Evaluation of Efficacy and Safety of Antithrombin III Human in Patients with Congenital Antithrombin Deficiency Undergoing Surgical Procedures or Parturition

The primary objective of this study is to assess the incidence of the composite of **Thrombotic Events** (TEs) and **Thromboembolic Events** (TEEs) in patients with congenital antithrombin deficiency under the cover of Atenativ during surgical procedures or parturition. This is clinically relevant as it aims to evaluate the effectiveness of Atenativ in preventing potentially life-threatening thrombotic complications in a vulnerable patient population.

Secondary objectives include:

• Assessing the single-dose pharmacokinetics (PK) of Atenativ in patients with congenital antithrombin deficiency.
• Evaluating coagulation parameters in patients with congenital antithrombin deficiency undergoing surgical procedures or parturition.
• Assessing the safety and tolerability of Atenativ in patients with congenital antithrombin deficiency.

The clinical trial involves a total of **18 participants** diagnosed with **congenital antithrombin deficiency**. The study population includes both male and female subjects, with an age range primarily between **18 and 80 years**. However, in the United States, a subset of 4 participants aged between **12 and 16 years** will be included in the pharmacokinetic phase and potentially the treatment phase. Participants were selected based on documented congenital antithrombin deficiency, defined by a plasma level of antithrombin ≤60%, and a personal or family history of thrombotic or thromboembolic events. The trial includes both surgical patients scheduled for elective procedures associated with a high risk of thrombotic events and pregnant patients at least 27 weeks gestational age scheduled for caesarean section or delivery. The study population is considered vulnerable, and informed consent was obtained from all participants. Lifestyle factors such as diet and physical activity were not specified in the trial data provided.

The clinical trial is designed as a **Phase III** study to evaluate the efficacy, safety, and pharmacokinetics of Atenativ in patients with **congenital antithrombin deficiency** undergoing surgery or delivery. This is a multicenter, prospective, open-label, uncontrolled study. The primary objective is to assess the incidence of thrombotic and thromboembolic events in patients treated with Atenativ during surgical procedures or parturition. The trial is expected to conclude by December 31, 2025, with recruitment having commenced on February 14, 2023.

Participants will be involved in the study for a maximum treatment period of 9 days, with the possibility of early termination if adverse events or other safety concerns arise. The study includes several key visits: an initial screening visit to confirm eligibility, followed by treatment visits where Atenativ is administered via **intravenous infusion**. Follow-up visits will monitor the incidence of thrombotic events and assess pharmacokinetic parameters such as area under the curve, maximum plasma concentration, and half-life. The end-of-study visit will evaluate the overall safety and efficacy outcomes, including adverse events and vital signs.

Inclusion criteria require participants to be adults aged 18 to 80 years, with documented congenital antithrombin deficiency and a history of thrombotic events. Specific criteria apply to surgical and pregnant patients, including a negative pregnancy test for females of childbearing potential. The primary endpoint is the incidence of thrombotic events up to 30 days post-treatment initiation. Secondary endpoints include pharmacokinetic parameters, antithrombin activity, coagulation parameters, and safety assessments. The study is not categorized as low intervention, and participation is contingent upon informed consent.

The clinical trial involves the administration of **Atenativ**, a pharmaceutical product containing **Antithrombin III Human** as the active substance. The product is available in various formulations, including "ATENATIV 50 UI/mL, poudre et solvant pour solution pour perfusion," "Atenativ 1000 I.E. Pulver und Lösungsmittel zur Herstellung einer Infusionslösung," and "Atenativ 1000 UI/20 ml polvere e solvente per soluzione per infusione endovenosa." These formulations are presented as a **solution for infusion** or **solution for injection/infusion**. The route of administration is **intravenous infusion**. The dosing regimen specifies a maximum daily dose of 140.2 IU/kg and a maximum total dose of 701 IU/kg over a treatment period not exceeding 9 days. The pharmaceutical form is consistent across all products, ensuring uniformity in administration and therapeutic effect.

The active substance, **Antithrombin III Human**, is derived from human plasma and classified under the ATC code B01AB02. It is a protein-based therapeutic agent used to manage patients with congenital antithrombin deficiency, particularly during surgical procedures or childbirth. The product is not formulated for pediatric use and is not classified as an orphan drug. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol and to evaluate the efficacy and safety of the treatment regimen.

The efficacy of Atenativ in patients with congenital **antithrombin deficiency** undergoing surgery or delivery will be assessed through a multicentre, prospective, open-label, uncontrolled Phase 3 study. The primary endpoint for evaluating efficacy is the incidence of the composite of Thrombotic Events (TEs) and Thromboembolic Events (TEEs) in patients treated with Atenativ, measured up to 30 days post-treatment initiation. Secondary endpoints include pharmacokinetic (PK) parameters such as area under the curve (AUCnorm(0–∞)), maximum plasma concentration (Cmax), half-life (t1/2), mean residence time (MRT), clearance (CL), incremental in vivo recovery (IVR), volume of distribution at steady state (Vss), and time to reach maximum plasma concentration (Tmax).

Additional efficacy parameters include antithrombin activity and coagulation parameters, specifically activated partial thromboplastin time (aPTT), prothrombin time (PT), international normalised ratio (INR), and fibrinogen levels. These parameters will be collected and analyzed using validated laboratory tests and scales at specified timepoints throughout the study. The study aims to provide comprehensive data on the efficacy of Atenativ in preventing thrombotic complications in this patient population.