Trial Outcomes & Findings for EINSTEIN Junior: Oral Rivaroxaban in Children With Venous Thrombosis (NCT NCT02234843)

Last Updated: 2020-04-01

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

500 participants

Primary outcome timeframe

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

Results posted on

2020-04-01

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Rivaroxaban, Aged 12-<18 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.	Rivaroxaban, Aged 6-<12 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.	Rivaroxaban, Aged 2-<6 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.	Rivaroxaban, Aged 0.5-<2 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.	Rivaroxaban, Aged Birth-<0.5 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.	Comparator, Aged 12-<18 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 Vitamin K Antagonist (VKA) therapy. VKA dosages were adjusted to maintain the international normalized ratio (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.	Comparator, Aged 6-<12 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.	Comparator, Aged 2-<6 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.	Comparator, Aged 0.5-<2 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.	Comparator, Aged Birth-<0.5 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.
Overall Study STARTED	184	67	47	21	16	92	34	22	9	8
Overall Study COMPLETED	162	61	44	16	14	79	32	20	8	8
Overall Study NOT COMPLETED	22	6	3	5	2	13	2	2	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Rivaroxaban, Aged 12-<18 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.	Rivaroxaban, Aged 6-<12 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.	Rivaroxaban, Aged 2-<6 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.	Rivaroxaban, Aged 0.5-<2 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.	Rivaroxaban, Aged Birth-<0.5 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.	Comparator, Aged 12-<18 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 Vitamin K Antagonist (VKA) therapy. VKA dosages were adjusted to maintain the international normalized ratio (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.	Comparator, Aged 6-<12 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.	Comparator, Aged 2-<6 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.	Comparator, Aged 0.5-<2 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.
Overall Study Death	1	0	0	0	0	0	0	0	0
Overall Study Protocol Violation	1	0	1	0	0	0	0	0	0
Overall Study Efficacy outcome reached	2	0	0	0	0	2	0	0	0
Overall Study Patient convenience	2	0	0	0	0	1	0	0	0
Overall Study Withdrawal by Subject	5	1	1	0	0	7	0	0	0
Overall Study Recovery	1	0	0	0	0	0	0	0	0
Overall Study Other	0	2	0	1	0	1	0	1	0
Overall Study Physician Decision	4	1	0	1	0	0	0	1	0
Overall Study Adverse Event	5	1	1	3	2	1	0	0	1
Overall Study Non-compliance with study drug	1	0	0	0	0	1	1	0	0
Overall Study Lost to Follow-up	0	1	0	0	0	0	1	0	0

