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

Rivaroxaban in Chinese Children With Giant Coronary Artery Aneurysm After Kawasaki Disease: a Pilot Study

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.

Study Overview

• Status: Recruiting
• Conditions: Kawasaki Disease; Coronary Artery Aneurysm; Rivaroxaban; Pilot Study
• Intervention / Treatment: Drug: Rivaroxaban (Xarelto)

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Fang Liu, MD; Phone Number: 18017590880; Email: liufang@fudan.edu.cn
• Study Contact Backup: Name: Guangan Dai, MD; Phone Number: 13580762996; Email: gadai24@m.fudan.edu.cn

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 201102
      • Recruiting
      • Children's Hospital of Fudan University
      • Contact: Fang Liu, MD.; Phone Number: 18017590880; Email: liufang@fudan.edu.cn
      • Principal Investigator: Fang Liu, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Study Population

Study participants were recruited from patients hospitalized at the Children's Hospital of Fudan University.

Description

Inclusion Criteria:

1. Giant coronary artery aneurysm(s) in any coronary artery after acute stage of Kawasaki disease. Giant coronary artery aneurysm(s) should be confirmed by two-dimensional echocardiography and meet the diagnostic criteria of Z-score ≥10 or coronary artery internal diameter ≥8mm;
2. Anticoagulant with antiplatelet drug therapy for anti-thromboprophylaxis is recommended 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 Criteria:

1. Active bleeding or bleeding risk contraindicating anticoagulant therapy
2. With history of venous thromboembolism or risk factors related with venous thromboembolism, like congenital heart disease, carcinoma, central venous catheter or long-term immobilization.
3. Hypersensitivity or any other contraindications listed in the local labeling for the comparator treatment or experimental treatment
4. An eGFR <30 mL/min/1.73 m2 (For children younger than 1 year, serum creatinine results above 97.5th percentile)
5. Platelet count < 100 x 109/L
6. Hepatic disease which is associated with either: coagulopathy leading to a clinically relevant bleeding risk, or alanine aminotransferase > 5x ULN or total bilirubin > 2x ULN with direct bilirubin > 20% of the total
7. Sustained uncontrolled hypertension defined as systolic and/or diastolic blood pressure >95 th age percentile
8. Concomitant use of strong inhibitors of both CYP3A4 and P-glycoprotein, including but not limited to all human immunodeficiency virus protease inhibitors and the following 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 to rifampicin, rifabutin, phenobarbital, phenytoin and carbamazepine
10. Hypersensitivity or any other contraindications listed in the local labeling for the comparator 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rivaroxaban; Rivaroxaban as anticoagulant will be administered for children with giant coronary artery aneurysm after Kawasaki disease. The initial dosing regimen of rivaroxaban is a 15 mg-equivalent, age and bodyweight-adjusted dosing regimen, which was proposed by the model-informed dose optimization study.	Drug: Rivaroxaban (Xarelto); Administered in an age- and bodyweight-adjusted, 15 mg-equivalent dose regimen proposed by model-informed dose optimization study; Other Names: Anticoagulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of new thrombosis in coronary arteries	It is a binary variable. Every echocardiography conducted during study period will be assessed and documented. Investigators will evaluate whether new thrombosis occurs in coronary arteries.	From enrollment to the 6th month after treatment
Composite of Major bleeding or Clinically relevant non-major bleeding event	It is a binary variable. Major bleeding is defined as 1.Fatal bleeding; 2.Clinically overt bleeding associated with a decrease in Hgb of ≥20 g/L (2 g/dL) in a 24-h period; 3.Critical site bleeding, such as retroperitoneal, pulmonary, pericardial, intracranial, or otherwise involves the central nervous system; 4.Bleeding that requires an intervention via an invasive procedure; 5.Overt bleeding for which a reversal agent is administered. Clinically relevant non-major bleeding event is defined as 1.Bleeding that results in a medical or procedural intervention not meeting major bleeding criteria, including a medication change (reducing, holding, or changing anticoagulation or addition of new medication) ; 2.Bleeding that results in hospitalization or increased level of care; 3.Overt bleeding for which a blood product is administered, and does not meet the criteria for major bleeding	From enrollment to the 6th month after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Any adverse events	It is a text variable. If any adverse events( including durg allergy, severe infection, hepatic dysfunction, renal dysfunction, hypertension, fatigue, abdominal pain or others) occur will be reported to the data and safety monitoring board. The detail of adverse event will be recorded, including classification of adverse event, time of occurrence, symptoms, treatment, resolution time, and outcome.	From enrollment to the 6th month after treatment
Occurrence of major adverse cardiovascular event	It is a binary variable. Major adverse cardiovascular event (MACE) includes unstable angina, acute myocardial infarction, stroke, hospitalization for heart failure, unplanned revascularization, cardiovascular death. If any of the MACEs occur during the study period, it will be recorded as 1; otherwise, it will be recorded as 0. The definition of each MACE refers to the following guidelines and consensus: 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials, 2019 European Society of Cardiology Guidelines for the diagnosis and management of chronic coronary syndromes, Fourth universal definition of myocardial infarction, and 2023 European Society of Cardiology Guidelines for the management of acute coronary syndromes.	From enrollment to the 6th month after treatment
Any dose adjustments for rivaroxaban	It is a text variable. Any dose adjustments for rivaroxaban will be recorded, including time of dose adjustment, reason for dose adjustment, dosage, and outcome. Rivaroxaban plasma concentration and rivaroxaban-calibrated anti-factor Xa activity will be measured after at least 3 consecutive doses	From enrollment to the 6th month after treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma concentration of rivaroxaban at specific timepoint	Rivaroxaban plasma concentration will be measured by high performance liquid chromatography tandem mass spectrometer at specific timepoint. It includes 1. 20 minutes to 1 hour after the first dose; 2. 7 ± 1 hours after the first dose; 3. Ctrough: before the scheduled dose after at least three consecutive doses; 4. Cmax: 3 ± 1 hours after at least three consecutive doses. And Ctrough and Cmax will be re-measured after each dose adjustment.	From enrollment to the 6th month after treatment
Rivaroxaban-calibrated anti-factor Xa activity at specific timepoint	Rivaroxaban-calibrated anti-factor Xa activity will be measured at specific timepoint. It includes 1. 20 minutes to 1 hour after the first dose; 2. 7 ± 1 hours after the first dose; 3. Ctrough: before the scheduled dose after at least three consecutive doses; 4. Cmax: 3 ± 1 hours after at least three consecutive doses. And Ctrough and Cmax will be re-measured after each dose adjustment.	From enrollment to the 6th month after treatment

Collaborators and Investigators

• Sponsor: Children's Hospital of Fudan University
• Investigators: Study Director: Fang Liu, MD, Children's Hospital of Fudan University

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2024
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: May 11, 2025
• First Submitted That Met QC Criteria: May 11, 2025
• First Posted (Actual): May 18, 2025

Study Record Updates

• Last Update Posted (Estimated): September 8, 2025
• Last Update Submitted That Met QC Criteria: September 1, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: anticoagulant; rivaroxaban; kawasaki disease; giant coronary artery aneurysm; model-informed dose optimization
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Heart Diseases; Skin Diseases; Lymphatic Diseases; Skin Diseases, Vascular; Coronary Disease; Myocardial Ischemia; Vasculitis; Aneurysm; Skin and Connective Tissue Diseases; Hemic and Lymphatic Diseases; Mucocutaneous Lymph Node Syndrome; Coronary Aneurysm; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Morpholines; Oxazines; Thiophenes; Rivaroxaban
• Other Study ID Numbers: RIVA-KD-pilot

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No