ^[70]

End point description

Ctrough,ss refers to the drug concentration at the end of the dosage interval at steady state

End point type

Secondary

End point timeframe

0 hours to 24 hours, 0 hours to 12 hours or 0 hours to 8 hours(one sampling interval in steady state)

Notes
[70] - 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 done, no inferential statistical analyses were performed. Only for Rivaroxaban age groups values were provided.

End point values	Rivaroxaban, aged 12-<18	Rivaroxaban, aged 6-<12	Rivaroxaban, aged 2-<6	Rivaroxaban, aged 0.5-<2	Rivaroxaban, aged birth-<0.5
Number of subjects analysed	173 ^[71]	65 ^[72]	44 ^[73]	21 ^[74]	13 ^[75]
Units: microgram per liter
geometric mean (geometric coefficient of variation)	20.7 ( 45.8 )	21.4 ( 62.7 )	31.6 ( 70.1 )	22.9 ( 68.6 )	18.5 ( 50.4 )

Notes
[71] - Number of observations N = 174. One child with two sets of PK parameters due to regimen switch. PKS
[72] - Number of observations N = 67.Two children with two sets of PK parameters due to regimen switch.PKS
[73] - PKS
[74] - Number of observations N = 22. One child with two sets of PK parameters due to regimen switch. PKS
[75] - PKS

No statistical analyses for this end point

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered once daily (suspension and tablet) in the age group 12-<18 years

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End point title

Prothrombin time (PT) ratios to baseline: Rivaroxaban administered once daily (suspension and tablet) in the age group 12-<18 years ^[76]

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.

End point type

Secondary

End point timeframe

Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60

Notes
[76] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 12-<18
Number of subjects analysed	156 ^[77]
Units: ratio
arithmetic mean (standard deviation)
Day 30 (0.5-1.5h) n=156	1.29 ( 0.28 )
Day 30 (2.5-4h) n=150	1.57 ( 0.36 )
Day 60 (2-8h) n=156	1.52 ( 0.29 )

Notes
[77] - PDS

No statistical analyses for this end point

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered once daily (suspension and tablet) in the age group 6-<12 years

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End point title

Prothrombin time (PT) ratios to baseline: Rivaroxaban administered once daily (suspension and tablet) in the age group 6-<12 years ^[78]

End point description

End point type

Secondary

End point timeframe

Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60

Notes
[78] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 6-<12
Number of subjects analysed	20 ^[79]
Units: ratio
arithmetic mean (standard deviation)
Day 30 (0.5-1.5h) n=18	1.46 ( 0.25 )
Day 30 (2.5-4h) n=20	1.67 ( 0.39 )
Day 60 (2-8h) n=20	1.52 ( 0.33 )

Notes
[79] - PDS

No statistical analyses for this end point

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered twice daily (suspension and tablet) in the age group 6-<12 years

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End point title

Prothrombin time (PT) ratios to baseline: Rivaroxaban administered twice daily (suspension and tablet) in the age group 6-<12 years ^[80]

End point description

End point type

Secondary

End point timeframe

Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60

Notes
[80] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 6-<12
Number of subjects analysed	34 ^[81]
Units: ratio
arithmetic mean (standard deviation)
Day 30 (0.5-1.5h) n=33	1.17 ( 0.23 )
Day 30 (2.5-4h) n=33	1.26 ( 0.22 )
Day 60 (2-8h) n=34	1.21 ( 0.19 )

Notes
[81] - PDS

No statistical analyses for this end point

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered twice daily (suspension) in the age group 2-<6 years

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End point title

Prothrombin time (PT) ratios to baseline: Rivaroxaban administered twice daily (suspension) in the age group 2-<6 years ^[82]

End point description

End point type

Secondary

End point timeframe

Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60

Notes
[82] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 2-<6
Number of subjects analysed	34 ^[83]
Units: ratio
arithmetic mean (standard deviation)
Day 30 (0.5-1.5h) n=1	0.99 ( 99999 )
Day 30 (2.5-4h) n=34	1.36 ( 0.28 )
Day 60 (2-8h) n=32	1.33 ( 0.26 )

Notes
[83] - PDS

No statistical analyses for this end point

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered twice daily (suspension) in the age group 0.5-<2 years

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End point title

Prothrombin time (PT) ratios to baseline: Rivaroxaban administered twice daily (suspension) in the age group 0.5-<2 years ^[84]

End point description

End point type

Secondary

End point timeframe

Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60

Notes
[84] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 0.5-<2
Number of subjects analysed	2 ^[85]
Units: ratio
arithmetic mean (standard deviation)
Day 30 (0.5-1.5h) n=0	99999 ( 99999 )
Day 30 (2.5-4h) n=1	1.41 ( 99999 )
Day 60 (2-8h) n=2	1.05 ( 0.17 )

Notes
[85] - PDS

No statistical analyses for this end point

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group 2-<6 years

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End point title

Prothrombin time (PT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group 2-<6 years ^[86]

End point description

End point type

Secondary

End point timeframe

Up to 3 hours post dose on Day30, and up to 6 hours post dose on Day 60

Notes
[86] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 2-<6
Number of subjects analysed	4 ^[87]
Units: ratio
arithmetic mean (standard deviation)
Day 30 (0.5-3h) n=4	1.87 ( 1.09 )
Day 60 (2-6h) n=4	1.32 ( 0.12 )

Notes
[87] - PDS

No statistical analyses for this end point

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group 0.5-<2 years

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End point title

Prothrombin time (PT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group 0.5-<2 years ^[88]

End point description

End point type

Secondary

End point timeframe

Up to 3 hours post dose on Day30, and up to 6 hours post dose on Day 60

Notes
[88] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 0.5-<2
Number of subjects analysed	9 ^[89]
Units: ratios
arithmetic mean (standard deviation)
Day 30 (0.5-3h) n=9	1.25 ( 0.18 )
Day 60 (2-6h) n=7	2.00 ( 2.22 )

Notes
[89] - PDS

No statistical analyses for this end point

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group birth-<0.5 years

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End point title

Prothrombin time (PT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group birth-<0.5 years ^[90]

End point description

End point type

Secondary

End point timeframe

Up to 3 hours post dose on Day30, and up to 6 hours post dose on Day 60

Notes
[90] - 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: Descriptitive statistics were done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged birth-<0.5
Number of subjects analysed	11 ^[91]
Units: ratio
arithmetic mean (standard deviation)
Day 30 (0.5-3h) n=11	1.35 ( 0.20 )
Day 60 (2-6h) n=4	1.45 ( 0.16 )

Notes
[91] - PDS

No statistical analyses for this end point

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered once daily (suspension and tablet) in the age group 12-<18 years

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End point title

Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered once daily (suspension and tablet) in the age group 12-<18 years ^[92]

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. The initial read-out is in seconds.

End point type

Secondary

End point timeframe

Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60

Notes
[92] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 12-<18
Number of subjects analysed	154 ^[93]
Units: ratio
arithmetic mean (standard deviation)
Day 30 (0.5-1.5h) n=154	1.17 ( 0.28 )
Day 30 (2.5-4h) n=149	1.38 ( 0.50 )
Day 60 (2-8h) n=153	1.33 ( 0.38 )

Notes
[93] - PDS

No statistical analyses for this end point

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered once daily (suspension and tablet) in the age group 6-<12 years

Top of page

End point title

Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered once daily (suspension and tablet) in the age group 6-<12 years ^[94]

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. The initial read-out is in seconds.

