Rivaroxaban for Treatment in Venous or Arterial Thrombosis in Neonates (Einstein Jr)

7-day Study of the Safety, Efficacy and the Pharmacokinetic and Pharmacodynamic Properties of Oral Rivaroxaban in Children From Birth to Less Than 6 Months With Arterial or Venous Thrombosis

The purpose of this study is to find out whether rivaroxaban is safe and effective to use in children age newborn to less than 6 months and how long it stays in the body and how it is used in the body. Safety will be assessed by looking at the incidence and types of bleeding events. There will also be a check for worsening of blood clots.

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 vitamin K antagonist (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 central independent adjudication committee (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 pharmacokinetic (PK)/pharmacodynamics (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.

Rivaroxaban oral suspension from granules will be dosed according to body weight as oral 0.1% suspension (1 mg/mL)

Body weight adjusted dosing of rivaroxaban to achieve a similar exposure in the range as that observed in adults treated for venous thromboembolism (VTE) with 20 mg once daily.

30 minutes to 1.5 hours post-dose; 2 to 4 hours post-dose (bid dosing) and 30 minutes to 3 hours post-dose; 7 to 8 hours post-dose on Day 1 (tid dosing)

2 to 8 hours post-dose (bid dosing) and 30 minutes to 3 hours post-dose; 7 to 8 hours post-dose on Day 3 (tid dosing)

Prothrombin time is a global clotting test used for the assessment of the extrinsic pathway of the blood coagulation cascade.

10-16 hours post-dose on Day 8 (baseline), 2-4 hours after the first dose on Day 1 (bid dosing) and 7-8 hours after the first dose on Day 1 (tid dosing)

Prothrombin time is a global clotting test used for the assessment of the extrinsic pathway of the blood coagulation cascade.

10-16 hours post-dose on Day 8 (baseline), 2-8 hours post-dose on Day 3 (bid dosing) and 0.5-3 hours post-dose on Day 3 (tid dosing)

The Activated partial thromboplastin time (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.

10-16 hours post-dose on Day 8 (baseline), 2-4 hours after the first dose on Day 1 (bid dosing) and 7-8 hours after the first dose on Day 1 (tid dosing)

The Activated partial thromboplastin time (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.

10-16 hours post-dose on Day 8 (baseline), 2-8 hours post-dose on Day 3 (bid dosing) and 0.5-3 hours post-dose on Day 3 (tid dosing)

2-4 hours after the first dose on Day 1 (bid dosing) and 7-8 hours after the first dose on Day 1 (tid dosing)

Central independent adjudication committee (CIAC) classified bleeding as follows: Major bleeding is defined as overt bleeding and •associated with a fall in hemoglobin of 2 gram/deciliter (g/dL) or more, •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, example: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal, or •contributing to death. Clinically relevant non-major bleeding is 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 •cessation (temporary) of study treatment, or •discomfort for the child such as pain

Number of Participants With Symptomatic Recurrent Venous Thromboembolism and Asymptomatic Deterioration in Thrombotic Burden on Repeat Imaging

Symptomatic recurrence of thromboembolism and asymptomatic deterioration was documented using the appropriate imaging test and confirmed by CIAC which was unaware of treatment assignment. Asymptomatic deterioration in thrombotic burden on repeat imaging, as assessed by the CIAC. Adjudication results were the basis for the final analyses.

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 non-peripherally 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.

Monagle P, Lensing AWA, Thelen K, Martinelli I, Male C, Santamaria A, Samochatova E, Kumar R, Holzhauer S, Saracco P, Simioni P, Robertson J, Grangl G, Halton J, Connor P, Young G, Molinari AC, Nowak-Gottl U, Kenet G, Kapsa S, Willmann S, Pap AF, Becka M, Twomey T, Beyer-Westendorf J, Prins MH, Kubitza D; EINSTEIN-Jr Phase 2 Investigators. Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies. Lancet Haematol. 2019 Oct;6(10):e500-e509. doi: 10.1016/S2352-3026(19)30161-9. Epub 2019 Aug 13.

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