Baseline Characteristics

EINSTEIN Junior: Oral Rivaroxaban in Children With Venous Thrombosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rivaroxaban, Aged 12-<18 n=184 Participants 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.	Rivaroxaban, Aged 6-<12 n=67 Participants 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.	Rivaroxaban, Aged 2-<6 n=47 Participants 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.	Rivaroxaban, Aged 0.5-<2 n=21 Participants 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.	Rivaroxaban, Aged Birth-<0.5 n=16 Participants 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.	Comparator, Aged 12-<18 n=92 Participants 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.	Comparator, Aged 6-<12 n=34 Participants 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.	Comparator, Aged 2-<6 n=22 Participants 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.	Comparator, Aged 0.5-<2 n=9 Participants 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.	Comparator, Aged Birth-<0.5 n=8 Participants 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.	Total n=500 Participants Total of all reporting groups
Age, Customized 12-<18 years	184 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	92 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=24 Participants	0 Participants n=42 Participants	0 Participants n=42 Participants	276 Participants n=42 Participants
Age, Customized 6-<12 years	0 Participants n=5 Participants	67 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	34 Participants n=8 Participants	0 Participants n=24 Participants	0 Participants n=42 Participants	0 Participants n=42 Participants	101 Participants n=42 Participants
Age, Customized 2-<6 years	0 Participants n=5 Participants	0 Participants n=7 Participants	47 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	22 Participants n=24 Participants	0 Participants n=42 Participants	0 Participants n=42 Participants	69 Participants n=42 Participants
Age, Customized 0.5-<2 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	21 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=24 Participants	9 Participants n=42 Participants	0 Participants n=42 Participants	30 Participants n=42 Participants
Age, Customized Birth-<0.5 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	16 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=24 Participants	0 Participants n=42 Participants	8 Participants n=42 Participants	24 Participants n=42 Participants
Sex: Female, Male Female	97 Participants n=5 Participants	24 Participants n=7 Participants	24 Participants n=5 Participants	10 Participants n=4 Participants	5 Participants n=21 Participants	55 Participants n=8 Participants	15 Participants n=8 Participants	9 Participants n=24 Participants	5 Participants n=42 Participants	1 Participants n=42 Participants	245 Participants n=42 Participants
Sex: Female, Male Male	87 Participants n=5 Participants	43 Participants n=7 Participants	23 Participants n=5 Participants	11 Participants n=4 Participants	11 Participants n=21 Participants	37 Participants n=8 Participants	19 Participants n=8 Participants	13 Participants n=24 Participants	4 Participants n=42 Participants	7 Participants n=42 Participants	255 Participants n=42 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	164 Participants n=5 Participants	58 Participants n=7 Participants	42 Participants n=5 Participants	15 Participants n=4 Participants	12 Participants n=21 Participants	79 Participants n=8 Participants	26 Participants n=8 Participants	19 Participants n=24 Participants	8 Participants n=42 Participants	6 Participants n=42 Participants	429 Participants n=42 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	7 Participants n=5 Participants	5 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants	1 Participants n=21 Participants	6 Participants n=8 Participants	5 Participants n=8 Participants	1 Participants n=24 Participants	0 Participants n=42 Participants	0 Participants n=42 Participants	29 Participants n=42 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	13 Participants n=5 Participants	4 Participants n=7 Participants	4 Participants n=5 Participants	3 Participants n=4 Participants	3 Participants n=21 Participants	7 Participants n=8 Participants	3 Participants n=8 Participants	2 Participants n=24 Participants	1 Participants n=42 Participants	2 Participants n=42 Participants	42 Participants n=42 Participants

PRIMARY outcome

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

Population: Full analysis set (FAS)

Outcome measures

Outcome measures
Measure	Comparator, Aged Birth-<0.5 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.	Rivaroxaban Group n=335 Participants 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.	Comparator Group n=165 Participants Children randomized to the comparator group will continue with UFH, LMWH or fondaparinux or may switch to VKA therapy. VKA dosages will be adjusted to maintain the 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	Rivaroxaban, Aged 2-<6 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.	Rivaroxaban, Aged 0.5-<2 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.	Rivaroxaban, Aged Birth-<0.5 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.	Comparator, Aged 12-<18 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.	Comparator, Aged 6-<12 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.	Comparator, Aged 2-<6 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.	Comparator, Aged 0.5-<2 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.
Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During the Main Treatment Period	—	1.2 Percentage of participants Interval 0.4 to 3.0	3.0 Percentage of participants Interval 1.2 to 6.6	—	—	—	—	—	—	—

PRIMARY outcome

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)

Population: Full analysis set (FAS)