End point type

Secondary

End point timeframe

Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60

Notes
[94] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 6-<12
Number of subjects analysed	19 ^[95]
Units: ratio
arithmetic mean (standard deviation)
Day 30 (0.5-1.5h) n=17	1.27 ( 0.20 )
Day 30 (2.5-4h) n=17	1.39 ( 0.26 )
Day 60 (2-8h) n=19	1.24 ( 0.20 )

Notes
[95] - PDS

No statistical analyses for this end point

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered twice daily (suspension and tablet) in the age group 6-<12 years

Top of page

End point title

Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered twice daily (suspension and tablet) in the age group 6-<12 years ^[96]

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. The initial read-out is in seconds.

End point type

Secondary

End point timeframe

Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60

Notes
[96] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 6-<12
Number of subjects analysed	31 ^[97]
Units: ratio
arithmetic mean (standard deviation)
Day 30 (0.5-1.5h) n=30	1.11 ( 0.24 )
Day 30 (2.5-4h) n=30	1.15 ( 0.22 )
Day 60 (2-8h) n=31	1.18 ( 0.24 )

Notes
[97] - PDS

No statistical analyses for this end point

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered twice daily (suspension) in the age group 2-<6 years

Top of page

End point title

Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered twice daily (suspension) in the age group 2-<6 years ^[98]

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. The initial read-out is in seconds. '99999' denotes the data that cannot be calculated.

End point type

Secondary

End point timeframe

Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60

Notes
[98] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 2-<6
Number of subjects analysed	32 ^[99]
Units: ratio
arithmetic mean (standard deviation)
Day 30 (0.5-1.5h) n=1	0.90 ( 99999 )
Day 30 (2.5-4h) n=32	1.29 ( 0.33 )
Day 60 (2-8h) n=29	1.23 ( 0.21 )

Notes
[99] - PDS

No statistical analyses for this end point

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered twice daily (suspension) in the age group 0.5-<2 years

Top of page

End point title

Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered twice daily (suspension) in the age group 0.5-<2 years ^[100]

End point description

End point type

Secondary

End point timeframe

Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60

Notes
[100] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 0.5-<2
Number of subjects analysed	2 ^[101]
Units: ratio
arithmetic mean (standard deviation)
Day 30 (0.5-1.5h) n=0	99999 ( 99999 )
Day 30 (2.5-4h) n=1	1.13 ( 99999 )
Day 60 (2-8h) n=2	1.10 ( 0.02 )

Notes
[101] - PDS

No statistical analyses for this end point

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group 2-<6 years

Top of page

End point title

Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group 2-<6 years ^[102]

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. The initial read-out is in seconds.

End point type

Secondary

End point timeframe

Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60

Notes
[102] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 2-<6
Number of subjects analysed	4 ^[103]
Units: ratio
arithmetic mean (standard deviation)
Day 30 (0.5-3h) n=4	1.50 ( 0.83 )
Day 60 (2-6h) n=4	1.13 ( 0.06 )

Notes
[103] - PDS

No statistical analyses for this end point

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group 0.5-<2 years

Top of page

End point title

Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group 0.5-<2 years ^[104]

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. The initial read-out is in seconds.

End point type

Secondary

End point timeframe

Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60

Notes
[104] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 0.5-<2
Number of subjects analysed	9 ^[105]
Units: ratio
arithmetic mean (standard deviation)
Day 30 (0.5-3h) n=9	1.20 ( 0.39 )
Day 60 (2-6h) n=6	1.10 ( 0.47 )

Notes
[105] - PDS

No statistical analyses for this end point

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group birth-<0.5 years

Top of page

End point title

Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group birth-<0.5 years ^[106]

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. The initial read-out is in seconds.

End point type

Secondary

End point timeframe

Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60

Notes
[106] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged birth-<0.5
Number of subjects analysed	9 ^[107]
Units: ratio
arithmetic mean (standard deviation)
Day 30 (0.5-3h) n=9	1.31 ( 0.15 )
Day 60 (2-6h) n=3	1.21 ( 0.16 )

Notes
[107] - PDS

No statistical analyses for this end point

Secondary: Anti-Xa values: Rivaroxaban administered once daily (suspension and tablet) in the age group 12-<18 years

Top of page

End point title

Anti-Xa values: Rivaroxaban administered once daily (suspension and tablet) in the age group 12-<18 years ^[108]

End point description

This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method.

End point type

Secondary

End point timeframe

Up to 4 hours post dose on Day 30, up to 8 hours post dose on Day 60, and up to 24 hours on Day 90

Notes
[108] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 12-<18
Number of subjects analysed	167 ^[109]
Units: microgram per liter (mcg/L)
arithmetic mean (standard deviation)
Day 30 (0.5-1.5h) n=141	164.46 ( 124.46 )
Day 30 (2.5-4h) n=164	254.66 ( 188.64 )
Day 60 (2-8h) n=167	255.40 ( 171.59 )
Day 90 (20-24h) n=58	62.12 ( 175.87 )

Notes
[109] - PDS

No statistical analyses for this end point

Secondary: Anti-Xa values: Rivaroxaban administered once daily (suspension and tablet) in the age group 6-<12 years

Top of page

End point title

Anti-Xa values: Rivaroxaban administered once daily (suspension and tablet) in the age group 6-<12 years ^[110]

End point description

This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method.

End point type

Secondary

End point timeframe

Up to 4 hours post dose on Day 30, up to 8 hours post dose on Day 60, and up to 24 hours on Day 90

Notes
[110] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 6-<12
Number of subjects analysed	23 ^[111]
Units: microgram per liter (mcg/L)
arithmetic mean (standard deviation)
Day 30 (0.5-1.5h) n=22	206.89 ( 105.01 )
Day 30 (2.5-4h) n=23	263.24 ( 156.73 )
Day 60 (2-8h) n=22	243.45 ( 124.92 )
Day 60 (20-24h) n=9	27.39 ( 14.66 )

Notes
[111] - PDS

No statistical analyses for this end point

Secondary: Anti-Xa values: Rivaroxaban administered twice daily (suspension and tablet) in the age group 6-<12 years

Top of page

End point title

Anti-Xa values: Rivaroxaban administered twice daily (suspension and tablet) in the age group 6-<12 years ^[112]

End point description

This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method.

End point type

Secondary

End point timeframe

Up to 4 hours post dose on Day 30, up to 8 hours post dose on Day 60, and up to 16 hours on Day 90

Notes
[112] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 6-<12
Number of subjects analysed	37 ^[113]
Units: microgram per liter (mcg/L)
arithmetic mean (standard deviation)
Day 30 (0.5-1.5h) n=37	96.82 ( 76.77 )
Day 30 (2.5-4h) n=36	139.10 ( 102.19 )
Day 60 (2-8h) n=35	126.53 ( 81.78 )
Day 90 (10-16h) n=20	47.49 ( 66.88 )

Notes
[113] - PDS

No statistical analyses for this end point

Secondary: Anti-Xa values: Rivaroxaban administered twice daily (suspension) in the age group 2-<6 years

Top of page

End point title

Anti-Xa values: Rivaroxaban administered twice daily (suspension) in the age group 2-<6 years ^[114]

End point description

This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method.

End point type

Secondary

End point timeframe

Up to 4 hours post dose on Day 30, up to 8 hours post dose on Day 60, and up to 16 hours on Day 90

Notes
[114] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 2-<6
Number of subjects analysed	37 ^[115]
Units: microgram per liter (mcg/L)
arithmetic mean (standard deviation)
Day 30 (2.5-4h) n=37	177.78 ( 147.29 )
Day 60 (2-8h) n=36	150.03 ( 95.77 )
Day 90 (10-16h) n=18	54.40 ( 51.52 )

Notes
[115] - PDS

No statistical analyses for this end point

Secondary: Anti-Xa values: Rivaroxaban administered twice daily (suspension) in the age group 0.5-<2 years

Top of page

End point title

Anti-Xa values: Rivaroxaban administered twice daily (suspension) in the age group 0.5-<2 years ^[116]

End point description

This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. '99999' denotes the data that cannot be calculated.

