Model-informed Dose Optimization for Rivaroxaban in Children With Giant Coronary Artery Aneurysm After Kawasaki Disease

Last updated: September 1, 2025
Sponsor: Children's Hospital of Fudan University
Overall Status: Active - Recruiting

Phase

4

Condition

Kawasaki Disease

Aneurysm

Treatment

Rivaroxaban (Xarelto)

Clinical Study ID

NCT06978439
RIVA-KD-pilot
  • Ages 1-18
  • All Genders

Study Summary

Based on a population pharmacokinetic model-based dose optimization study, a 15 mg-equivalent, age-, and bodyweight-adjusted dosing regimen for Chinese children with giant coronary artery aneurysms after Kawasaki disease was proposed. This single-center, single-arm, pilot study aims to evaluate the feasibility of the 15 mg-equivalent dosing regimen within a limited sample size.

Patients will be followed for more than 6 months. Clinical outcomes, including coronary artery thrombosis, major adverse cardiovascular events, and bleeding events, will be recorded. Rivaroxaban levels will be measured to assess the robustness of the model-informed dose optimization.

Eligibility Criteria

Inclusion

Inclusion Criteria:

  1. Giant coronary artery aneurysm(s) in any coronary artery after acute stage ofKawasaki disease. Giant coronary artery aneurysm(s) should be confirmed bytwo-dimensional echocardiography and meet the diagnostic criteria of Z-score ≥10 orcoronary artery internal diameter ≥8mm;

  2. Anticoagulant with antiplatelet drug therapy for anti-thromboprophylaxis isrecommended for the next 6 months;

  3. Participant should be able to tolerate oral feeding, nasogastric or gastric feeding;

  4. Children aged 1 Month to<18 years, bodyweight ≥ 2600g.

Exclusion

Exclusion Criteria:

  1. Active bleeding or bleeding risk contraindicating anticoagulant therapy

  2. With history of venous thromboembolism or risk factors related with venousthromboembolism, like congenital heart disease, carcinoma, central venous catheteror long-term immobilization.

  3. Hypersensitivity or any other contraindications listed in the local labeling for thecomparator treatment or experimental treatment

  4. An eGFR <30 mL/min/1.73 m2 (For children younger than 1 year, serum creatinineresults above 97.5th percentile)

  5. Platelet count < 100 x 109/L

  6. Hepatic disease which is associated with either: coagulopathy leading to aclinically relevant bleeding risk, or alanine aminotransferase > 5x ULN or totalbilirubin > 2x ULN with direct bilirubin > 20% of the total

  7. Sustained uncontrolled hypertension defined as systolic and/or diastolic bloodpressure >95 th age percentile

  8. Concomitant use of strong inhibitors of both CYP3A4 and P-glycoprotein, includingbut not limited to all human immunodeficiency virus protease inhibitors and thefollowing azole-antimycotics agents: ketoconazole, itraconazole, voriconazole,posaconazole, if used systemically (fluconazole is allowed)

  9. Concomitant use of strong inducers of CYP3A4, including but not limited torifampicin, rifabutin, phenobarbital, phenytoin and carbamazepine

  10. Hypersensitivity or any other contraindications listed in the local labeling for thecomparator treatment or experimental treatment

  11. Inability to cooperate with the study procedures and follow-up visits

  12. Refuse to provide informed consent

eGFR, estimated glomerular filtration rate; ULN, upper level of normal; TB, total bilirubin (TB); CYP3A4, cytochrome P450 isoenzyme 3A4

Study Design

Total Participants: 10
Treatment Group(s): 1
Primary Treatment: Rivaroxaban (Xarelto)
Phase: 4
Study Start date:
January 10, 2024
Estimated Completion Date:
December 31, 2025

Study Description

Giant coronary artery aneurysm (GCAA) is a rare but severe cardiac complication of Kawasaki disease (KD). Due to the abnormal blood rheology and the hyper-inflammatory response accompanied by thrombocytosis during the acute phase, patients with GCAA are at high risk of coronary artery thrombosis and major adverse cardiovascular events.In such instances, lifelong antiplatelet (aspirin or clopidogrel) and anticoagulant therapy (warfarin or low molecular weight heparin, LMWH) may become necessary.

In 2022, two compounds, the direct activated Factor X (FXa) inhibitor rivaroxaban was approved by international regulatory agencies for two specific pediatric indications, supported by pharmacometrics models. For instance, a dosing regimen matching exposures of 20 mg daily in adults (the 20 mg-equivalent dosing regimen) is indicated for children under 18 years with venous thromboembolism (VTE). Secondly, a dosing regimen matching exposures of 10 mg daily in adults (the 10 mg-equivalent dosing regimen) is indicated for post-Fontan patients aged two years or older, as shown in the UNIVERSE study, which compared rivaroxaban to aspirin. However, no trials have yet compared rivaroxaban with warfarin/LMWH in pediatric patients with GCAA after KD.

Inter-ethnic population pharmacokinetic (PPK) analyses have suggested that Asian patients may require a lower dosage of rivaroxaban, consistent with the findings from the J-ROCKET trail in Japanese adults. Accordingly, the maximum dosage for Japanese children with VTE (≥ 50 kg) has reduced from 20 mg q24h (every 24 hours) to 15 mg q24h. However, reports on rivaroxaban use in pediatric patients with GCAA after KD, especially in those from Asian countries, remains limited. Its application is more challenging due to (i) increased bleeding risk from concomitant antiplatelet drug use; (ii) the predominance of younger patients (typically < 3 years) with variability in hepatic and renal function, as well as growth and development.3 Given the low incidence of GCAA, quantitative pharmacometrics is a highly promising approach for precision dosing of rivaroxaban in these patients.

Therefore, the investigators retrospectively collected the clinical experience of rivaroxaban off-label use in Chinese pediatric patients with GCAA after KD from 2023.1 to 2023.12. With clinical evidence and model-extrapolation, the investigators conducted a quantitative pharmacometrics model-based dose optimization study and proposed a 15 mg-equivalent dosing regimen for thromboprophylaxis in Chinese children with GCAA after KD, those who require dual antithrombotic therapy.

This pilot study aims to assess the potential of rivaroxaban for thromboprophylaxis in pediatric patients with KD after GCAA. Specifically, this study seeks to: (ⅰ) preliminarily evaluate the feasibility, efficacy and safety of the 15 mg-equivalent dosing regimen in target population, (ii) provide pharmacokinetic (PK)/pharmacodynamic (PD) data on rivaroxaban in Chinese children.

Connect with a study center

  • Children's Hospital of Fudan University

    Shanghai, Shanghai 201102
    China

    Site Not Available

  • Children's Hospital of Fudan University

    Shanghai 1796236, Shanghai Municipality 1796231 201102
    China

    Active - Recruiting

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