Human Plasma Derived Antithrombin (Atenativ) in Heparin-Resistant Cardiac Surgery Patients: Protocol Update for an Ongoing Phase 3, Double-Blind, Placebo-Controlled, Multicenter Study

Background and Significance: Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) require anticoagulation to prevent hemostatic activation and circuit thrombosis. Unfractionated heparin (UFH) is the primary anticoagulant used clinically and requires antithrombin (AT) to be effective. However, heparin resistance can occur in up to 26% of patients undergoing CPB, often due to reduced AT levels. AT concentrate, used to manage heparin resistance, is not approved in the US for acquired AT deficiency. The aim of the ATN-108 study is to assess the efficacy of two doses of AT concentrate (Atenativ, Octapharma) versus placebo in restoring and maintaining heparin responsiveness in adult patients undergoing cardiac surgery requiring CPB.

Study Design and Methods: ATN-108 (NCT06096116) is an ongoing, prospective, double-blind, multicenter, placebo-controlled Phase 3 study that adheres to the ethical principles outlined in the Declaration of Helsinki. The study will include patients aged ≥18 and ≤85 years who are heparin-resistant (pre-CPB Hemochron activated clotting time [ACT] <480 s between 2 and 5 min following intravenous administration of 500 U/kg UFH) with planned cardiac surgery with CPB.

Exclusion criteria include patients receiving anticoagulant therapies (warfarin, direct oral anticoagulants, ticlopidine, prasugrel, clopidogrel, ticagrelor or a glycoprotein IIb/IIIa antagonist) directly before the study, pre-existing coagulopathy, renal insufficiency (serum creatinine level >1.5 mg/dL), a history of bleeding problems or a laboratory-diagnosed bleeding disorder. Participation in another interventional clinical trial or previous participation with investigational product treatment in the current trial within 30 days is not allowed.

Patients will be randomized 2:2:1:1 to receive AT concentrate (15 IU/kg or 30 IU/kg), or saline (0.3 mL/kg or 0.6 mL/kg). After administration of AT concentrate or placebo, the need for further pre-CPB therapy to restore heparin responsiveness in patients failing to achieve a Hemochron ACT measurement of ≥480 s within 2 and 10 min will be analyzed. The primary endpoint is the proportion of patients requiring no further AT therapy to restore and maintain pre-CPB heparin responsiveness during CPB, after administration of AT concentrate or placebo. The groups will be compared using a one-sided Fisher's Exact Test.

Secondary endpoints include the amount of further AT therapy needed to restore and maintain pre-CPB heparin responsiveness, the change in ACT values and AT plasma levels, and heparin usage following infusion of AT concentrate or placebo. The study will also measure the intraoperative, postoperative, and cumulative administration of coagulation factor concentrates, other allogeneic blood products, hemostatic-relevant therapies, and the number of units of frozen plasma transfused for reasons other than restoring or maintaining heparin responsiveness. Additional secondary endpoints include postoperative use of AT concentrates for reasons other than restoring heparin responsiveness (from surgery end until 24 h after the start of AT concentrate or placebo infusion and until discharge or 7 d after surgery), postoperative and total chest tube drainage volume (24 h after the start of AT concentrate or placebo infusion and until discharge or 7 d post-surgery, respectively), cell saver volume until surgery end, and the need for reoperation for bleeding specifying surgical versus non-surgical causes. Secondary safety endpoints include the incidence of adverse events, survival status, and standard hematological parameters (i.e., red blood cell count, white blood cell count, hemoglobin levels, hematocrit, and platelet count) following AT concentrate or placebo infusion, after the end of CPB, at the end of surgery, and 24 h after the start of AT concentrate or placebo infusion.

ATN-108 is expected to start recruiting patients in Q3 2024 and will be conducted across ~20 European and US centers. Study completion is anticipated in Q3 2026. Target enrollment is ~120 patients.

The findings of this study could confirm the efficacy and safety of AT concentrate in re-establishing and maintaining heparin responsiveness for acquired AT deficiency in patients undergoing CPB.

Levy:Bayer: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Werfen: Membership on an entity's Board of Directors or advisory committees. Argyle:Octapharma AG: Current Employment. Solomon:Octapharma AG: Current Employment. Knaub:Octapharma AG: Current Employment.

Antithrombin concentrate, used to manage heparin resistance, is approved in the United States for treating congenital antithrombin deficiency but not for acquired cases. Antithrombin concentrate is approved for the treatment of acquired antithrombin deficiency elsewhere.