Rivaroxaban for Treatment in Venous or Arterial Thrombosis in Neonates

Neonates and infants aged less than 6 months who pass the screen of in- and exclusion
criteria, who have been treated for at least five days with heparin and /or VKA for confirmed
symptomatic or asymptomatic arterial or venous thrombosis are eligible for the study. Study
treatment consists of a 7-day treatment with an age- and body weight-adjusted three times
daily, approximately 8 hours apart oral rivaroxaban dosing to achieve a similar exposure as
that observed in adults treated for venous thromboembolism (VTE) with 20 mg rivaroxaban once
daily. Rivaroxaban will be provided as granules for preparation of an oral suspension (1
mg/mL after re-suspension) using a t.i.d. regimen with 8-hour intervals. An ultrasound will
be performed before starting rivaroxaban at treatment day 1 and after the end of rivaroxaban
treatment at day 8. The last dose of rivaroxaban treatment will be followed by a 30-day post
study treatment period, regardless of the duration of study drug administration. After
cessation of rivaroxaban, it is at the investigator's discretion to continue with
anticoagulants. The principal safety outcome is the combination of major and clinically
relevant non-major bleeding. The efficacy outcome is the composite of all symptomatic
recurrent thromboembolism and asymptomatic deterioration in thrombotic burden on repeat
imaging. All suspected recurrent thromboembolism, asymptomatic deterioration in thrombotic
burden on repeat imaging, deaths, as well as all episodes of bleeding will be evaluated by a
CIAC. Adjudication results will be the basis for the final analyses.

For all children, visits are scheduled at regular time points (see Table 1). Enrolled
children who are not treated or those with premature discontinuation of rivaroxaban will at
least be seen at the end of the study treatment period. During all contacts, the treatment
and clinical course of the child will be evaluated. Children with suspected efficacy or
safety outcomes will undergo confirmatory testing as per standard of care. Blood samples for
PK/PD will be taken at defined time points (see Table 2).

An Independent Data Monitoring Committee (DMC) will monitor the children's safety during the
study and give recommendations to the steering committee.

Inclusion Criteria:

- Children from birth to less than 6 months with documented symptomatic or asymptomatic
venous or arterial thrombosis who have been treated with anticoagulant therapy for at
least 5 days.

- Gestational age at birth of at least 37 weeks.

- Hemoglobin, platelets, creatinine, ALT and total and direct bilirubin assessed within
10 days prior to enrollment.

- Oral feeding/nasogastric/gastric feeding for at least 10 days.

- Informed consent provided.

- Body weight >2600 g

Exclusion Criteria:

- Active bleeding or high risk for bleeding contraindicating anticoagulant therapy,
including history of intra-ventricular bleeding.

- Symptomatic progression of thrombosis during preceding anticoagulant treatment.

- Planned invasive procedures, including lumbar puncture and removal of nonperipherally
placed central lines during study treatment.

- Hepatic disease which is associated with either: coagulopathy leading to a clinically
relevant bleeding risk, or alanine aminotransferase (ALT) > 5x upper level of normal
(ULN) or total bilirubin (TB) > 2x ULN with direct bilirubin > 20% of the total.

- Creatinine >1.5 times of normal.

- Uncontrolled Hypertension defined as >95th percentile.

- History of gastrointestinal disease or surgery associated with impaired absorption.

- Platelet count <100 x 109/L.

- Concomitant use of strong inhibitors of both cytochrome P450 isoenzyme 3A4 (CYP3A4)
and P-glycoprotein (P-gp), e.g. all human immunodeficiency virus protease inhibitors
and the following azole-antimycotics agents: ketoconazole, itraconazole, voriconazole,
posaconazole, if used systemically (fluconazole is allowed)

- Concomitant use of strong inducers of CYP3A4, e.g. rifampicin, rifabutin,
phenobarbital, phenytoin and carbamazepine

- Indication for anticoagulant therapy other than current thrombosis.

- Indication for antiplatelet therapy or non-steroid anti-inflammatory drug (NSAID)
therapy. Incidental use is allowed.

- Hypersensitivity to rivaroxaban or its excipients.

- Participation in a study with an investigational drug or medical device within 30 days
prior to enrollment.