Outcome measures

Outcome measures
Measure	Comparator, Aged Birth-<0.5 n=8 Participants 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.	Rivaroxaban Group n=184 Participants 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.	Comparator Group n=67 Participants Children randomized to the comparator group will continue with UFH, LMWH or fondaparinux or may switch to VKA therapy. VKA dosages will be adjusted to maintain the 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	Rivaroxaban, Aged 2-<6 n=47 Participants 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.	Rivaroxaban, Aged 0.5-<2 n=21 Participants 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.	Rivaroxaban, Aged Birth-<0.5 n=16 Participants 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.	Comparator, Aged 12-<18 n=92 Participants 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.	Comparator, Aged 6-<12 n=34 Participants 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.	Comparator, Aged 2-<6 n=22 Participants 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.	Comparator, Aged 0.5-<2 n=9 Participants 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.
Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During the Main Treatment Period	0.0 Percentage of participants 95% Confidence Interval 0.0 • Interval 0.0 to 29.9	2.2 Percentage of participants 95% Confidence Interval 0.7 • Interval 0.7 to 5.3	0.0 Percentage of participants 95% Confidence Interval 0.0 • Interval 0.0 to 5.3	0.0 Percentage of participants 95% Confidence Interval 0.0 • Interval 0.0 to 6.8	0.0 Percentage of participants 95% Confidence Interval 0.0 • Interval 0.0 to 8.3	0.0 Percentage of participants 95% Confidence Interval 0.0 • Interval 0.0 to 14.6	3.3 Percentage of participants 95% Confidence Interval 0.9 • Interval 0.9 to 8.6	2.9 Percentage of participants 95% Confidence Interval 0.2 • Interval 0.2 to 15.1	4.5 Percentage of participants 95% Confidence Interval 0.2 • Interval 0.2 to 20.7	0.0 Percentage of participants 95% Confidence Interval 0.0 • Interval 0.0 to 18.4

PRIMARY outcome

Timeframe: During extended treatment period: up to month 12.

Population: Full analysis set (FAS)

Incidence rates for all children except those aged \< 2 years with catheter-related thrombosis. If no participant in the specific subgroup entered in the specific optional extension period, no analysis of an outcome was possible., 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.

Outcome measures

Outcome measures
Measure	Comparator, Aged Birth-<0.5 n=1 Participants 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.	Rivaroxaban Group n=93 Participants 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.	Comparator Group n=46 Participants Children randomized to the comparator group will continue with UFH, LMWH or fondaparinux or may switch to VKA therapy. VKA dosages will be adjusted to maintain the 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	Rivaroxaban, Aged 2-<6 n=21 Participants 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.	Rivaroxaban, Aged 0.5-<2 n=19 Participants 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.	Rivaroxaban, Aged Birth-<0.5 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.	Comparator, Aged 12-<18 n=2 Participants 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.	Comparator, Aged 6-<12 n=8 Participants 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.	Comparator, Aged 2-<6 n=7 Participants 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.	Comparator, Aged 0.5-<2 n=1 Participants 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.
Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During Extended Treatment Period Extension 1 (month 3 to 6)	0.0 Percentage of participants Interval 0.0 to 95.0	0.0 Percentage of participants Interval 0.0 to 3.8	2.2 Percentage of participants Interval 0.1 to 10.9	0.0 Percentage of participants Interval 0.0 to 14.6	0.0 Percentage of participants Interval 0.0 to 16.3	—	0.0 Percentage of participants Interval 0.0 to 77.6	0.0 Percentage of participants Interval 0.0 to 14.6	0.0 Percentage of participants Interval 0.0 to 37.7	0.0 Percentage of participants Interval 0.0 to 95.0
Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During Extended Treatment Period Extension 2 (month 6 to 9)	—	2.6 Percentage of participants Interval 0.1 to 13.4	5.3 Percentage of participants Interval 0.3 to 24.4	0.0 Percentage of participants Interval 0.0 to 29.9	0.0 Percentage of participants Interval 0.0 to 40.2	—	—	0.0 Percentage of participants Interval 0.0 to 63.2	0.0 Percentage of participants Interval 0.0 to 77.6	—
Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During Extended Treatment Period Extension 3 (month 9 to 12)	—	0.0 Percentage of participants Interval 0.0 to 11.6	0.0 Percentage of participants Interval 0.0 to 23.0	0.0 Percentage of participants Interval 0.0 to 63.2	0.0 Percentage of participants Interval 0.0 to 77.6	—	—	0.0 Percentage of participants Interval 0.0 to 95.2	0.0 Percentage of participants Interval 0.0 to 77.6	—

PRIMARY outcome

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

Population: Full analysis set (FAS)

