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.
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.