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

闭塞性 DVT 导管定向溶栓临床试验计划资助

• 批准号: 8355734
• 负责人: Marilyn J Manco-Johnson
• 金额: $ 28.35万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8355734
• 关键词: Adult; Adverse effects; Affect; Age; Alteplase; Am 80; Anticoagulant therapy; Anticoagulation; Applications Grants; Blood Clot; Blood Vessels; Blood coagulation; Blood flow; Catheters; Child; Childhood; Chronic; Clinical; Clinical Research; Clinical Trials; Coagulation Process; Cohort Studies; Consensus; Consensus Development; Consent; Data Analyses; Deep Vein Thrombosis; Development; Devices; Disease; Enrollment; Ensure; Equipoise; Event; Excision; Feasibility Studies; Femoral vein; Frequencies; Funding; Future; Generic Drugs; Goals; Grant; Hematologist; Hematology; Hemorrhage; Inferior vena cava structure; Institutional Review Boards; Intervention; Intervention Studies; Investigation; Investigational New Drug Application; Leg; Life; Limb structure; Logistics; Longevity; Lower Extremity; Manuals; Measurable; Measures; Multicenter Trials; Outcome; Outcome Measure; Pain; Pain Disorder; Patient Outcomes Assessments; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Population; Postphlebitic Syndrome; Prevention; Procedures; Prognostic Factor; Prospective Studies; Protocols documentation; Publishing; Pulmonary Embolism; Quality of life; Randomized; Randomized Clinical Trials; Rare Diseases; Recommendation; Recruitment Activity; Recurrence; Reporting; Research; Research Personnel; Research Subjects; Resolution; Resource Development; Resources; Risk; Risk Reduction; Safety; Sampling; Secondary Prevention; Severities; Signs and Symptoms; Site; Subgroup; Surgeon; System; Techniques; Testing; Therapeutic; Thrombectomy; Thrombosis; Thrombus; Training; Translating; United States; United States Food and Drug Administration; Validity and Reliability; Veno-occlusive; Venous Insufficiency; Weight; Work; abstracting; adverse outcome; arm; base; cohort; design; disability; electronic data; high risk; human subject; instrument; intervention effect; outreach; prevent; sound; standard of care; success; systematic review; tertiary care; thrombolysis

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)

描述(由申请人提供)：2008年，美国卫生局局长关于预防深静脉血栓(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。血栓后综合征(PTS)是深静脉血栓形成后慢性静脉功能不全引起的一种临床疼痛和残疾的疾病，成人和儿童都会受到影响。在最近对儿科PTS的系统回顾中，包括1000多名儿童在内的已发表研究中PTS的平均加权频率为26%。DVT后PTS的高频率及其对生活质量的不良影响支持PTS是预防PTS的关键结果。前瞻性研究中确定的PTS的最强预后因素是使用溶栓治疗和相关的血栓消退。来自申请人的9至20岁患有近端下肢深静脉血栓的机构队列的初步结果显示，92%的儿童完全闭塞静脉，其中31%受累于下腔静脉，71%受累于下腔静脉或髂骨，这表明近端腿深静脉血栓在儿童中是一种比成人更严重的疾病。目前，根据疾病的严重性和成人的令人鼓舞的报告，儿科血液学家越来越多地对儿童使用溶栓治疗，但没有证据表明其安全性或有效性。这项申请提出了一项计划拨款，以开发一项干预性随机临床试验，以确定与单纯标准抗凝相比，溶栓和标准抗凝对降低近端闭塞DVT儿童PTS发生率的影响。患有血栓的儿童构成了血液学中一种罕见的疾病群体，但没有得到足够的服务。在临床试验发展资源(CTDR)的辅助下，这一规划拨款对于开发一种科学合理的方案是关键，该方案可以在三级保健儿童医院忠实地复制，从而产生高质量的证据。此外，CTDR的资源对于确保预测的受试者数量和结果预测尽可能准确，以便开展一项全面的研究并及时完成登记至关重要。试验开发的建议方法包括改进Manco-Johnson PTS结果，并将其与替代患者报告的结果进行比较，包括改进的Villalta PTS仪器、在成人中验证的疾病特定生活质量测量Vinees-QOL以及PedsQS，这是一种已广泛应用于各种慢性儿科疾病的经验证的儿童通用生活质量测量工具。拟议的临床试验开发方法涉及对标准化血管干预的共识发展，该方法将适用于大多数儿童医院，将被合作者随机接受，并承诺高度的安全性和有效性。申请者将与临床试验开发资源受赠人合作，建立一个指导委员会，将最终方案转化为程序、临床研究表格、电子数据捕获系统、培训材料和人类受试者同意的手册，并细化估计样本效应量，使用预测效应量进行功率分析，并制定数据分析计划。申请还将被开发并提交给美国食品和药物管理局，以获得研究人员发起的新药和研究人员发起的设备豁免批准。最后，将致力于对研究的可行性进行分析，以便在拟议的登记期限内充分招募受试者，并在研究前对潜在地点进行外联，以确保患者数量、资源、研究人员承诺和对随机化的共识足以完成一项全额资助的试验。 公共卫生相关性：血栓后综合征(PTS)是一种慢性疼痛和残疾状态，伴随着肢体的血液凝块。血凝块在儿童中很少见，但一定要注意PTS。这项U34申请计划进行一项随机临床试验，对照溶解或清除血栓的新技术进行标准抗凝治疗，以预防PTS。这项试验将具有挑战性，因为这种疾病在儿童中很罕见，许多儿童医院将需要合作来招募所需数量的研究对象。这笔赠款对于提供资源以最好地开展试验以最大限度地取得成功非常重要。(摘要结束)