End point type

Secondary

End point timeframe

Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60

Notes
[116] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints..

End point values	Rivaroxaban, aged 0.5-<2
Number of subjects analysed	4 ^[117]
Units: microgram per liter (mcg/L)
arithmetic mean (standard deviation)
Day 30 (0.5-1.5h) n=1	247.54 ( 99999 )
Day 30 (2.5-4h) n=2	160.71 ( 153.84 )
Day 60 (2-8h) n=4	121.09 ( 81.94 )

Notes
[117] - PDS

No statistical analyses for this end point

Secondary: Anti-Xa values: Rivaroxaban administered three times daily (suspension) in the age group 2-<6 years

Top of page

End point title

Anti-Xa values: Rivaroxaban administered three times daily (suspension) in the age group 2-<6 years ^[118]

End point description

This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. '99999' denotes the data that cannot be calculated.

End point type

Secondary

End point timeframe

Up to 3 hours post dose on Day 30, up to 6 hours post dose on Day 60, and up to 16 hours on Day 90

Notes
[118] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 2-<6
Number of subjects analysed	4 ^[119]
Units: microgram per liter (mcg/L)
arithmetic mean (standard deviation)
Day 30 (0.5-3h) n=4	209.67 ( 127.86 )
Day 60 (2-6h) n=4	140.46 ( 78.82 )
Day 90 (10-16h) n=1	62.56 ( 99999 )

Notes
[119] - PDS

No statistical analyses for this end point

Secondary: Anti-Xa values: Rivaroxaban administered three times daily (suspension) in the age group 0.5-<2 years

Top of page

End point title

Anti-Xa values: Rivaroxaban administered three times daily (suspension) in the age group 0.5-<2 years ^[120]

End point description

This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. '99999' denotes the data that cannot be calculated.

End point type

Secondary

End point timeframe

Up to 3 hours post dose on Day 30, up to 6 hours post dose on Day 60, and up to 16 hours on Day 90

Notes
[120] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged 0.5-<2
Number of subjects analysed	12 ^[121]
Units: microgram per liter (mcg/L)
arithmetic mean (standard deviation)
Day 30 (0.5-3h) n=12	111.35 ( 97.03 )
Day 30 (2-6h) n=11	147.24 ( 125.40 )
Day 90 (10-16h) n=3	23.40 ( 4.51 )
Follow-up n=1	71.30 ( 99999 )

Notes
[121] - PDS

No statistical analyses for this end point

Secondary: Anti-Xa values: Rivaroxaban administered three times daily (suspension) in the age group birth-<0.5 years

Top of page

End point title

Anti-Xa values: Rivaroxaban administered three times daily (suspension) in the age group birth-<0.5 years ^[122]

End point description

This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method.

End point type

Secondary

End point timeframe

Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60

Notes
[122] - 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 done, no inferential statistical analyses were performed. Baseline period arms were reported as separate endpoints.

End point values	Rivaroxaban, aged birth-<0.5
Number of subjects analysed	10 ^[123]
Units: microgram per liter (mcg/L)
arithmetic mean (standard deviation)
Day 30 (0.5-3h) n=10	118.12 ( 82.08 )
Day 60 (2-6h) n=5	228.03 ( 181.08 )

Notes
[123] - PDS

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

After randomization until last intake of study medication plus 2 days.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

21.1

Reporting group title

Comparator group

Reporting group description

Children randomized to the comparator group will continue with UFH, LMWH or fondaparinux or may switch to VKA therapy. VKA dosages will be adjustedto maintain the INR within the therapeutic range (target 2.5, range 2.0 - 3.0). UFH, LMWH or fondaparinux can be discontinued once the INR is above 2.0 on two separate occasions, 24 hours apart

