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.

项目概要 血栓后综合症（PTS）是一种慢性衰弱疾病，其特征是肢体肿胀和不适， 色素沉着过度、皮肤溃疡和生活质量受损。发生于深静脉血栓形成后2年内 50-60% 的髂股血栓患者和 30-50% 的所有 DVT 患者均接受 DVT 治疗 血栓形成部位 (1).即使采用药物导管定向溶栓 (PCDT) 或导管溶栓 最近临床试验中使用的定向血栓切除术 (CDT)（例如 ATTRACT、CaVenT 和 CAVA）， PTS 的比例仍为 40-50%。例如，在 NHLBI/NIH 资助的 ATTRACT 随机试验中，PCDT 与单独抗凝治疗相比，24 个月内并没有降低 PTS 的发生率。在子组中 分析显示，PCDT 可以降低髂股 DVT 中度至重度的 PTS (2,3)，并且 PCDT 没有任何益处 症状出现后 8 天后给药 (4)。总体而言，扩大服务范围的需求仍然明显未得到满足。 在减少 PTS 的临床和经济负担方面，除了选择性 PCDT 之外还有其他治疗方法。 血栓后综合征是由多种因素相互作用演变而来：纤维化静脉壁硬化导致 静脉瓣膜受损和随后的瓣膜反流，以及由于以下原因导致静脉流出持续受阻 血栓持续存在，导致静脉高压。这些结果中的每一个都可能由静脉引起 炎症，现在被认为是 DVT 治疗后 PTS 恶化过程中的关键 (5,6)。 因此，假设具有抗炎特性的药物可能具有预防 PTS 的能力 (7-10)。它 更有可能的是，如果局部进行抗炎治疗可能会更有效， 同时进行导管定向清除血栓（例如 PCDT/CDT）。 Mercator MedSystems 是局部血管周围药物输送领域的先驱，特别是抗炎药物 地塞米松（一种强效、廉价的糖皮质激素）等药物。通过 Bullfrog® 微输注 导管平台（目前可用于治疗直径 2-8 毫米的血管），墨卡托正在开发一种设备 治疗较大的髂股静脉，其直径可达 20 毫米。局部抗炎剂 分娩被提议作为一种新疗法，以减少 DVT 治疗后进展为 PTS。 在这一阶段的 STTR 提案中，目标 1 将研究血管周围的抗炎能力 Aim 2 将设计一个更大的 Bullfrog® 设备，用于 DVT 小鼠模型中的地塞米松输送 人类可用于直径达 20 毫米的静脉。一期工程完成后，中央 DVT 治疗后对静脉壁进行局部抗炎治疗的假设是 在第二阶段研究中对大型动物和人体试验进行了调查。