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

Outcome measures

Outcome measures
Measure	Comparator, Aged Birth-<0.5 n=8 Participants 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.	Rivaroxaban Group n=184 Participants 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.	Comparator Group n=92 Participants Children randomized to the comparator group will continue with UFH, LMWH or fondaparinux or may switch to VKA therapy. VKA dosages will be adjusted to maintain the 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	Rivaroxaban, Aged 2-<6 n=67 Participants 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.	Rivaroxaban, Aged 0.5-<2 n=47 Participants 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.	Rivaroxaban, Aged Birth-<0.5 n=21 Participants 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.	Comparator, Aged 12-<18 n=16 Participants 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.	Comparator, Aged 6-<12 n=34 Participants 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.	Comparator, Aged 2-<6 n=22 Participants 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.	Comparator, Aged 0.5-<2 n=9 Participants 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.
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)	0 Participants	0 Participants	2 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants

PRIMARY outcome

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)

Population: Safety analysis set (SAF)

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 criteria for major bleeding, but associated with: medical intervention, or unscheduled contact (visit or telephone call) with a physician, or (temporary) cessation of study treatment, or discomfort for the child such as pain or impairment of activities of daily life (such as loss of school days or hospitalization).

Outcome measures

Outcome measures
Measure	Comparator, Aged Birth-<0.5 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.	Rivaroxaban Group n=329 Participants 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.	Comparator Group n=162 Participants Children randomized to the comparator group will continue with UFH, LMWH or fondaparinux or may switch to VKA therapy. VKA dosages will be adjusted to maintain the 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	Rivaroxaban, Aged 2-<6 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.	Rivaroxaban, Aged 0.5-<2 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.	Rivaroxaban, Aged Birth-<0.5 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.	Comparator, Aged 12-<18 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.	Comparator, Aged 6-<12 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.	Comparator, Aged 2-<6 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.	Comparator, Aged 0.5-<2 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.
Incidence Rates of the Composite of Treatment Emergent Overt Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding During Main Treatment Period	—	3 Percentage of participants Interval 1.6 to 5.5	1.9 Percentage of participants Interval 0.5 to 3.3	—	—	—	—	—	—	—

PRIMARY outcome

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)

Population: Safety analysis set (SAF)

Outcome measures

Outcome measures
Measure	Comparator, Aged Birth-<0.5 n=8 Participants 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.	Rivaroxaban Group n=180 Participants 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.	Comparator Group n=67 Participants Children randomized to the comparator group will continue with UFH, LMWH or fondaparinux or may switch to VKA therapy. VKA dosages will be adjusted to maintain the 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	Rivaroxaban, Aged 2-<6 n=46 Participants 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.	Rivaroxaban, Aged 0.5-<2 n=21 Participants 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.	Rivaroxaban, Aged Birth-<0.5 n=15 Participants 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.	Comparator, Aged 12-<18 n=89 Participants 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.	Comparator, Aged 6-<12 n=34 Participants 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.	Comparator, Aged 2-<6 n=22 Participants 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.	Comparator, Aged 0.5-<2 n=9 Participants 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.
Incidence Rates of the Composite of Treatment Emergent Overt Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding During Main Treatment Period	0.0 Percentage of participants 95% Confidence Interval 0.0 • Interval 0.0 to 34.9	1.7 Percentage of participants 95% Confidence Interval 0.5 • Interval 0.5 to 4.7	3.0 Percentage of participants 95% Confidence Interval 0.5 • Interval 0.5 to 9.6	6.5 Percentage of participants 95% Confidence Interval 1.8 • Interval 1.8 to 17.7	4.8 Percentage of participants 95% Confidence Interval 0.2 • Interval 0.2 to 21.8	6.7 Percentage of participants 95% Confidence Interval 0.3 • Interval 0.3 to 30.2	2.2 Percentage of participants 95% Confidence Interval 0.4 • Interval 0.4 to 7.3	0.0 Percentage of participants 95% Confidence Interval 0.0 • Interval 0.0 to 9.0	0.0 Percentage of participants 95% Confidence Interval 0.0 • Interval 0.0 to 13.9	11.1 Percentage of participants 95% Confidence Interval 0.6 • Interval 0.6 to 44.3

PRIMARY outcome

Timeframe: During extended treatment period: up to month 12.

