Multicenter, Open-label, Active-controlled, Randomized Study to Evaluate the Efficacy and Safety of an age-and Body Weight-adjusted Rivaroxaban Regimen Compared to Standard of Care in Children With Acute Venous Thromboembolism
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- Bayer
- 入组人数
- 500
- 主要终点
- Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During the Main Treatment Period
研究概览
简要总结
The purpose of this study is to evaluate comparative efficacy and safety of rivaroxaban to standard of care in children with acute venous thromboembolism.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Children aged birth to < 18 years with confirmed venous thromboembolism who receive initial treatment with therapeutic dosages of UFH (unfractionated heparin), LMWH (low molecular weight heparin) or fondaparinux and require anticoagulant therapy for at least 90 days. However, children aged birth to < 2 years with catheter-related thrombosis require anticoagulant therapy for at least 30 days.
- •For children younger than 6 months:
- •Gestational age at birth of at least 37 weeks.
- •Oral feeding/nasogastric/gastric feeding for at least 10 days.
- •Body weight ≥2600 g
排除标准
- •Active bleeding or bleeding risk contraindicating anticoagulant therapy
- •An estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m*2 (in children younger than 1 year, serum creatinine results above 97.5th percentile excludes participation)
- •Hepatic disease which is associated with either: coagulopathy leading to a clinically relevant bleeding risk, or ALT> 5x upper level of normal (ULN) or total bilirubin > 2x ULN with direct bilirubin > 20% of the total
- •Platelet count < 50 x 109/L
- •Sustained uncontrolled hypertension defined as > 95th age percentile
- •Life expectancy < 3 months
- •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
- •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
研究组 & 干预措施
BAY59-7939
Rivaroxaban (tablets and oral suspension) Dose: Age and body weight-adjusted dosing of rivaroxaban to achieve a similar exposure as that observed in adults treated for venous thromboembolism (VTE) with 20 mg rivaroxaban.
干预措施: Rivaroxaban (Xarelto, BAY59-7939) (Drug)
Standard of Care
Subcutaneous low molecular weight heparin (LMWH), subcutaneous fondaparinux and/or oral vitamin K antagonist (VKA) Dose : as per standard of care
干预措施: Standard of Care (Drug)
结局指标
主要结局
Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During the Main Treatment Period
时间窗: During the main study treatment period (i.e., 3 months, except for children with CVC-VTE aged <2 years for whom it was 1 month)
The Central independent adjudication committee (CIAC) classified symptomatic recurrent venous thromboembolism (VTE). Incidence = number of events / number at risk, where: number of events = number of subjects having the event in the time window. number at risk = number of subjects in reference population
Incidence Rates of All Symptomatic Recurrent Venous Thromboembolism During Extended Treatment Period
时间窗: During extended treatment period: up to month 12.
Incidence rates for all children except those aged \< 2 years with catheter-related thrombosis. If no participant in the specific subgroup entered in the specific optional extension period, no analysis of an outcome was possible., The Central independent adjudication committee (CIAC) classified symptomatic recurrent venous thromboembolism (VTE). Incidence = number of events / number at risk, where: number of events = number of subjects having the event in the time window. number at risk = number of subjects in reference Population.
Number of Subjects With the Composite of All Symptomatic Recurrent Venous Thromboembolism During the 30 Days Post-study Treatment Period (i.e. >2 and ≤ 30 Days After Stop of Study Medication)
时间窗: More than 2 and up to 30 days after stop of study medication
The Central independent adjudication committee (CIAC) classified symptomatic recurrent venous thromboembolism (VTE). Age group with primary efficacy outcome was reported.
Incidence Rates of the Composite of Treatment Emergent Overt Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding During Main Treatment Period
时间窗: During the main study treatment period (i.e., 3 months, except for children with CVC-VTE aged <2 years for whom it was 1 month)
The Central independent adjudication committee (CIAC) classified bleeding as: Major bleeding 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 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).
Incidence Rates of the Composite of Treatment Emergent Overt Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding During Extended Treatment Period
时间窗: During extended treatment period: up to month 12.
