Clinical Trial Planning Grant in Catheter-Directed Thrombolysis of Occlusive DVT

描述（由申请人提供）：2008年，美国（US）外科医生关于预防深静脉血栓形成（DVT）和肺栓塞（PE）的行动呼吁强调DVT后的慢性静脉功能不全是未来研究的重要优先事项。血栓形成后综合征（Post-thrombotic syndrome，PTS）是一种由下肢深静脉血栓形成（DVT）后慢性静脉功能不全引起的疼痛和残疾的临床疾病。在最近一项儿科PTS的系统性综述中，已发表的研究（包括1000多名儿童）中PTS的平均加权频率为26%。DVT后PTS的高发生率及其对生活质量的不良影响支持PTS作为预防的关键结果。在前瞻性研究中确定的PTS最强的预后因素是溶栓的使用和相关的血栓消退。来自申请人的9至20岁近端下肢DVT儿童机构队列的初步结果表明，92%完全静脉闭塞，31%累及IVC，71%累及IVC或髂动脉，表明儿童近端下肢DVT比成人更严重。目前，儿科血液学家越来越多地在儿童中使用溶栓，但没有证据表明其安全性或有效性，这是基于疾病的严重程度和令人鼓舞的成人报告。该申请提出了一项计划拨款，用于开发一项干预性随机临床试验，以确定溶栓和标准抗凝与单独标准抗凝相比对降低近端闭塞性深静脉血栓形成儿童的PTS发生率的影响。患有血栓的儿童是血液学中一种罕见的疾病人群，目前尚未得到充分的治疗。这项规划补助金在临床试验开发资源（CTDR）的伴随援助下，对于制定一项科学合理的方案至关重要，该方案可以在三级儿童医院忠实地复制，从而产生高质量的证据。此外，CTDR的资源对于确保预计的受试者数量和结局预测尽可能准确至关重要，以便开发完全把握度的研究并及时完成入组。拟定的试验开发方法包括改进Manco-Johnson PTS结局，并与替代患者报告的结局进行比较，包括改良的Villalta PTS工具、VEINES-QoL（一种在成人中验证的疾病特异性生活质量测量方法）和PedsQS（一种经验证的儿童通用生活质量工具，已广泛应用于各种慢性儿科疾病）。临床试验开发的拟议方法涉及标准化血管介入的共识开发，该标准化血管介入将适用于大多数儿童医院，将被合作者接受随机化，并承诺高度的安全性和有效性。申请人将与临床试验开发资源受让人合作，建立一个指导委员会，将最终方案转化为程序手册、临床研究表格、电子数据采集系统、培训材料和人类受试者同意书，并细化估计的样本效应量，使用预计的效应量进行功效分析，并制定数据分析计划。还将开发申请并提交给美国食品药品监督管理局，以获得研究者发起的新药和研究者发起的器械豁免批准。最后，大量工作将用于分析研究可行性，以便在拟定入组期内招募足够的受试者，并在研究前与潜在研究中心联系，以确保患者数量、资源、研究者承诺和对随机分组的共识足以完成一项完全资助的试验。 公共卫生相关性：血栓形成后综合征（PTS）是一种慢性疼痛和残疾的条件下，血液凝块到四肢。血凝块在儿童中很少见，但确实会引起PTS。该U34申请计划进行一项标准抗凝治疗与溶解或清除凝块以预防PTS的新技术的随机临床试验。这项试验将具有挑战性，因为这种疾病在儿童中很少见，许多儿童医院需要合作招募所需数量的研究对象。赠款对于提供资源以最好地开发试验以最大限度地取得成功非常重要。(End摘要）

DESCRIPTION (provided by applicant): In 2008, the United States (US) Surgeon General's Call-to-Action on Prevention of Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) emphasized chronic venous insufficiency following DVT as an important priority for future investigation. Post-thrombotic syndrome (PTS) is a clinical disorder of pain and disability caused by chronic venous insufficiency following DVT, which affects both adults and children. In a recent systematic review of pediatric PTS, mean weighted frequency of PTS across published studies, including over 1000 children, was 26%. The high frequency of PTS after DVT and its adverse effects on QOL support PTS as a key outcome for prevention. The strongest prognostic factors for PTS identified in prospective studies were use of thrombolysis and related thrombus resolution. Pilot results from the applicants' institutional cohort of children from 9 to 20 years f age with proximal lower extremity DVT demonstrate that 92% were completely veno-occlusive with IVC involvement in 31% and IVC or iliac involvement in 71%, suggesting that proximal leg DVT is a more severe disorder in children than in adults. Currently, pediatric hematologists are increasingly using thrombolysis in children without evidence for its safety or efficacy based on the severity of the disorder and encouraging reports in adults. This application proposes a planning grant to develop an interventive randomized clinical trial to determine the impact of thrombolysis and standard anticoagulation in comparison to standard anticoagulation alone on decreasing the rate of PTS in children with proximal occlusive DVT. Children with thrombosis comprise a rare disease population in hematology that is been underserved. This planning grant, with the attendant assistance of the Clinical Trials Development Resource (CTDR), is key in order to develop a scientifically sound protocol that can be faithfully reproduced at tertiary care Children's Hospitals that will generate high-quality evidence. In addition, resource of the CTDR are critical to ensure that projected subject numbers and outcome predictions are as accurate as possible in order to develop a fully powered study and to complete enrollment in a timely fashion. Proposed approaches to the trial development include refinement of the Manco-Johnson PTS outcome measured in comparison with alternative patient-reported outcomes, including the modified Villalta PTS instrument, the VEINES-QoL, a disease-specific quality of life measure validated in adults, and the PedsQS, a validated generic quality of life instrument for children that has been widely applied to various chronic pediatric disorders. The proposed approach to the clinical trial development involves a consensus development of a standardized vascular intervention that will be applicable to most children's hospitals, will be acceptable to collaborators for randomization, and promises a high degree of safety and efficacy. The applicant will work with the Clinical Trials Development Resource grantee to develop a Steering Committee, translate the final protocol into a manual of procedures, clinical research forms, electronic data capture system, training materials, and human subject consent, as well as to refine an estimated sample effect size, use the projected effect size to conduct a power analysis and develop a plan for data analysis. Applications will also be developed and submitted to the US Food and Drug Administration for investigator initiated new drug and investigator initiated device exemption approvals. Finally, substantial work will be devoted to an analysis of study feasibility for adequate subject recruitment within the proposed enrollment period and pre-study outreach to potential sites to ensure that patient numbers, resources, investigator commitment and consensus on the randomization arms are adequate to complete a fully funded trial. PUBLIC HEALTH RELEVANCE: Post thrombotic syndrome (PTS) is a chronic condition of pain and disability following a blood clot to an extremity. Blood clots are rare in children, but do caue PTS. This U34 application proposes to plan a randomized clinical trial of standard anticoagulant therapy against newer techniques to dissolve or remove clot in order to prevent PTS. This trial will be challenging because the disorder is rare in children and many children's hospitals will need to collaborate to recruit the required number of research subjects. The grant is important to provide resources to best develop the trial to maximize its success. (End of Abstract)