Rivaroxaban Versus Warfarin for Thromboprophylaxis in Children Aged Over 2 Years With Giant Coronary Artery Aneurysms After Kawasaki Disease: a Multicenter, Open-label, Parallel, Exploratory, Randomized Controlled Trial
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 100
- 试验地点
- 1
- 主要终点
- Composite of new thrombosis in coronary arteries, major bleeding, clinically relevant non-major bleeding event or major adverse cardiovascular event
研究概览
简要总结
Based on population pharmacokinetic model-based simulation, a 15 mg-equivalent, age-, and bodyweight-adjusted dosing regimen for Chinese children with giant coronary artery aneurysms after acute Kawasaki disease was proposed. This exploratory trial aims to evaluate the feasibility, safety and effectiveness of rivaroxaban compared to warfarin for thromboprophylaxis in children aged over 2 years with giant coronary artery aneurysms after Kawasaki disease
详细描述
Lifelong anticoagulant treatment is required in children with giant coronary artery aneurysm after Kawasaki disease, imposing social and psychologic burdens on patients and parents. Rivaroxaban is a potential oral anticoagulant in this population. Considering the impact of ethnic difference and growth development, we proposed a Chinese-specific, optimized dosing regimen based on model- and clinical evidence-informed precision dosing. In the previous pilot study, this optimized dosing regimen demonstrated a favorable feasibility among 11 Chinese pediatric patients aged over 2 years with giant coronary artery aneurysm after Kawasaki disease, with no thrombosis or major bleeding over 6 months.
This study is a multicenter, open-label, exploratory, randomized controlled trial to evaluate the feasibility, safety and effectiveness of rivaroxaban for thromboprophylaxis in children aged over 2 years with giant coronary artery aneurysms after Kawasaki disease, following the 15 mg-equivalent dosing regimen. Participants will be randomly assigned to the control or experimental groups. Randomization ratio will be 2:1. The control group will receive warfarin plus aspirin or clopidogrel, and the experimental group will receive rivaroxaban plus aspirin or clopidogrel. Baseline characteristics, treatment effect outcomes, bleeding events, adverse events and compliance of intervention of each participant will be collected.
Because this is an exploratory study and the low incidence of giant coronary artery aneurysm in children with Kawasaki disease, the study plans to recruit 100 participants. The aims include:
- The feasibility
- The safety and efficacy profile of the optimized, 15 mg-equivalent dosing regimen
- The group differences in safety and treatment effect between warfarin and rivaroxaban
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Single (Outcomes Assessor)
盲法说明
Investigator, Participant and Care provider will not be masked. However, sonographer who is responsible for assessing coronary artery lesions should be masked.
入排标准
- 年龄范围
- 2 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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;
- •Anticoagulant with antiplatelet drug therapy for anti-thromboprophylaxis is recommended for the next 3 months;
- •Participant should be able to tolerate oral feeding, nasogastric or gastric feeding;
- •Children aged ≥ 2 years
排除标准
- •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 two-dimensional echocardiography, computed tomography angiography in coronary artery or coronary angiography
- •An eGFR <30mL/min/1.73 m2 (For children younger than 1 year, serum creatinine results above 97.5th percentile)
- •Platelet count < 100 x 109/L
- •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
- •Sustained uncontrolled hypertension defined as systolic and/or diastolic blood pressure >95 th age percentile
- •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)
- •Concomitant use of strong inducers of CYP3A4, including but not limited to rifampicin, rifabutin, phenobarbital, phenytoin and carbamazepine
- •Hypersensitivity or any other contraindications listed in the local labeling for the comparator treatment or experimental treatment
- •Inability to cooperate with the study procedures and follow-up visits
- •Refuse to provide informed consent eGFR, estimated glomerular filtration rate; ULN, upper level of normal; TB, total bilirubin; CYP3A4, cytochrome P450 isoenzyme 3A4
研究组 & 干预措施
Rivaroxaban+Antiplatelet drug
Rivaroxaban as anticoagulant will be administered with antiplatelet drug for 3 months. Antiplatelet drug can choose Aspirin or Clopidogrel depending on participant medical history and physician's recommendation.
干预措施: Rivaroxaban Oral Tablet [Xarelto] (Drug)
Rivaroxaban+Antiplatelet drug
Rivaroxaban as anticoagulant will be administered with antiplatelet drug for 3 months. Antiplatelet drug can choose Aspirin or Clopidogrel depending on participant medical history and physician's recommendation.
干预措施: Aspirin or Clopidogrel (Drug)
Standard antithrombotic care
Warfarin as anticoagulant will be administered with antiplatelet drug for 3 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[ 1.0 mg/kg; once daily] according to experienced clinician recommendation and individual condition.
干预措施: Aspirin or Clopidogrel (Drug)
Standard antithrombotic care
Warfarin as anticoagulant will be administered with antiplatelet drug for 3 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[ 1.0 mg/kg; once daily] according to experienced clinician recommendation and individual condition.
干预措施: Warfarin (Drug)
结局指标
主要结局
Composite of new thrombosis in coronary arteries, major bleeding, clinically relevant non-major bleeding event or major adverse cardiovascular event
时间窗: From Day 1 of treatment to the third month after treatment initiation
It is a binary variable. This composite outcome indicates whether any of the following events occurred within 3 months after treatment initiation: (a) newly developed coronary artery thrombosis; (b) major bleeding event; (c) clinically relevant non-major bleeding event; or (d) major adverse cardiovascular event (defined as unstable angina, acute myocardial infarction, hospitalization for heart failure, unplanned coronary revascularization, stroke, or cardiovascular death).
次要结局
- Occurence of minor bleeding(From Day 1 of treatment to the third month after treatment initiation)
- Plasma concentration of rivaroxaban at specific timepoints(From Day 1 of treatment to the third month after treatment initiation)
- Time to first new thrombosis in coronary arteries(From Day 1 of treatment to the third month after treatment initiation)
- Composite of Major bleeding or Clinically relevant non-major bleeding event(From Day 1 of treatment to the third month after treatment initiation)
- Occurrence of major bleeding(From Day 1 of treatment to the third month after treatment initiation)
- Occurrence of new thrombosis in coronary arteries(From Day 1 of treatment to the third month after treatment initiation)
- Changes in Z-score of each coronary artery aneurysms(From Day 1 of treatment to the third month after treatment initiation)
- Occurrence of clinically relevant non-major bleeding (CRNM)(From Day 1 of treatment to the third month after treatment initiation)
- Occurence of patient important bleeding, no intervention (PIBNI)(From Day 1 of treatment to the third month after treatment initiation)
- Occurrence of major adverse cardiovascular event(From Day 1 of treatment to the third month after treatment initiation)
- Time to major adverse cardiovascular event(From Day 1 of treatment to the third month after treatment initiation)
- Any adverse events(From Day 1 of treatment to the third month after treatment initiation)
- Anti-factor Xa activity at specific timepoints(From Day 1 of treatment to the third month after treatment initiation)
- Discontinuation anticoagulant due to regression of coronary artery lesions(From Day 1 of treatment to the third month after treatment initiation)
- Anticoagulation Monitoring-Related Cost(From Day 1 of treatment to the third months after treatment initiation)