Rivaroxaban Versus Warfarin for Thromboprophylaxis in Children With Giant Coronary Aneurysms After Kawasaki Disease

Study Overview
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Brief Summary
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To evaluate the efficacy and safety of rivaroxaban compared to warfarin for thromboprophylaxis in children with giant coronary aneurysms after Kawasaki disease

Detailed Description
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This study is a multicenter, open-label, active-controlled, randomized, non-inferiority trial to assess the efficacy and safety of rivaroxaban for thromboprophylaxis in children with giant coronary aneurysms after Kawasaki disease. Participants will be randomly assigned to the control or experiment groups. Randomization ratio will be 1:1. The control group will receive warfarin plus aspirin or clopidogrel, and the experiment group will receive Rivaroxaban plus aspirin or clopidogrel. This study will last for 6 months. Baseline characters, efficacy outcomes, bleeding events, adverse events and compliance of intervention of each participant will be collected. Two-dimensional echocardiography will be performed at admission and each scheduled visits to detect whether new thrombogenesis occurred in the giant coronary aneurysms.

Official Title
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Multicenter, Randomized, Non-inferiority Trial to Evaluate the Safety and Efficacy of Rivaroxaban Compared to Warfarin for Thromboprophylaxis in Children With Giant Coronary Aneurysms After Kawasaki Disease

Conditions
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Kawasaki Disease, Coronary Aneurysm, Rivaroxaban, Warfarin, Antithrombotic Drug

Intervention / Treatment
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* Drug: Rivaroxaban Oral Tablet or Suspension [Xarelto]
* Drug: Aspirin or Clopidogrel
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children aged 1 Month to <18 years with confirmed giant coronary aneurysm(s) in any coronary artery during acute or cardiac sequelae phase of Kawasaki disease. Giant coronary aneurysm(s) should confirmed by diagnostic imaging examination and meet the diagnostic criteria of Z-score ≥10 or coronary artery internal lumen diameter ≥8mm. Current anticoagulation therapy is long-term oral Warfarin treatment with stable INR. INR monitoring has reached the target range (1.5-2.5) for two consecutive times in the past month, with each examination interval of at least one week Participant should be able to tolerate oral/nasogastric/gastric feeding and require antithrombotic drug therapy for at least 1 year. For children with history of severe occlusion of coronary artery and performed coronary artery bypass grafting, percutaneous coronary intervention or thrombolytic therapy: At least 1 week after medical intervention Clinically stable Body weight ≥ 2600g Informed consent from parents or legal guardians provided. If children aged ≥ 10 years, informed consent from children is required. Exclusion Criteria: Active bleeding or bleeding risk contraindicating anticoagulant therapy With history of venous thromboembolism or risk factors related with venous thromboembolism, like congenital heart disease, carcinoma, central venous catheter or long-term immobilization. Thrombus within giant coronary aneurysm was confirmed by previous imaging examinations, including echocardiography, computed tomography angiography in coronary artery or coronary angiography An estimated glomerular filtration rate (eGFR) <30mL/min/1.73 m2 (in children younger than 1 year, serum creatinine results above 97.5th percentile excludes participation) Platelet count < 50 x 109/L Hepatic disease which is associated w ith 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 Sustained uncontrolled hypertension defined as systolic and/or diastolic blood pressure >95 th age percentile Concomitant use of strong inhibitors of both cytochrome P450 isoenzyme 3A4 (CYP3A4) and P-glycoprotein (P-gp),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) Concomitant use of strong inducers of CYP3A4, including but not limited to rifampicin, rifabutin, phenobarbital, phenytoin and carbamazepine Childbearing potential without proper contraceptive measures, pregnancy or breast feeding Life expectancy <3 Month Hypersensitivity or any other contraindication listed in the local labeling for the comparator treatment or experimental treatment Inability to cooperate with the study procedures Participation in a study with an investigational drug or medical device within 30 days prior to randomization