Population: Safety analysis set (SAF)

Incidence rates for all children except those aged \< 2 years with catheter-related thrombosis. If no participant entered in the specific optional extension period, no analysis of an outcome was possible. 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 criteria for major bleeding, but associated with: medical intervention, or unscheduled contact with a physician, or (temporary) cessation of study treatment, or discomfort for the child such as pain or impairment of activities of daily life.

Outcome measures

Outcome measures
Measure	Comparator, Aged Birth-<0.5 n=1 Participants 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.	Rivaroxaban Group n=93 Participants 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.	Comparator Group Children randomized to the comparator group will continue with UFH, LMWH or fondaparinux or may switch to VKA therapy. VKA dosages will be adjusted to maintain the 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	Rivaroxaban, Aged 2-<6 n=46 Participants 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.	Rivaroxaban, Aged 0.5-<2 n=1 Participants 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.	Rivaroxaban, Aged Birth-<0.5 n=21 Participants 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.	Comparator, Aged 12-<18 n=19 Participants 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.	Comparator, Aged 6-<12 n=2 Participants 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.	Comparator, Aged 2-<6 n=8 Participants 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.	Comparator, Aged 0.5-<2 n=7 Participants 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.
Incidence Rates of the Composite of Treatment Emergent Overt Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding During Extended Treatment Period Extension 1 (month 3 to 6)	0.0 Percentage of participants Interval 0.0 to 95.0	1.1 Percentage of participants Interval 0.1 to 5.3	—	0.0 Percentage of participants Interval 0.0 to 6.9	0.0 Percentage of participants Interval 0.0 to 95.0	0.0 Percentage of participants Interval 0.0 to 14.6	0.0 Percentage of participants Interval 0.0 to 16.3	0.0 Percentage of participants Interval 0.0 to 77.6	0.0 Percentage of participants Interval 0.0 to 34.9	0.0 Percentage of participants Interval 0.0 to 37.7
Incidence Rates of the Composite of Treatment Emergent Overt Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding During Extended Treatment Period Extension 2 (month 6 to 9)	—	2.6 Percentage of participants Interval 0.1 to 13.4	—	5.3 Percentage of participants Interval 0.3 to 24.4	—	0.0 Percentage of participants Interval 0.0 to 29.9	0.0 Percentage of participants Interval 0.0 to 40.2	—	0.0 Percentage of participants Interval 0.0 to 63.2	0.0 Percentage of participants Interval 0.0 to 77.6
Incidence Rates of the Composite of Treatment Emergent Overt Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding During Extended Treatment Period Extension 3 (month 9 to 12)	—	0.0 Percentage of participants Interval 0.0 to 11.6	—	0.0 Percentage of participants Interval 0.0 to 23.0	—	0.0 Percentage of participants Interval 0.0 to 63.2	0.0 Percentage of participants Interval 0.0 to 77.6	—	0.0 Percentage of participants Interval 0.0 to 95.0	0.0 Percentage of participants Interval 0.0 to 77.6

SECONDARY outcome

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)

Population: Full analysis set (FAS)

