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

PROJECT SUMMARY Post-thrombotic syndrome (PTS) is a chronic debilitating condition characterized by limb swelling, discomfort, hyperpigmentation, skin ulcers, and impaired quality of life. Within 2 years of deep vein thrombosis (DVT) treatment, 50-60% of patients with iliofemoral thrombosis and 30-50% of all DVT patients regardless of thrombosis location experience PTS (1). Catheter-based therapies to remove the obstructive thrombus have fared no better in clinical trials (e.g. ATTRACT, CaVenT and CAVA) than anti-coagulant therapy alone in preventing PTS onset. In the NHLBI/NIH-funded ATTRACT randomized trial, for example, catheter-based thrombolysis with or without thrombectomy did not reduce the incidence of PTS vs. control anticoagulation alone. In subgroup analysis, catheter-based thrombus removal conferred reduced moderate-to-severe PTS in more proximal (iliofemoral) DVT (2,3), but no benefit in either iliofemoral veins when treatment was administered later than 8 days post-symptom onset (4) nor in more distal (femoropopliteal) disease regardless of timing (5). There remains a clear unmet need in the treatment of DVT, because catheter technologies that clear the thrombus burden do nothing to treat the underlying vascular inflammation that (a) led to the DVT formation in the first place, and (b) resulted from the thrombus organization and resolution process. Left untreated, inflammation lays down a thick collagen layer causing fibrotic vein wall stiffening, damaged venous valves, reduced venous compliance, and venous insufficiency (6,7). Preventing this scar-like process from damaging the vein and leading to PTS is the central goal of this project. In response to the inflammatory hypothesis, a field of research has emerged to fight venous inflammation and reverse the course of DVT progression toward PTS (8-13), but systemic drug therapies aimed at specific inflammatory targets have proven ineffective (14). It has now been shown through the Phase I research phase of this project that locally delivered anti-inflammatory (dexamethasone) therapy is an effective means of blocking collagen deposition and reducing thrombus burden in a mouse model. In tandem with the Phase I STTR preclinical research, Mercator MedSystems has launched an open-label clinical trial to determine the effect of local dexamethasone delivery to perivascular tissues surrounding veins undergoing DVT recanalization, with positive results in comparison to historical data from the ATTRACT trial. Based on the Phase I preclinical research and the clinical data to date, the Phase II aims are proposed with confidence. In this Phase II SBIR proposal, we will enroll a 60-patient, dual-blinded, randomized controlled trial (Specific Aim 1) and follow primary and secondary safety and efficacy signals (Specific Aim 2) in acute DVT to determine the ability for perivenous dexamethasone therapy to improve outcomes between the two groups. Subsequent Phase 3 clinical trials will be powered based on the signals seen in this Phase 2 trial.