Incidence rates for all children except those aged \< 2 years with catheter-related thrombosis. If no participant entered in the specific optional extension period, no analysis of an outcome was possible. The CIAC classified bleeding as: Major bleeding 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 defined as overt bleeding not meeting the criteria for major bleeding, but associated with: medical intervention, or unscheduled contact with a physician, or (temporary) cessation of study treatment, or discomfort for the child such as pain or impairment of activities of daily life.
次要结局
- Incidence Rates of the Composite of All Symptomatic Recurrent Venous Thromboembolism and Asymptomatic Deterioration in Thrombotic Burden on Repeat Imaging During the Main Treatment Period(During the main study treatment period (i.e., 3 months, except for children with CVC-VTE aged <2 years for whom it was 1 month))
- AUC(0-24)ss in Plasma(over 24 hours)
- Cmax,ss in Plasma(0 hours to 24 hours, 0 hours to 12 hours or 0 hours to 8 hours (one dosing interval in steady state))
- Ctrough,ss in Plasma(0 hours to 24 hours, 0 hours to 12 hours or 0 hours to 8 hours(one sampling interval in steady state))
- Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 12-<18 Years(Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60)
- Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 6-<12 Years(Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60)
- Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension and Tablet) in the Age Group 6-<12 Years(Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60)
- Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 2-<6 Years(Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60)
- Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 0.5-<2 Years(Up to 4 hours post dose on Day30, and up to 8 hours post dose on Day 60)
- Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 2-<6 Years(Up to 3 hours post dose on Day30, and up to 6 hours post dose on Day 60)
- Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 0.5-<2 Years(Up to 3 hours post dose on Day30, and up to 6 hours post dose on Day 60)
- Prothrombin Time (PT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group Birth-<0.5 Years(Up to 3 hours post dose on Day30, and up to 6 hours post dose on Day 60)
- Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 12-<18 Years(Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60)
- Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 6-<12 Years(Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60)
- Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension and Tablet) in the Age Group 6-<12 Years(Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60)
- Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 2-<6 Years(Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60)
- Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 0.5-<2 Years(Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60)
- Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 2-<6 Years(Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60)
- Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 0.5-<2 Years(Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60)
- Activated Partial Thromboplastin Time (aPTT) Ratios to Baseline: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group Birth-<0.5 Years(Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60)
- Anti-Xa Values: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 12-<18 Years(Up to 4 hours post dose on Day 30, up to 8 hours post dose on Day 60, and up to 24 hours on Day 90)
- Anti-Xa Values: Rivaroxaban Administered Once Daily (Suspension and Tablet) in the Age Group 6-<12 Years(Up to 4 hours post dose on Day 30, up to 8 hours post dose on Day 60, and up to 24 hours on Day 90)
- Anti-Xa Values: Rivaroxaban Administered Twice Daily (Suspension and Tablet) in the Age Group 6-<12 Years(Up to 4 hours post dose on Day 30, up to 8 hours post dose on Day 60, and up to 16 hours on Day 90)
- Anti-Xa Values: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 2-<6 Years(Up to 4 hours post dose on Day 30, up to 8 hours post dose on Day 60, and up to 16 hours on Day 90)
- Anti-Xa Values: Rivaroxaban Administered Twice Daily (Suspension) in the Age Group 0.5-<2 Years(Up to 4 hours post dose on Day 30, and up to 8 hours post dose on Day 60)
- Anti-Xa Values: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 2-<6 Years(Up to 3 hours post dose on Day 30, up to 6 hours post dose on Day 60, and up to 16 hours on Day 90)
- Anti-Xa Values: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group 0.5-<2 Years(Up to 3 hours post dose on Day 30, up to 6 hours post dose on Day 60, up to 16 hours on Day 90 and follow-up up to 30 days)
- Anti-Xa Values: Rivaroxaban Administered Three Times Daily (Suspension) in the Age Group Birth-<0.5 Years(Up to 3 hours post dose on Day 30, and up to 6 hours post dose on Day 60)