Reporting group title

Rivaroxaban group

Reporting group description

Serious adverse events	Comparator group	Rivaroxaban group
Total subjects affected by serious adverse events
subjects affected / exposed	35 / 162 (21.60%)	78 / 329 (23.71%)
number of deaths (all causes)	0	2
number of deaths resulting from adverse events	0	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Craniopharyngioma
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myxofibrosarcoma
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Vascular disorders
Haematoma
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Colostomy
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mastoidectomy
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sclerotherapy
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lumboperitoneal shunt
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Faecal disimpaction
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	1 / 162 (0.62%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	2 / 162 (1.23%)	6 / 329 (1.82%)
occurrences causally related to treatment / all	0 / 3	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral swelling
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Autoimmune disorder
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Menorrhagia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic ovarian cyst
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Diaphragmatic paralysis
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory failure
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary vein stenosis
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopneumopathy
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Laryngeal haemorrhage
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Drug abuse
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Device malfunction
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oxygen saturation decreased
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Drug clearance decreased
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal stoma output decreased
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haemorrhage
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic fracture
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post lumbar puncture syndrome
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural haemorrhage
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic haemothorax
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Accidental underdose
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Incorrect route of product administration
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Muscular dystrophy
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrial tachycardia
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Low cardiac output syndrome
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Postural orthostatic tachycardia syndrome
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebral infarction
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dysaesthesia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
subjects affected / exposed	3 / 162 (1.85%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Intracranial pressure increased
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	2 / 162 (1.23%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sciatic nerve neuropathy
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalitis autoimmune
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hemianaesthesia
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hemiparaesthesia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	1 / 162 (0.62%)	8 / 329 (2.43%)
occurrences causally related to treatment / all	0 / 1	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sickle cell anaemia with crisis
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bone marrow failure
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Papilloedema
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Retinal haemorrhage
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 162 (0.62%)	3 / 329 (0.91%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis haemorrhagic
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal dilatation
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 162 (0.00%)	6 / 329 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Paraesthesia oral
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Drug-induced liver injury
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
IgA nephropathy
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nephropathy
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrotic syndrome
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary bladder haemorrhage
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Joint range of motion decreased
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Bacteraemia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Eczema herpeticum
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mastoiditis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Meningitis
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Meningitis bacterial
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nasopharyngitis
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyoderma streptococcal
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tonsillitis streptococcal
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Varicella
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis viral
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Implant site infection
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Parainfluenzae virus infection
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis norovirus
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infected dermal cyst
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Candida infection
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Acidosis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fluid overload
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Comparator group	Rivaroxaban group
Total subjects affected by non serious adverse events
subjects affected / exposed	121 / 162 (74.69%)	275 / 329 (83.59%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Craniopharyngioma
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Ewing's sarcoma
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Lymphangioma
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Skin papilloma
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Vascular disorders
Arterial thrombosis
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Flushing
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Haematoma
subjects affected / exposed	1 / 162 (0.62%)	2 / 329 (0.61%)
occurrences all number	1	2
Hypertension
subjects affected / exposed	2 / 162 (1.23%)	3 / 329 (0.91%)
occurrences all number	2	4
Hypotension
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Pallor
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	5
Phlebitis
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Varicose vein
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Post thrombotic syndrome
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences all number	0	4
Deep vein thrombosis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Extremity necrosis
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Hot flush
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Superficial vein prominence
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
May-Thurner syndrome
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Surgical and medical procedures
Bladder catheterisation
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Intra-uterine contraceptive device insertion
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Ventricular drainage
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Gastrointestinal tube insertion
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Central venous catheterisation
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences all number	0	3
Hepatitis B immunisation
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Oophorectomy
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Mastoid operation
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Tooth extraction
subjects affected / exposed	0 / 162 (0.00%)	4 / 329 (1.22%)
occurrences all number	0	5
Stem cell transplant
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	2
Central venous catheter removal
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Endotracheal intubation
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Ventriculo-cardiac shunt
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Laryngeal mask airway insertion
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 162 (0.62%)	3 / 329 (0.91%)
occurrences all number	1	5
Chest discomfort
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Chest pain
subjects affected / exposed	5 / 162 (3.09%)	16 / 329 (4.86%)
occurrences all number	6	18
Cyst
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Fatigue
subjects affected / exposed	6 / 162 (3.70%)	21 / 329 (6.38%)
occurrences all number	6	23
Feeling abnormal
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Feeling cold
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Gait disturbance
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Granuloma
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Hyperthermia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Hypothermia
subjects affected / exposed	2 / 162 (1.23%)	0 / 329 (0.00%)
occurrences all number	2	0
Influenza like illness
subjects affected / exposed	1 / 162 (0.62%)	2 / 329 (0.61%)
occurrences all number	1	2
Injection site bruising
subjects affected / exposed	8 / 162 (4.94%)	0 / 329 (0.00%)
occurrences all number	8	0
Injection site extravasation
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	2	0
Injection site haematoma
subjects affected / exposed	3 / 162 (1.85%)	0 / 329 (0.00%)
occurrences all number	3	0
Injection site haemorrhage
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Injection site induration
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	3	0
Injection site mass
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Injection site pruritus
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Malaise
subjects affected / exposed	2 / 162 (1.23%)	1 / 329 (0.30%)
occurrences all number	2	1
Mucosal inflammation
subjects affected / exposed	0 / 162 (0.00%)	4 / 329 (1.22%)
occurrences all number	0	4
Oedema
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences all number	0	3
Oedema peripheral
subjects affected / exposed	1 / 162 (0.62%)	4 / 329 (1.22%)
occurrences all number	1	4
Pain
subjects affected / exposed	0 / 162 (0.00%)	7 / 329 (2.13%)
occurrences all number	0	7
Pyrexia
subjects affected / exposed	14 / 162 (8.64%)	37 / 329 (11.25%)
occurrences all number	22	51
Application site vesicles
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Peripheral swelling
subjects affected / exposed	4 / 162 (2.47%)	5 / 329 (1.52%)
occurrences all number	5	5
Catheter site haemorrhage
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Puncture site haemorrhage
subjects affected / exposed	5 / 162 (3.09%)	1 / 329 (0.30%)
occurrences all number	8	1
Catheter site pain
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Catheter site rash
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Vessel puncture site haemorrhage
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Nodule
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Non-cardiac chest pain
subjects affected / exposed	2 / 162 (1.23%)	0 / 329 (0.00%)
occurrences all number	2	0
Application site hypersensitivity
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Infusion site extravasation
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Vaccination site pain
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Medical device site haemorrhage
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Immune system disorders
Allergy to animal
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Anaphylactic reaction
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	2	0
Hypogammaglobulinaemia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Serum sickness
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Seasonal allergy
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Secondary immunodeficiency