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rivaroxaban+Antiplatelet drug<br>Rivaroxaban as antithrombotic drug will be administered jointly with Antiplatelet drug for 6 months. Antiplatelet drug can choose Aspirin or Clopidogrel depending on participant medical history and physician's recommendation. | Drug: Rivaroxaban Oral Tablet or Suspension [Xarelto]<br>* Administered in a body weight-adjusted 20 mg-equivalent total daily dose regimen<br>* Other names: Xarelto;Drug: Aspirin or Clopidogrel<br>* Aspirin [3  5mg/(kg·d) once daily] or Clopidogrel [0.2 1.0 mg/kg(<2 years old),1 mg/kg(≥2 years old); once daily]<br>|
| Active Comparator: Standard antithrombotic care<br>Warfarin as antithrombotic drug will be administered jointly with Antiplatelet drug for 6 months. Antiplatelet drug can choose Aspirin or Clopidogrel depending on participant medical history and physician's recommendation. International normalized ratio(INR) should be tested once a month and maintained in target range(1.5 2.5). 2.Aspirin[3  5mg/(kg·d), once daily] or Clopidogrel[ <2 years: 0.2 1.0mg/kg, ≥2 years: 1 mg/kg; once daily] according to experienced clinician recommendation and individual condition. | Drug: Aspirin or Clopidogrel<br>* Aspirin [3  5mg/(kg·d) once daily] or Clopidogrel [0.2 1.0 mg/kg(<2 years old),1 mg/kg(≥2 years old); once daily]<br>Drug: Warfarin<br>* Warfarin 0.05 0.12 mg/(kg·d) once daily. INR should maintain within 1.5 to 2.5<br>* Other names: Vitamin K Antagonist;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence rate of new thrombogenesis within giant coronary aneurysm | Echocardiography will be performed when participant present symptoms suggesting cardiac infarction (like palpitation, chest pain, decline in exercise capacity and etc.) or at each scheduled visits(Enrollment,1 month, 2 month, 3 month, 4 month, 5 month and 6 month) New thrombogenesis will be assessed and confirmed by masked sonographer.Incidence = Number of events / Number at risk, where: number of events = number of participant having the event in the time window. number at risk = number of participant in assigned arm | from enrollment to the 6th month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence rate of new thrombogenesis within giant coronary aneurysm | It is time to event data. Echocardiography will be perform when participant present symptoms suggesting cardiac infarction (like palpitation, chest pain, decline in exercise capacity and etc.) or each scheduled visits(Enrollment,1 month, 2 month, 3 month, 4 month, 5 month and 6 month) New thrombogenesis will be assessed and confirmed by masked sonographer. | from enrollment to the 6th month | 
| Incidence Rate of the Composite of Major bleeding event or Clinically relevant non-major bleeding event | According to International society of thrombosis and hemostasis(ISTH), major bleeding event is defined as overt bleeding and: associated with a fall in hemoglobin of 2 g/dL or more, or 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, e.g. intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, retroperitoneal, or contributing to death. Clinically relevant non-major bleeding event 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 (temporary) cessation of study treatment, or discomfort for the child such as pain or impairment of activities of daily life (such as loss of school days or hospitalization). | from enrollment to the 6th month | 
| Incidence rate of any adverse events | It is a binary variable. If any adverse events( including durg allergy, severe infection, hepatic dysfunction, renal dysfunction, hypertension, fatigue, abdominal pain or others) happens, this variable would be recorded as 1 or it would be recorded as 0. | from enrollment to the 6th month | 
| Changes in Z-score of giant coronary aneurysm | This is a repeated measurement. The internal diameter of giant coronary aneurysm will be measured by echocardiography at each scheduled visit(Enrollment, 1 month, 2 month,3 month, 4 month, 5 month and 6 month). Z score will be calculated based on the height, weight and coronary artery internal diameter. | Enrollment, 1 month, 2 month,3 month, 4 month, 5 month and 6 month | 
| Changes in Z-score of Left Main Coronary Artery(LMCA) | This is a repeated measurement. The internal diameter of LMCA will be measured by echocardiography at each scheduled visit(Enrollment, 1 month, 2 month,3 month, 4 month, 5 month and 6 month). Z score will be calculated based on the height, weight and coronary artery internal diameter. | Enrollment, 1 month, 2 month,3 month, 4 month, 5 month and 6 month | 
| Changes in Z-score of Left Anterior Descending Artery(LAD) | This is a repeated measurement. The internal diameter of LAD will be measured by echocardiography at each scheduled visit(Enrollment, 1 month, 2 month,3 month, 4 month, 5 month and 6 month). Z score will be calculated based on the height, weight and coronary artery internal diameter. | Enrollment, 1 month, 2 month,3 month, 4 month, 5 month and 6 month | 
| Changes in Z-score of Left Circumflex Artery(LCX) | This is a repeated measurement. The internal diameter of LCX will be measured by echocardiography at each scheduled visit(Enrollment, 1 month, 2 month,3 month, 4 month, 5 month and 6 month). Z score will be calculated based on the height, weight and coronary artery internal diameter. | Enrollment, 1 month, 2 month,3 month, 4 month, 5 month and 6 month | 
| Changes in Z-score of Proximal segment of Right Coronary Artery(RCA) | This is a repeated measurement. The internal diameter of Proximal segment of RCA will be measured by echocardiography at each scheduled visit(Enrollment, 1 month, 2 month,3 month, 4 month, 5 month and 6 month). Z score will be calculated based on the height, weight and coronary artery internal diameter. | Enrollment, 1 month, 2 month,3 month, 4 month, 5 month and 6 month | 
| Changes in Z-score of Middle segment of Right Coronary Artery(RCA) | This is a repeated measurement. The internal diameter of Middle segment of RCA will be measured by echocardiography at each scheduled visit(Enrollment, 1 month, 2 month,3 month, 4 month, 5 month and 6 month). Z score will be calculated based on the height, weight and coronary artery internal diameter. | Enrollment, 1 month, 2 month,3 month, 4 month, 5 month and 6 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kawasaki disease, Giant coronary aneurysm, Rivaroxaban, Warfarin