Atenativ, a Plasma-Derived Antithrombin Concentrate, Used in Patients with Congenital Antithrombin Deficiency Undergoing Surgery or Parturition: Study Description (NCT04918173)

Background: Antithrombin is an endogenous anticoagulant inhibiting the activity of thrombin, FXa, and other serine proteases. Persons with heterozygous variants are at increased risk for thrombosis and are often insensitive to heparin therapy. Type I homozygous variants are lethal embryologically attesting to antithrombin's indispensability. Current clinical wisdom is to use on-demand anticoagulation with or without antithrombin concentrate for high-risk periods and secondary prophylaxis (prophylaxis after a thrombotic event) for those persons experiencing a thrombus. Two high-risk periods are perioperative and peripartum.

Methods: This is a multinational, prospective, open-label, uncontrolled phase 3 study to assess efficacy, safety, and single-dose pharmacokinetics of Atenativ in patients with congenital antithrombin deficiency undergoing surgery or delivery (NCT04918173). Atenativ is a lyophilized, highly pure antithrombin concentrate free of denatured antithrombin prepared from human plasma. The primary objective of the study is to determine the incidence of thrombotic and thromboembolic events after antithrombin replacement therapy in the high risk perioperative and peripartum scenarios. The secondary objectives are to determine single-dose pharmacokinetics (PK), assess coagulation parameters (activated partial thromboplastin time [aPTT], prothrombin time [PT], international normalized ratio [INR] and fibrinogen), and safety and tolerability of Atenativ. We will enroll 18 non-pregnant adult subjects older than 18 and younger than 80 years (4 of which will be 12-16 years of age from the US) to the pharmacokinetics phase and 20 subjects to the treatment phase of the study. Subjects may participate in both phases of the study, but only 1 surgery or delivery per subject is eligible. Salient inclusion criteria are: congenital antithrombin deficiency, defined by plasma activity of antithrombin ≤60%; personal or family history of thrombotic or thromboembolic events; and written informed consent from subject or legal guardian. Salient exclusion criteria are: emergency surgery, precipitous parturition or recent surgery; prior diagnosis of heparin-induced thrombocytopenia; and recent thrombotic or thromboembolic event. Lower extremity venous Doppler examination will be performed for patients entering the treatment phase. Subjects in the PK phase will receive a single dose of 60IU/kg with blood draws at baseline, 20 minutes, 1, 3, and 8 hours, and 2-8, 10, 12, and 14 days after the end of Atenativ infusion. The table illustrates Atenativ dosing schedule for surgical subjects and parturients. Statistics is confined to descriptive analyses without the need for a sample size estimation.

Results: Site initiation has begun (8 countries and 15 sites), and subject enrollment has commenced and is planned to continue until Q4 of 2024.

Conclusion: This study will endeavor to determine and decrease the incidence of thrombotic and thromboembolic events in subjects with congenital antithrombin deficiency during high-risk periods.

Sandoval:OctapharmaUSA: Current Employment. Jansen:Octapharma: Current Employment. Solomon:OctapharmaAG: Current Employment. Knaub:Octapharma AG: Current Employment. Tarantino:OctapharmaUSA: Honoraria, Research Funding, Speakers Bureau; Grifols: Speakers Bureau; Pfizer: Research Funding.