KidsDOTT-DCC

摘要 近年来，静脉血栓栓塞（VTE）的发病率在儿童中急剧增加，每200名住院儿童中就有1名。仅在美国，每年的医疗保健费用就估计为7200万美元。目前国际上对儿童VTE抗凝治疗持续时间的建议是基于成人随机对照试验（RCT）的结果，但需要专门的儿童试验。本提案的主要目的是进行一项确定性多中心RCT，以确定儿童静脉血栓形成抗凝治疗的持续时间（Kids-DOTI试验）。临床协调中心是美国领先的学术医疗和研究中心之一，约翰霍普金斯大学，由其独立的儿科三级保健医院，所有儿童医院约翰霍普金斯医学的首席研究官和儿科血栓形成项目主任领导。数据协调中心是科罗拉多大学及其附属的非营利性学术研究组织CPC临床研究，该组织在血管疾病试验方面拥有丰富的DCC经验和独立的委员会管理。Kids-DOTT的主要假设是，在首次发作急性静脉血栓形成的儿童中，缩短抗凝治疗时间（6周）同样有效，至少同样安全（即，“非劣效性”），与常规持续时间治疗（3个月）相比。主要疗效和安全性终点是由设盲临床终点裁定委员会裁定的症状性复发性VTE和抗凝剂依赖性临床相关出血。该试验由指导委员会和数据和安全性监测委员会监督。该研究利用了国际儿科指南，用于常规临床护理中给予的抗凝剂的统一剂量和监测，并在次要目的中测试特定抗凝药物的任何亚组效应。作为另一个目标，将建立一个血浆和遗传物质的试验生物储存库，以促进未来对静脉血栓形成儿童预后标志物的研究。试验的试点/可行性阶段是在NHLBI K23下启动的，最近完成（目标样本量， 100例患者在多中心基础上入组），其验证了招募和保留的假设，显示了随机化放射学标准的高评分者间可靠性，证明了重大方案偏离的发生率非常低，并提供了终点率的关键估计值。

ABSTRACT The incidence of venous thromboembolism (VTE) has dramatically increased in children in recent years, to 1 in 200 hospitalized children. Annual health care costs can be estimated at $72M in the U.S. alone. Current international recommendations for duration of anticoagulant therapy in pediatric VTE are based upon findings of randomized controlled trials (RCTs) in adults, but call for devoted pediatric trials. The PRINCIPAL OBJECTIVE of this proposal is to conduct a definitive multicenter RCT to establish the duration of anticoagulation for venous thrombosis in children (the Kids-DOTI trial). The Clinical Coordinating Center is one of the nation's leading academic medical and research centers, Johns Hopkins University, and is led by the Chief Research Officer and Pediatric Thrombosis Program Director of its stand-alone pediatric tertiary care hospital, All Children's Hospital Johns Hopkins Medicine. The Data Coordinating Center is the University of Colorado and its affiliated non-profit Academic Research Organization CPC Clinical Research, which has extensive DCC experience and independent committee management in vascular disease trials. The PRIMARY HYPOTHESIS of Kids-DOTT is that, in children with a first episode of provoked acute venous thrombosis, a shortened duration of anticoagulation (6 weeks) is just as effective, and at least as safe (i.e., "non-inferior"), to conventional-duration therapy (3 months). The primary efficacy and safety endpoints are symptomatic recurrent VTE and anticoagulant­ associated, clinically-relevant bleeding, adjudicated by a blinded Clinical Endpoint Adjudication Committee. The trial is overseen by a Steering Committee and a Data and Safety Monitoring Committee. The research takes advantage of international pediatric guidelines for uniform dosing and monitoring of anticoagulants administered in routine clinical care, and tests for any subgroup effects of specific anticoagulant drugs in a secondary aim. As an additional aim, a trial biorepository of plasma and genetic material will be established to faciliate future research on prognostic markers in well-characterized children with venous thrombosis. The pilot/feasibility phase of the trial was initiated under an NHLBI K23 and recently completed (target sample size, 100 patients enrolled on a multicenter basis), which has validated assumptions regarding recruitment and retention, shown high inter-rater reliability of radiologic criteria for randomization, demonstrated a very low rate of major protocol deviations, and provided key estimates on endpoint rates.