Preventing Post-Thrombotic Syndrome after Deep Vein Thrombosis with Perivascular Anti-Inflammatory Agent Delivery

通过血管周围抗炎剂输送预防深静脉血栓形成后的血栓后综合征

• 批准号: 10325584
• 负责人: Farouc Amin Jaffer
• 金额: $ 29.97万
• 依托单位: MERCATOR MEDSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-06-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325584
• 关键词: Address; Affect; American; Animals; Anti-Inflammatory Agents; Anticoagulation; Area; Blood Vessels; Blood flow; COVID-19; Caliber; Catheters; Chronic; Cicatrix; Clinical; Clinical Trials; Combined Modality Therapy; Deep Vein Thrombosis; Deterioration; Devices; Dexamethasone; Drug Delivery Systems; Economic Burden; Engineering; Excision; Fibrosis; Funding; Future; General Hospitals; Glucocorticoids; Health; Human; Hyperpigmentation; Hypertension; Impairment; Incidence; Individual; Inferior vena cava structure; Inflammation; Inflammatory; Infusion procedures; Injury; Intervention; Lead; Ligation; Limb structure; Location; Long-Term Effects; Massachusetts; Measurement; Mechanics; Mediating; Medical; Methods; Modeling; Modification; Mus; National Heart, Lung, and Blood Institute; Notification; Obstruction; Outcome; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phosphate Buffer; Postphlebitic Syndrome; Process; Property; Publishing; Quality of life; Rana catesbeiana; Reflux; Reporting; Research; Resolution; Risk; Saline; Severities; Signal Pathway; Small Business Technology Transfer Research; Stents; Subgroup; Swelling; Symptoms; Testing; Therapeutic; Thrombectomy; Thrombophilia; Thrombosis; Thrombus; Translating; United States National Institutes of Health; Veins; Venous; base; case-based; cytokine; design; experience; improved; innovation; mouse model; non-compliance; novel; novel therapeutics; prevent; randomized trial; research study; response to injury; restoration; skin ulcer; stent thrombosis; success; technological innovation; thrombolysis; thrombotic complications

PROJECT SUMMARY Post-thrombotic syndrome (PTS) is a chronic debilitating condition characterized by limb swelling and discomfort, hyperpigmentation, skin ulcers, and impaired quality of life. It occurs within 2 years of deep vein thrombosis (DVT) treatment in 50-60% of patients with iliofemoral thrombosis and in 30-50% of all DVT patients regardless of thrombosis location (1). Even with pharmacological catheter-directed thrombolysis (PCDT) or catheter- directed thrombectomy (CDT) as used in the most recent clinical trials (e.g. ATTRACT, CaVenT and CAVA), there remains a 40-50% rate of PTS. In the NHLBI/NIH-funded ATTRACT randomized trial, for example, PCDT did not reduce the incidence of PTS over 24 months, compared to control anticoagulation alone. In subgroup analysis, PCDT conferred reduced moderate-to-severe PTS in iliofemoral DVT (2,3), and no benefit when PCDT was administered after 8 days post-symptom onset (4). Overall, there remains a clear unmet need to expand the armamentarium of therapies beyond selective PCDT in reducing the clinical and economic burden of PTS. Post-thrombotic syndrome evolves from an interplay of multiple factors: fibrotic vein wall stiffening leading to damaged venous valves and subsequent valvular reflux, and continued obstruction of venous outflow due to thrombus persistence, leading to venous hypertension. Each of these outcomes can arise from venous inflammation, which is now considered a key in the process of deterioration to PTS after DVT treatment (5,6). Hypothetically, drugs with anti-inflammatory properties may therefore have the ability to prevent PTS (7-10). It is further plausible that anti-inflammatory therapy may be more efficacious if delivered locally, concomitantly with catheter-directed clearance of thrombosis (e.g. PCDT/CDT). Mercator MedSystems is the pioneer in local perivascular drug delivery, particularly with anti-inflammatory agents such as dexamethasone (a powerful, inexpensive glucocorticoid). Via the Bullfrog® Micro-Infusion Catheter platform (currently available to treat vessels of 2-8 mm diameter), Mercator is developing a device to treat the larger iliofemoral veins, which will have diameter up to 20 mm. Localized anti-inflammatory agent delivery is proposed as a novel therapy to reduce the progression to PTS after DVT treatment. In this Phase I STTR proposal, Aim 1 will investigate the anti-inflammatory capability of perivascular dexamethasone delivery in a mouse model of DVT, and Aim 2 will engineer a larger Bullfrog® device for human use in up to 20 mm-diameter veins. After completion of this Phase I project, the central hypothesis of locally delivered anti-inflammatory treatment of the vein wall post-DVT treatment will be investigated in large animals and human trials in Phase II research.

项目摘要 血栓形成后综合征（PTS）是一种慢性衰弱状况，特征是肢体肿胀和不适， 色素沉着，皮肤溃疡和生活质量受损。它发生在深静脉血栓形成2年内 （DVT）在50-60％的Iliofemoral血栓形成患者和30-50％的所有DVT患者中进行治疗 血栓形成位置（1）。即使使用药物附件定向血栓形成（PCDT）或toter- 在最近的临床试验中使用的定向血栓切除术（CDT）（例如吸引，探测和卡瓦）， PT持有40-50％的率。在NHLBI/NIH资助的吸引随机试验中，例如PCDT 与单独对照抗凝治疗相比，在24个月内没有减少PT的事件。在子组中 分析，PCDT赋予了Iliofemoral DVT中的中度至重度PT（2,3），并且当PCDT时没有好处 在肿瘤发作后8天后进行（4）。总体而言，仍然有明显的未满足来扩展 除选择性PCDT以外的疗法的武器库减少了PT的临床和经济燃烧。 从多种因素的相互作用的促进后综合征的演变：纤维化静脉壁变硬导致 受损的静脉瓣损坏和随后的瓣膜反射X，并且由于 血栓持久性，导致静脉高血压。这些结果中的每一个都可以来自静脉 炎症，现在被认为是确定DVT治疗后PTS的关键（5,6）。 假设具有抗炎特性的药物可能具有预防PT的能力（7-10）。 更合理的是，如果本地交付抗炎疗法可能会更有效， 同时与导管指导的血栓形成清除率（例如PCDT/CDT）。 Mercator Medsystems是局部血管周围药物输送的先驱，尤其是抗炎 诸如地塞米松（一种强大，廉价的糖皮质激素）之类的药物。通过Bullfrog®微型融合 导管平台（目前可用于处理2-8毫米直径的VSSEL），Mercator正在开发一种设备 处理较大的伊洛夫静脉，该静脉的直径高达20毫米。局部抗炎剂 提出将递送作为一种新的疗法，以减少DVT治疗后对PTS的进展。 在此I阶段I STTR提案中，AIM 1将研究周围的抗炎能力 DVT的鼠标模型中的地塞米松交付，AIM 2将设计更大的Bullfrog®设备 人类最多直径静脉的使用。完成此阶段项目后，中央 DVT治疗后静脉壁壁处理的局部交付的抗炎治疗的假设将是 在大型动物和II期研究中的人类试验中进行了研究。