Design of SIRIUS: a randomized placebo-controlled Phase II study of inclocibart, an antibody against α2-antiplasmin, for proximal deep vein thrombosis

Background - Anticoagulant therapy is the cornerstone of treatment for deep vein thrombosis (DVT) but does not directly dissolve clots. In contrast, alpha-2-antiplasmin (α2AP), the principal endogenous inhibitor of plasmin, is a novel target for enhancing endogenous fibrinolysis. Inclocibart (BAY 3018250) is a first-in-class monoclonal antibody that inhibits α2AP and has demonstrated thrombolytic activity without increasing bleeding in preclinical studies. Here, we describe the study design and validation of the quantitative ultrasound method. Methods - SIRIUS is a randomized, double-blind, placebo-controlled, multicenter Phase II trial evaluating the efficacy and safety of inclocibart in patients with acute symptomatic proximal DVT. Patients were randomized 1:1:1 to receive a single intravenous infusion of inclocibart 750 mg, inclocibart 250 mg, or placebo, in addition to therapeutic anticoagulation. The primary efficacy outcome is the weighted average of thrombus size score ratios relative to baseline, assessed by quantitative compression ultrasonography at 6 hours, 24 hours, Day 7, and Day 30. The primary safety outcome is the incidence of major and clinically relevant non-major bleeding through Day 15. Secondary outcomes include recurrent venous thromboembolism (VTE), changes in leg pain, and post-VTE functional status. Pharmacokinetic and pharmacodynamic evaluations were conducted. Results - The study randomized 262 patients at 61 sites across 13 countries. Patient follow-up was completed in December 2025. Independent, blinded experts centrally adjudicated the thrombus size score, recurrent VTEs, and key safety outcomes. A reproducibility analysis of quantitative compression ultrasound assessments demonstrated good agreement, supporting the reliability of the primary efficacy measure. Conclusion - The SIRIUS trial (NCT06149520) is the first randomized study evaluating α2AP inhibition as a thrombolytic strategy in patients with acute proximal DVT. The study will provide important information on the efficacy and safety of inclocibart and help define the therapeutic potential of α2AP inhibition as a novel approach to enhancing endogenous fibrinolysis in thromboembolic disease.