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Allergy to arthropod sting
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Graft versus host disease in skin
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Graft versus host disease in liver
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Acute graft versus host disease in skin
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Reproductive system and breast disorders
Breast mass
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Dysmenorrhoea
subjects affected / exposed	2 / 162 (1.23%)	4 / 329 (1.22%)
occurrences all number	2	11
Genital rash
subjects affected / exposed	2 / 162 (1.23%)	0 / 329 (0.00%)
occurrences all number	2	0
Menometrorrhagia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Menorrhagia
subjects affected / exposed	5 / 162 (3.09%)	21 / 329 (6.38%)
occurrences all number	6	29
Menstruation irregular
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Metrorrhagia
subjects affected / exposed	2 / 162 (1.23%)	1 / 329 (0.30%)
occurrences all number	2	1
Ovarian cyst
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Pelvic pain
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Polycystic ovaries
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Priapism
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Uterine haemorrhage
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	2
Vaginal discharge
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Vaginal haemorrhage
subjects affected / exposed	1 / 162 (0.62%)	4 / 329 (1.22%)
occurrences all number	1	10
Genital tract inflammation
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Perineal erythema
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Cough
subjects affected / exposed	11 / 162 (6.79%)	18 / 329 (5.47%)
occurrences all number	11	20
Dyspnoea
subjects affected / exposed	1 / 162 (0.62%)	7 / 329 (2.13%)
occurrences all number	1	8
Dyspnoea exertional
subjects affected / exposed	1 / 162 (0.62%)	2 / 329 (0.61%)
occurrences all number	1	2
Epistaxis
subjects affected / exposed	20 / 162 (12.35%)	40 / 329 (12.16%)
occurrences all number	32	62
Haemoptysis
subjects affected / exposed	2 / 162 (1.23%)	0 / 329 (0.00%)
occurrences all number	2	0
Hiccups
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Nasal congestion
subjects affected / exposed	3 / 162 (1.85%)	6 / 329 (1.82%)
occurrences all number	4	7
Nasal obstruction
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Painful respiration
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Pleural adhesion
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Pleural effusion
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Pleurisy
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Pulmonary haemorrhage
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	3
Pulmonary infarction
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Pulmonary oedema
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Respiratory distress
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Rhinitis allergic
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Rhinorrhoea
subjects affected / exposed	2 / 162 (1.23%)	13 / 329 (3.95%)
occurrences all number	2	16
Sinus congestion
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Sleep apnoea syndrome
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Sneezing
subjects affected / exposed	1 / 162 (0.62%)	2 / 329 (0.61%)
occurrences all number	1	2
Tonsillar hypertrophy
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Wheezing
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Upper respiratory tract inflammation
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Mediastinal cyst
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Respiratory tract congestion
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Sinus disorder
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Oropharyngeal plaque
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Oropharyngeal pain
subjects affected / exposed	4 / 162 (2.47%)	8 / 329 (2.43%)
occurrences all number	4	9
Pulmonary pain
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Respiratory symptom
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Lower respiratory tract congestion
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	2
Anxiety
subjects affected / exposed	2 / 162 (1.23%)	4 / 329 (1.22%)
occurrences all number	2	5
Attention deficit/hyperactivity disorder
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Depressed mood
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Depression
subjects affected / exposed	1 / 162 (0.62%)	3 / 329 (0.91%)
occurrences all number	1	3
Disorientation
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Emotional disorder
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Insomnia
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Mood altered
subjects affected / exposed	2 / 162 (1.23%)	0 / 329 (0.00%)
occurrences all number	2	0
Nervousness
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Panic attack
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Somnambulism
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Phonophobia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Post stroke depression
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Product issues
Device leakage
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Device occlusion
subjects affected / exposed	1 / 162 (0.62%)	2 / 329 (0.61%)
occurrences all number	1	2
Hepatobiliary disorders
Cholangitis
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Cholelithiasis
subjects affected / exposed	2 / 162 (1.23%)	1 / 329 (0.30%)
occurrences all number	2	1
Gallbladder disorder
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Hepatic function abnormal
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Hypertransaminasaemia
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Alanine aminotransferase abnormal
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Alanine aminotransferase increased
subjects affected / exposed	6 / 162 (3.70%)	6 / 329 (1.82%)
occurrences all number	10	11
Aspartate aminotransferase abnormal
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Aspartate aminotransferase increased
subjects affected / exposed	1 / 162 (0.62%)	6 / 329 (1.82%)
occurrences all number	1	10
Aspiration bone marrow
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	2
Bilirubin conjugated increased
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences all number	0	4
Biopsy liver
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Blood bicarbonate decreased
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Blood bilirubin increased
subjects affected / exposed	1 / 162 (0.62%)	4 / 329 (1.22%)
occurrences all number	1	4
Blood bilirubin unconjugated increased
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Blood glucose decreased
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Blood thyroid stimulating hormone increased
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
C-reactive protein increased
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Cardiac murmur
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Coagulation factor VIII level increased
subjects affected / exposed	2 / 162 (1.23%)	0 / 329 (0.00%)
occurrences all number	2	0
Fibrin D dimer increased
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Full blood count abnormal
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences all number	0	3
Haemoglobin decreased
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences all number	0	3
International normalised ratio abnormal
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Lumbar puncture
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	3
Lymphocyte count increased
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Neutrophil count decreased
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	4
Neutrophil count increased
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	2
Nuclear magnetic resonance imaging
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Oxygen saturation decreased
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Platelet count decreased
subjects affected / exposed	2 / 162 (1.23%)	9 / 329 (2.74%)
occurrences all number	2	20
Prothrombin time prolonged
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Weight increased
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences all number	0	3
White blood cell count decreased
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Blood phosphorus decreased
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Platelet count increased
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Lymphocyte percentage decreased
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Lipoprotein (a) increased
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Transaminases increased
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Bacterial test positive
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	2
Blood alkaline phosphatase decreased
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Anticoagulation drug level above therapeutic
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Anticoagulation drug level below therapeutic
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Hepatic enzyme increased
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences all number	0	3
Angiogram
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Vitamin D decreased
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Epstein-Barr virus test positive
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Clostridium test positive
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Staphylococcus test positive
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Chlamydia test positive
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Influenza B virus test positive
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Influenza A virus test positive
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Human rhinovirus test positive
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Liver function test increased
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 162 (0.00%)	7 / 329 (2.13%)
occurrences all number	0	7
Alcohol poisoning
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Arthropod bite
subjects affected / exposed	1 / 162 (0.62%)	2 / 329 (0.61%)
occurrences all number	1	2
Concussion
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Fall
subjects affected / exposed	2 / 162 (1.23%)	5 / 329 (1.52%)
occurrences all number	2	6
Foot fracture
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Greenstick fracture
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Hand fracture
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Head injury
subjects affected / exposed	3 / 162 (1.85%)	2 / 329 (0.61%)
occurrences all number	3	4
Joint dislocation
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Ligament sprain
subjects affected / exposed	3 / 162 (1.85%)	1 / 329 (0.30%)
occurrences all number	3	1
Overdose
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Road traffic accident
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Subcutaneous haematoma
subjects affected / exposed	5 / 162 (3.09%)	14 / 329 (4.26%)
occurrences all number	5	21
Tibia fracture
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Transfusion reaction
subjects affected / exposed	1 / 162 (0.62%)	2 / 329 (0.61%)
occurrences all number	1	3
Wound secretion
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Mouth injury
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Exposure to communicable disease
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Muscle strain
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Contusion
subjects affected / exposed	9 / 162 (5.56%)	15 / 329 (4.56%)
occurrences all number	10	19
Incision site haemorrhage
subjects affected / exposed	0 / 162 (0.00%)	4 / 329 (1.22%)
occurrences all number	0	4
Wound haemorrhage
subjects affected / exposed	2 / 162 (1.23%)	13 / 329 (3.95%)
occurrences all number	3	14
Thermal burn
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Postoperative thoracic procedure complication
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Underdose
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences all number	0	3
Post procedural complication
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Stoma site rash
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Incision site haematoma
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Joint injury
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Limb injury
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Procedural pain
subjects affected / exposed	2 / 162 (1.23%)	4 / 329 (1.22%)
occurrences all number	2	4
Skin abrasion
subjects affected / exposed	1 / 162 (0.62%)	4 / 329 (1.22%)
occurrences all number	1	4
Anaphylactic transfusion reaction
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	2	0
Eye contusion
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Stoma site haemorrhage
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Stoma site erythema
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Accidental underdose
subjects affected / exposed	0 / 162 (0.00%)	7 / 329 (2.13%)
occurrences all number	0	8
Vascular access site haemorrhage
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Cerebral radiation injury
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Nasal injury
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Product prescribing error
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Congenital, familial and genetic disorders
Hydrocele
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Immunodeficiency congenital
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Protein S deficiency
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Cardiac disorders
Atrial tachycardia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Bradycardia
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Palpitations
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Sinus tachycardia
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Supraventricular tachycardia
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Tachycardia
subjects affected / exposed	0 / 162 (0.00%)	6 / 329 (1.82%)
occurrences all number	0	6
Nervous system disorders
Clumsiness
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Dizziness
subjects affected / exposed	4 / 162 (2.47%)	11 / 329 (3.34%)
occurrences all number	4	11
Dizziness exertional
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Head discomfort
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Headache
subjects affected / exposed	24 / 162 (14.81%)	56 / 329 (17.02%)
occurrences all number	28	75
Hyperaesthesia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Hypersomnia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Hypotonia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Intracranial pressure increased
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Memory impairment
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Migraine
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Muscle contractions involuntary
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	2
Neuropathy peripheral
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Paraesthesia
subjects affected / exposed	2 / 162 (1.23%)	5 / 329 (1.52%)
occurrences all number	2	5
Presyncope
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Psychomotor hyperactivity
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Seizure
subjects affected / exposed	2 / 162 (1.23%)	1 / 329 (0.30%)
occurrences all number	2	1
Syncope
subjects affected / exposed	1 / 162 (0.62%)	3 / 329 (0.91%)
occurrences all number	1	3
Tension headache
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Tremor
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Balance disorder
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
VIth nerve disorder
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Toxic neuropathy
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Choroid fissure cyst
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 162 (3.09%)	11 / 329 (3.34%)
occurrences all number	5	20
Coagulopathy
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Febrile neutropenia
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences all number	0	3
Haemolysis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Increased tendency to bruise
subjects affected / exposed	3 / 162 (1.85%)	1 / 329 (0.30%)
occurrences all number	3	1
Iron deficiency anaemia
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Leukocytosis
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	3
Leukopenia
subjects affected / exposed	1 / 162 (0.62%)	4 / 329 (1.22%)
occurrences all number	1	8
Lymphadenitis
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Lymphadenopathy
subjects affected / exposed	2 / 162 (1.23%)	2 / 329 (0.61%)
occurrences all number	2	2
Lymphopenia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	5
Neutropenia
subjects affected / exposed	4 / 162 (2.47%)	6 / 329 (1.82%)
occurrences all number	4	7
Pancytopenia
subjects affected / exposed	2 / 162 (1.23%)	1 / 329 (0.30%)
occurrences all number	2	1
Thrombocytopenia
subjects affected / exposed	2 / 162 (1.23%)	10 / 329 (3.04%)
occurrences all number	2	15
Thrombocytosis
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	2	2
Autoimmune neutropenia
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Haemorrhagic diathesis
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Bone marrow failure
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Cytopenia
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	2	0
Ear and labyrinth disorders
Conductive deafness
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Deafness
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Ear haemorrhage
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Ear pain
subjects affected / exposed	1 / 162 (0.62%)	6 / 329 (1.82%)
occurrences all number	1	7
Deafness unilateral
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Ear discomfort
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Ear pruritus
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Eye disorders
Amblyopia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Astigmatism
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Cataract
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Diplopia
subjects affected / exposed	1 / 162 (0.62%)	2 / 329 (0.61%)
occurrences all number	1	2
Eye inflammation
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Eye irritation
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Eye pain
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Eye swelling
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Eyelid ptosis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Glaucoma
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Heterophoria
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Myopia
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Ocular hyperaemia
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Ocular hypertension
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Optic disc haemorrhage
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Papilloedema
subjects affected / exposed	3 / 162 (1.85%)	4 / 329 (1.22%)
occurrences all number	3	5
Photophobia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Retinal haemorrhage
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Strabismus
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Vision blurred
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Visual impairment
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Conjunctival hyperaemia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Eye pruritus
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Abdominal distension
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Abdominal pain
subjects affected / exposed	9 / 162 (5.56%)	17 / 329 (5.17%)
occurrences all number	11	27
Abdominal pain upper
subjects affected / exposed	4 / 162 (2.47%)	11 / 329 (3.34%)
occurrences all number	4	12
Anal fissure
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	4
Anal fistula
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Aphthous ulcer
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences all number	0	3
Breath odour
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Constipation
subjects affected / exposed	10 / 162 (6.17%)	8 / 329 (2.43%)
occurrences all number	10	11
Dental caries
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Diarrhoea
subjects affected / exposed	11 / 162 (6.79%)	25 / 329 (7.60%)
occurrences all number	12	30
Diarrhoea haemorrhagic
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Dry mouth
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Dyspepsia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Faeces discoloured
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Flatulence
subjects affected / exposed	2 / 162 (1.23%)	0 / 329 (0.00%)
occurrences all number	2	0
Food poisoning
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Gastric haemorrhage
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Gastritis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 162 (0.62%)	3 / 329 (0.91%)
occurrences all number	1	3
Gastrointestinal disorder
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Gingival bleeding
subjects affected / exposed	1 / 162 (0.62%)	13 / 329 (3.95%)
occurrences all number	1	13
Gingival pain
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Glossitis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Haematemesis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Haematochezia
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Mouth haemorrhage
subjects affected / exposed	0 / 162 (0.00%)	6 / 329 (1.82%)
occurrences all number	0	6
Mouth ulceration
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Nausea
subjects affected / exposed	6 / 162 (3.70%)	22 / 329 (6.69%)
occurrences all number	7	25
Oral pain
subjects affected / exposed	2 / 162 (1.23%)	0 / 329 (0.00%)
occurrences all number	2	0
Rectal haemorrhage
subjects affected / exposed	3 / 162 (1.85%)	7 / 329 (2.13%)
occurrences all number	3	8
Stomatitis
subjects affected / exposed	1 / 162 (0.62%)	4 / 329 (1.22%)
occurrences all number	1	7
Tongue blistering
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Tongue coated
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Tongue geographic
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Tongue ulceration
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Toothache
subjects affected / exposed	2 / 162 (1.23%)	3 / 329 (0.91%)
occurrences all number	2	4
Vomiting
subjects affected / exposed	13 / 162 (8.02%)	36 / 329 (10.94%)
occurrences all number	17	42
Anal haemorrhage
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences all number	0	3
Anal inflammation
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Large intestinal haemorrhage
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Perianal erythema
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	2
Faecaloma
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Abdominal hernia
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Appendix disorder
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Gastrointestinal inflammation
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Tooth socket haemorrhage
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Anorectal discomfort
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Anal incontinence
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	2
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	1 / 162 (0.62%)	3 / 329 (0.91%)
occurrences all number	1	3
Alopecia
subjects affected / exposed	5 / 162 (3.09%)	8 / 329 (2.43%)
occurrences all number	5	8
Alopecia areata
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Blister
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Blood blister
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Dermatitis allergic
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	2	1
Dermatitis atopic
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Dermatitis contact
subjects affected / exposed	2 / 162 (1.23%)	1 / 329 (0.30%)
occurrences all number	2	1
Dermatitis diaper
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Drug eruption
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences all number	0	3
Dry skin
subjects affected / exposed	0 / 162 (0.00%)	4 / 329 (1.22%)
occurrences all number	0	4
Ecchymosis
subjects affected / exposed	2 / 162 (1.23%)	0 / 329 (0.00%)
occurrences all number	2	0
Eczema
subjects affected / exposed	2 / 162 (1.23%)	2 / 329 (0.61%)
occurrences all number	2	2
Erythema
subjects affected / exposed	1 / 162 (0.62%)	6 / 329 (1.82%)
occurrences all number	1	8
Erythema multiforme
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Hirsutism
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Livedo reticularis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Night sweats
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Petechiae
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Pruritus
subjects affected / exposed	2 / 162 (1.23%)	8 / 329 (2.43%)
occurrences all number	2	8
Rash
subjects affected / exposed	4 / 162 (2.47%)	17 / 329 (5.17%)
occurrences all number	4	19
Rash erythematous
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Rash follicular
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Rash maculo-papular
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	2	1
Rash papular
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Rash pruritic
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Skin discolouration
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Skin exfoliation
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences all number	0	3
Skin striae
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Skin ulcer
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Stasis dermatitis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Swelling face
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Umbilical haemorrhage
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Urticaria
subjects affected / exposed	1 / 162 (0.62%)	3 / 329 (0.91%)
occurrences all number	1	3
Skin swelling
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Skin haemorrhage
subjects affected / exposed	1 / 162 (0.62%)	4 / 329 (1.22%)
occurrences all number	1	4
Renal and urinary disorders
Dysuria
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Haematuria
subjects affected / exposed	1 / 162 (0.62%)	5 / 329 (1.52%)
occurrences all number	1	8
Hypercalciuria
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Nephrolithiasis
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences all number	0	3
Pollakiuria
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Renal atrophy
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Urinary bladder haemorrhage
subjects affected / exposed	0 / 162 (0.00%)	4 / 329 (1.22%)
occurrences all number	0	5
Urethral haemorrhage
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Urine odour abnormal
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Acute kidney injury
subjects affected / exposed	1 / 162 (0.62%)	2 / 329 (0.61%)
occurrences all number	3	2
Endocrine disorders
Cushingoid
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	4 / 162 (2.47%)	12 / 329 (3.65%)
occurrences all number	4	13
Back pain
subjects affected / exposed	3 / 162 (1.85%)	11 / 329 (3.34%)
occurrences all number	3	11
Bone pain
subjects affected / exposed	1 / 162 (0.62%)	2 / 329 (0.61%)
occurrences all number	1	2
Costochondritis
subjects affected / exposed	2 / 162 (1.23%)	1 / 329 (0.30%)
occurrences all number	2	3
Flank pain
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Groin pain
subjects affected / exposed	0 / 162 (0.00%)	5 / 329 (1.52%)
occurrences all number	0	5
Joint swelling
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Muscle spasms
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Musculoskeletal pain
subjects affected / exposed	2 / 162 (1.23%)	0 / 329 (0.00%)
occurrences all number	2	0
Myalgia
subjects affected / exposed	1 / 162 (0.62%)	4 / 329 (1.22%)
occurrences all number	1	5
Neck pain
subjects affected / exposed	1 / 162 (0.62%)	6 / 329 (1.82%)
occurrences all number	1	6
Pain in extremity
subjects affected / exposed	9 / 162 (5.56%)	23 / 329 (6.99%)
occurrences all number	12	25
Pain in jaw
subjects affected / exposed	1 / 162 (0.62%)	2 / 329 (0.61%)
occurrences all number	1	2
Tendonitis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Muscle tightness
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Musculoskeletal chest pain
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences all number	0	4
Musculoskeletal stiffness
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Musculoskeletal discomfort
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Infections and infestations
Angular cheilitis
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Bacteriuria
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Bronchiolitis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Bronchitis
subjects affected / exposed	0 / 162 (0.00%)	4 / 329 (1.22%)
occurrences all number	0	4
Cellulitis
subjects affected / exposed	2 / 162 (1.23%)	1 / 329 (0.30%)
occurrences all number	2	1
Conjunctivitis
subjects affected / exposed	2 / 162 (1.23%)	3 / 329 (0.91%)
occurrences all number	2	4
Ear infection
subjects affected / exposed	1 / 162 (0.62%)	3 / 329 (0.91%)
occurrences all number	1	3
Eye infection
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Eyelid infection
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Folliculitis
subjects affected / exposed	2 / 162 (1.23%)	2 / 329 (0.61%)
occurrences all number	2	2
Gastroenteritis
subjects affected / exposed	0 / 162 (0.00%)	7 / 329 (2.13%)
occurrences all number	0	7
Gastroenteritis viral
subjects affected / exposed	0 / 162 (0.00%)	4 / 329 (1.22%)
occurrences all number	0	4
Gastrointestinal infection
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Giardiasis
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Hand-foot-and-mouth disease
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Herpes virus infection
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Herpes zoster
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Hordeolum
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Impetigo
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Infection
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Influenza
subjects affected / exposed	3 / 162 (1.85%)	6 / 329 (1.82%)
occurrences all number	4	6
Injection site infection
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Localised infection
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences all number	0	4
Mastoiditis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Nasopharyngitis
subjects affected / exposed	10 / 162 (6.17%)	29 / 329 (8.81%)
occurrences all number	13	36
Oral candidiasis
subjects affected / exposed	1 / 162 (0.62%)	5 / 329 (1.52%)
occurrences all number	1	5
Osteomyelitis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Otitis media
subjects affected / exposed	1 / 162 (0.62%)	3 / 329 (0.91%)
occurrences all number	1	3
Otitis media acute
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Otitis media chronic
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Paronychia
subjects affected / exposed	1 / 162 (0.62%)	3 / 329 (0.91%)
occurrences all number	1	3
Periodontitis
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Pharyngitis
subjects affected / exposed	4 / 162 (2.47%)	2 / 329 (0.61%)
occurrences all number	4	2
Pharyngitis streptococcal
subjects affected / exposed	1 / 162 (0.62%)	2 / 329 (0.61%)
occurrences all number	3	2
Pneumonia
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Pneumonia mycoplasmal
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Postoperative wound infection
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Rhinitis
subjects affected / exposed	4 / 162 (2.47%)	11 / 329 (3.34%)
occurrences all number	4	12
Scarlet fever
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Sinusitis
subjects affected / exposed	1 / 162 (0.62%)	6 / 329 (1.82%)
occurrences all number	1	6
Skin infection
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Subcutaneous abscess
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Tonsillitis
subjects affected / exposed	4 / 162 (2.47%)	5 / 329 (1.52%)
occurrences all number	4	5
Tooth abscess
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Upper respiratory tract infection
subjects affected / exposed	8 / 162 (4.94%)	10 / 329 (3.04%)
occurrences all number	8	13
Urethritis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Urinary tract infection
subjects affected / exposed	2 / 162 (1.23%)	4 / 329 (1.22%)
occurrences all number	2	4
Varicella
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Viral infection
subjects affected / exposed	1 / 162 (0.62%)	4 / 329 (1.22%)
occurrences all number	1	4
Viral pharyngitis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Viral rash
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Viral upper respiratory tract infection
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Vulvitis
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Vulvovaginal candidiasis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Wound infection
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Oral infection
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Tooth infection
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Abscess limb
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Staphylococcal bacteraemia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Escherichia urinary tract infection
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Cardiac infection
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Tinea versicolour
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Asymptomatic bacteriuria
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Catheter site infection
subjects affected / exposed	1 / 162 (0.62%)	2 / 329 (0.61%)
occurrences all number	1	2
Enteritis infectious
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Implant site infection
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Sinusitis bacterial
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	2
Adenovirus infection
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Bacterial infection
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Mastoid abscess
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Respiratory syncytial virus infection
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Ear infection viral
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Parainfluenzae virus infection
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Respiratory tract infection viral
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	2
Respiratory tract infection
subjects affected / exposed	0 / 162 (0.00%)	3 / 329 (0.91%)
occurrences all number	0	3
Acarodermatitis
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Device related infection
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Vulvovaginal mycotic infection
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Oral herpes
subjects affected / exposed	0 / 162 (0.00%)	4 / 329 (1.22%)
occurrences all number	0	5
Gastrointestinal viral infection
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Candida infection
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Metabolism and nutrition disorders
Fluid overload
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Folate deficiency
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Hypercalcaemia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Hyperchloraemia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Hyperglycaemia
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Hyperkalaemia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Hypernatraemia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Hypertriglyceridaemia
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Hyperuricaemia
subjects affected / exposed	0 / 162 (0.00%)	1 / 329 (0.30%)
occurrences all number	0	1
Hypokalaemia
subjects affected / exposed	0 / 162 (0.00%)	8 / 329 (2.43%)
occurrences all number	0	8
Hypomagnesaemia
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	2
Hyponatraemia
subjects affected / exposed	1 / 162 (0.62%)	2 / 329 (0.61%)
occurrences all number	1	2
Hypophosphataemia
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	3
Iron deficiency
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Metabolic acidosis
subjects affected / exposed	0 / 162 (0.00%)	2 / 329 (0.61%)
occurrences all number	0	3
Selenium deficiency
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Vitamin B12 deficiency
subjects affected / exposed	1 / 162 (0.62%)	0 / 329 (0.00%)
occurrences all number	1	0
Vitamin D deficiency
subjects affected / exposed	2 / 162 (1.23%)	1 / 329 (0.30%)
occurrences all number	2	1
Hyperhomocysteinaemia
subjects affected / exposed	1 / 162 (0.62%)	1 / 329 (0.30%)
occurrences all number	1	1
Decreased appetite
subjects affected / exposed	0 / 162 (0.00%)	6 / 329 (1.82%)
occurrences all number	0	7

