Prospective, Phase III Study of the Efficacy, Safety, and Pharmacokinetics of a Human Antithrombin III Concentrate in Congenital Antithrombin Deficiency during Surgery or Childbirth

Abstract

Introduction: Congenital antithrombin deficiency (CAD) is a rare genetic blood disorder commonly associated with spontaneous thrombotic events (TEs) and thromboembolic events (TEEs) that can occur in connection with surgery and childbirth. Although regular prophylactic antithrombin substitution is not necessary, human plasma-derived antithrombin replacement therapy or recombinant antithrombin replacement therapy can be used for the prevention of TEs/TEEs during and after surgery or childbirth. This study will aim to evaluate the efficacy, safety, and pharmacokinetics (PK) of a high-purity, double virus inactivated, lyophilized human antithrombin III concentrate (Atenativ ®) in these settings.Methods: The ATN-106 study (NCT04918173) is a multicenter, prospective, interventional, single-group, open-label, Phase III study in adult (≥18 and ≤80 years) male and female patients with documented CAD (plasma antithrombin ≤60%), and personal or family history of TEs or TEEs. The study will enrol 34 patients with CAD, including >14 non-pregnant patients for the PK phase and ~20 patients who are either a) non-pregnant and scheduled to undergo an elective surgical procedure known to be associated with a high risk for occurrence of TEs or TEEs, or b) pregnant and scheduled for caesarean section or delivery.For PK analysis, patients will receive a single 60 IU/kg intravenous (IV) infusion of antithrombin concentrate. For efficacy and safety analyses, a single IV dose to target an antithrombin level of 120% of normal will be administered to patients prior to surgery/delivery followed by maintenance doses administered every 24 hours for ~2-7 (surgical patients) or ~5 (delivery patients) days to target an antithrombin level of 80-120% of normal. A schematic representation of the ATN-106 study design is presented in Figure 1.The primary outcome measure will be the incidence of the composite of TEs and TEEs; secondary outcome measures will include single-dose PK (area under the curve [AUC norm(0-∞)], maximum plasma concentration [C max], half-life [T 1/2], mean residence time [MRT], clearance [CL], incremental in vivo recovery [IVR], volume of distribution at steady state [V ss]) and coagulation (activated partial thromboplastin time [aPTT], prothrombin time [PT], international normalised ratio [INR], fibrinogen level) parameters, as well as safety and tolerability (number of adverse events [AEs]).Results: Enrollment of participants in the ATN-106 study is estimated to start in Q3 2021 and end in Q3 2024.Conclusions: The results from this pivotal registration study are expected to confirm and strengthen the available evidence indicating that human plasma-derived antithrombin concentrate is effective in preventing thrombotic and thromboembolic events in patients with CAD in surgery and delivery settings and has a favorable safety profile. [Display omitted] DisclosuresSchwartz: Octapharma: Current Employment. Solomon: Octapharma: Current Employment. Knaub: Octapharma: Current Employment. Kessler: Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding.