Presentation Details
| A Phase 3, Double-Blind, Placebo-Controlled, Multicenter Study of Human Plasma Derived Antithrombin (Atenativ) in Heparin-Resistant Cardiac Surgery Patients Cristina Solomon1, Catrin Argyle1, Jerrold H.Levy2, Sylvia Werner1. 1Octapharma AG, Lachen, Switzerland.2Duke University School of Medicine, Durham, NC, USA |
Abstract
Background: Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) require adequate high-dose anticoagulation to prevent hemostatic activation and circuit thrombosis. Unfractionated heparin (UFH) is the mainstay anticoagulant therapy; however, up to 26% of patients undergoing CPB experience heparin resistance, often associated with decreased antithrombin levels. Antithrombin concentrate, a treatment option for managing heparin resistance, is only approved in the US for congenital but not acquired antithrombin deficiency. Objective: To evaluate the efficacy of two doses of antithrombin concentrate (Atenativ, Octapharma) versus placebo in restoring and maintaining heparin responsiveness in adult patients undergoing cardiac surgery necessitating CPB. Methods: ATN-108 is an ongoing, prospective, ​double-blind, placebo-controlled, three-arm, multicenter Phase 3 study. The study adheres to the ethical principles outlined in the Declaration of Helsinki. Patients aged between 18 and 85 years with planned cardiac surgery with CPB are eligible for inclusion. All patients must be heparin-resistant (pre-CPB Hemochron activated clotting time [ACT] <480 s between 2 and 5 min following intravenous administration of 500 U/kg UFH) and provide voluntarily given written informed consent at the screening visit. All female patients of childbearing potential will require a pre-existing negative pregnancy test within 14 days before surgery. Exclusion criteria include patients who have received anticoagulant therapies directly prior to the study, including warfarin, direct oral anticoagulants, ticlopidine, prasugrel, clopidogrel, ticagrelor or a glycoprotein IIb/IIIa antagonist. Additionally, patients with pre-existing coagulopathy, renal insufficiency (serum creatinine level >1.5 mg/dL), history of anaphylactic reaction(s) to blood or blood components, refusal to receive transfusion of blood or blood-derived products, hypersensitivity or allergic reaction to antithrombin or any of the excipients in Atenativ will be excluded. Participation in another interventional clinical trial or previous participation in the current trial and treatment with any investigational product within 30 days is prohibited. Patients will be randomized 2:2:1:1 to receive 15 IU/kg Atenativ, 30 IU/kg Atenativ, 0.3 mL/kg saline, or 0.6 mL/kg saline. The need for additional pre-CPB therapy to restore heparin responsiveness (i.e., for those patients who do not achieve a Hemochron ACT measurement of ≥480 s within 2 to 10 min after administration of Atenativ or placebo) will be analyzed. The primary endpoint, the proportion of patients requiring no further therapy containing antithrombin for restoring pre-CPB heparin responsiveness, and for maintaining it during CPB, after administration of Atenativ or placebo, will be compared between groups using a one-sided Fisher’s Exact Test. Secondary and safety endpoints are outlined in Table 1. Results: ATN-108 is expected to start in Q2 2024 and will be performed across ~20 sites in Europe and the United States. Target enrollment is ~120 patients, assuming a 5% dropout rate. Study completion is anticipated in Q3 2026. Conclusion: The study findings could confirm the efficacy and safety of antithrombin concentrate in re-establishing and maintaining heparin responsiveness in patients undergoing CPB.
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