Hokusai Study in Pediatric Patients With Confirmed Venous Thromboembolism (VTE)

This is an event driven Phase 3, prospective, randomized, open-label, blinded endpoint evaluation (PROBE) parallel group study in subjects with confirmed VTE. This study is designed to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of edoxaban and to compare the efficacy and safety of edoxaban against standard of care in pediatric subjects with confirmed VTE.

The objective is to demonstrate the non-inferiority of edoxaban to standard of care (SOC; including low molecular weight heparin (LMWH), vitamin K antagonist (VKA), or synthetic pentasaccharide (SP) Xa inhibitors) in the treatment and secondary prevention of VTE in pediatric subjects with regard to the composite efficacy endpoint (ie, symptomatic recurrent VTE, death as result of VTE, and no change or extension of thrombotic burden) during the first 3-month treatment period.

Eligibility Criteria:
Inclusion Criteria:

1. Male or female pediatric subjects between birth (defined as 38 weeks gestational age) and less than 18 years of age at the time of consent.
2. Pediatric subjects with the presence of documented VTE confirmed by appropriate diagnostic imaging and requiring anticoagulant therapy for at least 90 days.
3. Subjects must have received at least 5 days of heparin therapy prior to randomization to treat the newly identified index VTE. In addition, prior to being randomized to edoxaban or SOC, subjects initially treated with VKA are recommended to have an international normalized ratio (INR) \< 2.0.
4. Subject and/or parent(s)/legal guardian(s) or legally acceptable representative is informed and provides signed consent for the child to participate in the study.
5. Female subjects who have menarche must test negative for pregnancy at Screening and must consent to avoid becoming pregnant by using an approved contraception method throughout the study.

Exclusion Criteria:

1. Subjects with active bleeding or high risk of bleeding contraindicating treatment with LMWH, SP Xa inhibitors, VKAs, or direct oral anticoagulants (DOACs; identified high risk of bleeding during prior experimental administration of DOACs).
2. Subjects who have been or are being treated with thrombolytic agents, thrombectomy or insertion of a caval filter for the newly identified index VTE.
3. Administration of antiplatelet therapy is contraindicated in both arms except for low dose aspirin defined as 1-5 mg/Kg/day with maximum of 100 mg/day.
4. Administration of rifampin is prohibited during the study and subjects on concomitant use of rifampin are excluded.
5. Subjects with hepatic disease associated with coagulopathy leading to a clinically relevant bleeding risk (aPTT \> 50 seconds or international normalized ratio \[INR\] \> 2.0 not related to anticoagulation therapy) or alanine aminotransferase (ALT) \> 5 × the upper limit of normal (ULN) or total bilirubin \> 2 × ULN with direct bilirubin \> 20% of the total at Screening Visit.
6. Subjects with glomerular filtration rate (GFR) \< 30% of normal for age and size as determined by the Schwartz formula.
7. Subjects with stage 2 hypertension defined as blood pressure (BP) systolic and/or diastolic confirmed \> 99th percentile + 5 mmHg.
8. Subject with thrombocytopenia \< 50 × 109/L at Screening Visit. Subjects with a history of heparin-induced thrombocytopenia may be enrolled in the study at the Investigator's discretion.
9. Life expectancy less than the expected study treatment duration (3 months).
10. Subjects who are known to be pregnant or breastfeeding.
11. Subjects with any condition that, as judged by the Investigator, would place the subject at increased risk of harm if he/she participated in the study, including contraindicated medications.
12. Subjects who participated in another clinical study or treated with an experimental therapy with less than a 30 day washout period prior to identifying the qualifying index VTE.