利伐沙班与标准抗凝治疗用于儿童急性静脉血栓栓塞症。EINSTEIN-Jr Ⅲ期研究设计。
Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study.
作者信息
Lensing Anthonie W A, Male Christoph, Young Guy, Kubitza Dagmar, Kenet Gili, Patricia Massicotte M, Chan Anthony, Molinari Angelo C, Nowak-Goettl Ulrike, Pap Ákos F, Adalbo Ivet, Smith William T, Mason Amy, Thelen Kirstin, Berkowitz Scott D, Crowther Mark, Schmidt Stephan, Price Victoria, Prins Martin H, Monagle Paul
机构信息
1Bayer AG, Research and Development, Thrombosis and Hematology, Building 402, room 304, Aprather Weg 18a, 42113 Wuppertal, Germany.
2Department of Paediatrics, Medical University of Vienna, Wien, Austria.
出版信息
Thromb J. 2018 Dec 21;16:34. doi: 10.1186/s12959-018-0188-y. eCollection 2018.
BACKGROUND
Venous thromboembolism (VTE) is a relatively rare condition in childhood with treatment mainly based on extrapolation from studies in adults. Therefore, clinical trials of anticoagulation in children require novel approaches to deal with numerous challenges. The EINSTEIN-Jr program identified pediatric rivaroxaban regimens commencing with in vitro dose finding studies followed by evaluation of children of different ages through phase I and II studies using extensive modeling to determine bodyweight-related doses. Use of this approach resulted in drug exposure similar to that observed in young adults treated with rivaroxaban 20 mg once-daily.
METHODS
EINSTEIN-Jr phase III is a randomized, open-label, study comparing the efficacy and safety of rivaroxaban 20 mg-equivalent dose regimens with those of standard anticoagulation for the treatment of any types of acute VTE in children aged 0-18 years.A total of approximately 500 children are expected to be included during the 4-year study window. Flexibility of treatment duration is allowed with study treatment to be given for 3 months with the option to continue treatment in 3-month increments, up to a total of 12 months. However, based on most common current practice, children younger than 2 years with catheter-related thrombosis will have a main treatment period of 1 month with the option to prolong treatment in 1-month increments, up to a total of 3 months.
CONCLUSIONS
EINSTEIN-Jr will compare previously established 20 mg-equivalent rivaroxaban dosing regimens with standard anticoagulation for the treatment of VTE in children. Demonstration of similarity of disease, as well as equivalent rivaroxaban exposure and exposure-response will enable extrapolation of efficacy from adult trials, which is critical given the challenges of enrollment in pediatric anticoagulation trials.
TRIAL REGISTRATION
Clinicaltrials.gov NCT02234843, registered on 9 September 2014.
背景
静脉血栓栓塞症（VTE）在儿童中相对少见，其治疗主要基于对成人研究的推断。因此，儿童抗凝临床试验需要新方法来应对诸多挑战。EINSTEIN-Jr项目确定了儿科利伐沙班治疗方案，首先进行体外剂量探索研究，随后通过I期和II期研究评估不同年龄段儿童，并使用广泛建模来确定与体重相关的剂量。采用这种方法导致的药物暴露与接受每日一次20mg利伐沙班治疗的年轻成年人中观察到的情况相似。
方法
EINSTEIN-Jr III期是一项随机、开放标签研究，比较20mg等效剂量利伐沙班治疗方案与标准抗凝方案治疗0至18岁儿童任何类型急性VTE的疗效和安全性。预计在4年研究期内共纳入约500名儿童。治疗持续时间具有灵活性，研究治疗为期3个月，可选择以3个月为增量继续治疗，最长可达12个月。然而，根据当前最常见的做法，患有导管相关血栓形成的2岁以下儿童主要治疗期为1个月，可选择以1个月为增量延长治疗，最长可达3个月。
结论
EINSTEIN-Jr将比较先前确定的20mg等效利伐沙班给药方案与标准抗凝方案治疗儿童VTE的效果。证明疾病的相似性以及利伐沙班暴露和暴露-反应的等效性将能够从成人试验推断疗效，鉴于儿科抗凝试验招募受试者面临的挑战，这一点至关重要。
试验注册
Clinicaltrials.gov NCT02234843，于2014年9月9日注册。
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