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

Outcome measures

Outcome measures
Measure	Comparator, Aged Birth-<0.5 n=8 Participants 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.	Rivaroxaban Group n=184 Participants 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.	Comparator Group n=67 Participants Children randomized to the comparator group will continue with UFH, LMWH or fondaparinux or may switch to VKA therapy. VKA dosages will be adjusted to maintain the 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	Rivaroxaban, Aged 2-<6 n=47 Participants 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.	Rivaroxaban, Aged 0.5-<2 n=21 Participants 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.	Rivaroxaban, Aged Birth-<0.5 n=16 Participants 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.	Comparator, Aged 12-<18 n=92 Participants 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.	Comparator, Aged 6-<12 n=34 Participants 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.	Comparator, Aged 2-<6 n=22 Participants 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.	Comparator, Aged 0.5-<2 n=9 Participants 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.
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	0.0 Percentage of participants 95% Confidence Interval 0.0 • Interval 0.0 to 34.9	2.2 Percentage of participants 95% Confidence Interval 0.7 • Interval 0.7 to 5.3	0.0 Percentage of participants 95% Confidence Interval 0.0 • Interval 0.0 to 5.3	2.1 Percentage of participants 95% Confidence Interval 0.1 • Interval 0.1 to 10.7	0.0 Percentage of participants 95% Confidence Interval 0.0 • Interval 0.0 to 14.6	0.0 Percentage of participants 95% Confidence Interval 0.0 • Interval 0.0 to 19.8	4.3 Percentage of participants 95% Confidence Interval 1.5 • Interval 1.5 to 10.3	2.9 Percentage of participants 95% Confidence Interval 0.2 • Interval 0.2 to 15.1	4.5 Percentage of participants 95% Confidence Interval 0.2 • Interval 0.2 to 20.7	0.0 Percentage of participants 95% Confidence Interval 0.0 • Interval 0.0 to 29.9

SECONDARY outcome

Timeframe: over 24 hours

Population: Pharmacokinetics analysis set (PKS)

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

Outcome measures

Outcome measures
Measure	Comparator, Aged Birth-<0.5 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.	Rivaroxaban Group n=173 Participants 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.	Comparator Group n=65 Participants Children randomized to the comparator group will continue with UFH, LMWH or fondaparinux or may switch to VKA therapy. VKA dosages will be adjusted to maintain the 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	Rivaroxaban, Aged 2-<6 n=44 Participants 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.	Rivaroxaban, Aged 0.5-<2 n=21 Participants 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.	Rivaroxaban, Aged Birth-<0.5 n=13 Participants 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.	Comparator, Aged 12-<18 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.	Comparator, Aged 6-<12 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.	Comparator, Aged 2-<6 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.	Comparator, Aged 0.5-<2 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.
AUC(0-24)ss in Plasma	—	2120 microgram*hour per liter Geometric Coefficient of Variation 26.4 • Interval 26.4 to	1960 microgram*hour per liter Geometric Coefficient of Variation 31.7 • Interval 31.7 to	2380 microgram*hour per liter Geometric Coefficient of Variation 40.7 • Interval 40.7 to	1840 microgram*hour per liter Geometric Coefficient of Variation 36.4 • Interval 36.4 to	1590 microgram*hour per liter Geometric Coefficient of Variation 29.6 • Interval 29.6 to	—	—	—	—

SECONDARY outcome

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

Population: Pharmacokinetics analysis set (PKS)

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

Outcome measures

Outcome measures
Measure	Comparator, Aged Birth-<0.5 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.	Rivaroxaban Group n=173 Participants 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.	Comparator Group n=65 Participants Children randomized to the comparator group will continue with UFH, LMWH or fondaparinux or may switch to VKA therapy. VKA dosages will be adjusted to maintain the 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	Rivaroxaban, Aged 2-<6 n=44 Participants 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.	Rivaroxaban, Aged 0.5-<2 n=21 Participants 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.	Rivaroxaban, Aged Birth-<0.5 n=13 Participants 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.	Comparator, Aged 12-<18 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.	Comparator, Aged 6-<12 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.	Comparator, Aged 2-<6 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.	Comparator, Aged 0.5-<2 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.
Cmax,ss in Plasma	—	237 microgram per liter Geometric Coefficient of Variation 20.6 • Interval 20.6 to	184 microgram per liter Geometric Coefficient of Variation 36.2 • Interval 36.2 to	182 microgram per liter Geometric Coefficient of Variation 31.2 • Interval 31.2 to	136 microgram per liter Geometric Coefficient of Variation 29.4 • Interval 29.4 to	119 microgram per liter Geometric Coefficient of Variation 24.1 • Interval 24.1 to	—	—	—	—

SECONDARY outcome

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

Population: Pharmacokinetics analysis set (PKS)

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