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

21 Jul 2015

- Implementation of dosing regimen for children aged between 6 to <12 years following confirmation of the body weight-adjusted dosing regimen for this age group in the phase II study (14373). - Inclusion of menstruation intensity assessments. The protocol was adjusted throughout to reflect that the intensity of menstruation has to be assessed from visit 2 to visit7. - Information was provided on continuing body weight-adjusted treatment in children who turned 2, 6, 12 and 18. If a child turned to the next highest age group, he/she continued treatment according to age- and body-weight dependent dosing of his/her inclusion age cohort. However, if a child’s weight increased (as measured at a visit), the child would be assigned to the appropriate dose group. - Heparins flushes were added to maintain catheter patency. It was decided to allow heparin flushes except for flushes before PK/PD samples. - Instructions for rivaroxaban administration with an o.d. and b.i.d. regimen for children aged between 6 and <12 years were added. - Instructions for handling of missed doses are provided for o.d. and bid dosing in children aged between 6 and <12 years.

20 Sep 2016

- The timeframe in which randomization can be done was extended from day 1-5 to day 1-9 of the initial treatment. - Information was added for switch from VKA to rivaroxaban. This modification clarified the procedure for children randomized to rivaroxaban, who had already started VKA therapy prior to randomization. - Update of exclusion criterion 1: “high risk for bleeding contraindicating anticoagulant therapy” was modified to read “bleeding risk contraindicating anticoagulant therapy”. - Clarification of exclusion criterion 5: it was clarified that children with sustained uncontrolled hypertension should be excluded from the study. - Clarification of concomitant medication in exclusion criteria 7 and 8; The modification indicated that the drugs listed in the exclusion criteria 7 and 8 were considered strong inhibitors of both CYP3A4 and P-gp, and strong inducers of CYP3A4, respectively, but that the lists was not limited to the drugs mentioned. - Collection of body weight was added for Visits 2 and 3. - The assessment of the incidence of post-thrombotic syndrome was added for children of ≥12 years with lower or upper extremity DVT at Visit 4, 5, 6 and 7. - The upper range for children completing the Taste- and Texture questionnaire was changed from <12 to <18 years. - Introduction of additional supplies for preparation and administration of oral suspension; Additional supplies were be provided to prepare, measure and administer the rivaroxaban oral suspension. These supplies included a syringe for measurement of 100 mL of water and liquid dosing devices for measurement of the dose volume. - Enrollment of children aged between 0.5 to <6 years was opened, and the structure of age cohort specific dosing and regiment instructions was resolved and replaced by a consistent description applicable for children aged between 0.5 and <18 years. - The suspension formulation was provided for children in all age cohorts.

11 Jan 2017

- A visit was added to be scheduled 2+1 days after start of rivaroxaban treatment for children treated according to a t.i.d. regimen. - The dosing table was extended to include dosing information for children with body weight of 6 kg to 12 kg. Children with body weight between 6 and <12 kg were to be treated according to a thrice-daily (t.i.d.) schedule with a time interval of approximately 8 hours between individual doses.

27 Sep 2017

- New dosing information for children with body weight between 2.6 and <6 kg, and inclusion of children aged between birth and 0.5 year was added.

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.

None reported

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Clinical trials

Clinical Trial Results: Multicenter, open-label, active-controlled, randomized study to evaluate the efficacy and safety of an age-and body weight-adjusted rivaroxaban regimen compared to standard of care in children with acute venous thromboembolism

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Incidence rates of all symptomatic recurrent venous thromboembolism during the main treatment period

Primary: Incidence rates of all symptomatic recurrent venous thromboembolism during the main treatment period

Primary: Incidence rates of all symptomatic recurrent venous thromboembolism during extended treatment period

Primary: Incidence rates of all symptomatic recurrent venous thromboembolism during extended treatment period

Primary: Number of subjects with the composite of all symptomatic recurrent venous thromboembolism during the 30 days post-study treatment period (i.e. >2 and ≤ 30 days after stop of study medication)

Primary: Number of subjects with the composite of all symptomatic recurrent venous thromboembolism during the 30 days post-study treatment period (i.e. >2 and ≤ 30 days after stop of study medication)

Primary: Incidence rates of the composite of treatment emergent overt major bleeding and clinically relevant non-major (CRNM) bleeding during main treatment period

Primary: Incidence rates of the composite of treatment emergent overt major bleeding and clinically relevant non-major (CRNM) bleeding during main treatment period

Primary: Incidence rates of the composite of treatment emergent overt major bleeding and clinically relevant non-major (CRNM) bleeding during extended treatment period

Primary: Incidence rates of the composite of treatment emergent overt major bleeding and clinically relevant non-major (CRNM) bleeding during extended treatment period

Secondary: Incidence rates of the composite of all symptomatic recurrent venous thromboembolism and asymptomatic deterioration in thrombotic burden on repeat imaging during the main treatment period

Secondary: Incidence rates of the composite of all symptomatic recurrent venous thromboembolism and asymptomatic deterioration in thrombotic burden on repeat imaging during the main treatment period

Secondary: AUC(0-24)ss in plasma

Secondary: AUC(0-24)ss in plasma

Secondary: Cmax,ss in plasma

Secondary: Cmax,ss in plasma

Secondary: Ctrough,ss in plasma

Secondary: Ctrough,ss in plasma

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered once daily (suspension and tablet) in the age group 12-<18 years

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered once daily (suspension and tablet) in the age group 12-<18 years

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered once daily (suspension and tablet) in the age group 6-<12 years

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered once daily (suspension and tablet) in the age group 6-<12 years

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered twice daily (suspension and tablet) in the age group 6-<12 years

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered twice daily (suspension and tablet) in the age group 6-<12 years

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered twice daily (suspension) in the age group 2-<6 years

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered twice daily (suspension) in the age group 2-<6 years

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered twice daily (suspension) in the age group 0.5-<2 years

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered twice daily (suspension) in the age group 0.5-<2 years

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group 2-<6 years

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group 2-<6 years

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group 0.5-<2 years

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group 0.5-<2 years

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group birth-<0.5 years

Secondary: Prothrombin time (PT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group birth-<0.5 years

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered once daily (suspension and tablet) in the age group 12-<18 years

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered once daily (suspension and tablet) in the age group 12-<18 years

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered once daily (suspension and tablet) in the age group 6-<12 years

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered once daily (suspension and tablet) in the age group 6-<12 years

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered twice daily (suspension and tablet) in the age group 6-<12 years

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered twice daily (suspension and tablet) in the age group 6-<12 years

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered twice daily (suspension) in the age group 2-<6 years

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered twice daily (suspension) in the age group 2-<6 years

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered twice daily (suspension) in the age group 0.5-<2 years

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered twice daily (suspension) in the age group 0.5-<2 years

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group 2-<6 years

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group 2-<6 years

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group 0.5-<2 years

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group 0.5-<2 years

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group birth-<0.5 years

Secondary: Activated partial thromboplastin time (aPTT) ratios to baseline: Rivaroxaban administered three times daily (suspension) in the age group birth-<0.5 years

Secondary: Anti-Xa values: Rivaroxaban administered once daily (suspension and tablet) in the age group 12-<18 years

Secondary: Anti-Xa values: Rivaroxaban administered once daily (suspension and tablet) in the age group 12-<18 years

Secondary: Anti-Xa values: Rivaroxaban administered once daily (suspension and tablet) in the age group 6-<12 years

Secondary: Anti-Xa values: Rivaroxaban administered once daily (suspension and tablet) in the age group 6-<12 years

Secondary: Anti-Xa values: Rivaroxaban administered twice daily (suspension and tablet) in the age group 6-<12 years

Secondary: Anti-Xa values: Rivaroxaban administered twice daily (suspension and tablet) in the age group 6-<12 years

Secondary: Anti-Xa values: Rivaroxaban administered twice daily (suspension) in the age group 2-<6 years

Secondary: Anti-Xa values: Rivaroxaban administered twice daily (suspension) in the age group 2-<6 years

Secondary: Anti-Xa values: Rivaroxaban administered twice daily (suspension) in the age group 0.5-<2 years

Secondary: Anti-Xa values: Rivaroxaban administered twice daily (suspension) in the age group 0.5-<2 years

Secondary: Anti-Xa values: Rivaroxaban administered three times daily (suspension) in the age group 2-<6 years

Secondary: Anti-Xa values: Rivaroxaban administered three times daily (suspension) in the age group 2-<6 years

Secondary: Anti-Xa values: Rivaroxaban administered three times daily (suspension) in the age group 0.5-<2 years

Secondary: Anti-Xa values: Rivaroxaban administered three times daily (suspension) in the age group 0.5-<2 years

Secondary: Anti-Xa values: Rivaroxaban administered three times daily (suspension) in the age group birth-<0.5 years

Secondary: Anti-Xa values: Rivaroxaban administered three times daily (suspension) in the age group birth-<0.5 years

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Clinical Trial Results:
Multicenter, open-label, active-controlled, randomized study to evaluate the efficacy and safety of an age-and body weight-adjusted rivaroxaban regimen compared to standard of care in children with acute venous thromboembolism