Efficacy and Safety of Human Plasma-Derived Antithrombin in Heparin-Resistant Patients Undergoing Cardiopulmonary Bypass Cardiac Surgery

The primary objective of this study is to evaluate the efficacy of two different doses of **Atenativ**, versus placebo, in restoring and maintaining heparin responsiveness in adult patients undergoing cardiac surgery necessitating cardiopulmonary bypass (CPB). This is clinically relevant as **acquired antithrombin deficiency** can lead to heparin resistance, complicating anticoagulation management during surgery.

Secondary objectives include: - Assessing the amounts of further therapy containing antithrombin required for restoring heparin responsiveness before CPB and maintaining it during CPB. - Evaluating the effect of Atenativ on the coagulation parameter used for evaluating heparin resistance, namely the activated clotting time (ACT). - Investigating the capacity of Atenativ to modify the antithrombin plasma concentration. - Determining the impact of Atenativ on the intraoperative use of heparin following the infusion of Atenativ or placebo. - Identifying any requirement for frozen plasma (FP) or antithrombin concentrates for reasons other than restoring or maintaining heparin responsiveness, both intraoperatively and postoperatively. - Monitoring any intraoperative and postoperative use of other allogeneic blood products, coagulation factor concentrates, and other haemostatic-relevant therapies. - Measuring the volume of chest tube drainage and the need for reoperation due to bleeding. - Evaluating the safety of Atenativ. - Assessing any post-CPB requirement for additional therapy containing antithrombin to restore heparin responsiveness. - Observing the patient’s postoperative course, as assessed by the length of intensive care unit (ICU) stay.

The clinical trial involves a total of **62 participants** diagnosed with **Acquired Antithrombin Deficiency (Heparin Resistance)**. The study population comprises both male and female adults aged between 18 and 85 years, who are scheduled for cardiac surgery requiring cardiopulmonary bypass (CPB). Participants were selected based on their heparin resistance, specifically those with a pre-CPB Hemochron ACT of less than 480 seconds following intravenous administration of 500 U/kg BW UFH. The trial includes individuals who have provided freely given written or electronic informed consent. Female participants of childbearing potential were required to have a negative pregnancy test within 14 days prior to surgery. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial population includes a vulnerable population, indicating additional ethical considerations in the study design.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of human plasma-derived **antithrombin** (Atenativ) in patients with **acquired antithrombin deficiency** undergoing cardiac surgery requiring cardiopulmonary bypass. The trial aims to assess the ability of Atenativ to restore and maintain heparin responsiveness in these patients. The study will involve multiple centers and is expected to commence recruitment on October 21, 2024, with an estimated completion date of December 30, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as planned cardiac surgery with cardiopulmonary bypass, heparin resistance, and age between 18 and 85 years. Following the screening, eligible participants will be randomized to receive either Atenativ or a placebo. The primary endpoint is the percentage of patients who do not require additional antithrombin therapy to restore and maintain heparin responsiveness during surgery. Secondary endpoints include comparisons of antithrombin levels, heparin usage, and postoperative outcomes.

The trial will include follow-up visits to monitor safety and efficacy outcomes, with assessments of adverse events, hematological parameters, and survival status. The end-of-study visit will occur either at discharge or seven days post-surgery, whichever comes first. Participant involvement is expected to last from the start of the Atenativ or placebo infusion until the end of the follow-up period. Conditions that may lead to early termination from the study include withdrawal of consent or the occurrence of significant adverse events.

The clinical trial involves the administration of **Atenativ**, a human plasma-derived **antithrombin III**. Atenativ is provided in various formulations, including a 50 IU/ml powder and solvent for solution for infusion, a 1000 I.E. powder and solvent for injection or infusion, and a 500 I.E. powder and solvent for injection or infusion. The pharmaceutical form is primarily a solution for infusion, with some formulations also suitable for injection. The active substance, antithrombin III human, is a protein derived from human plasma. The maximum daily and total dose is 30 IU/kg, administered intravenously. The treatment period is limited to one day. Atenativ is manufactured by Octapharma and is not a paediatric formulation or an orphan drug.

In addition to Atenativ, the trial utilizes **Isotone Natriumchloridlösung 0.9% Braun**, a sodium chloride solution for injection, produced by B.Braun Melsungen AG. This solution serves as a chemical solvent and diluting agent, classified under ATC code V07AB. It is administered intravenously with a maximum daily and total dose of 0.6 ml/kg, also limited to a one-day treatment period. The sodium chloride solution is used to maintain isotonicity and is not considered an experimental treatment in this study.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The trial is designed to evaluate the efficacy of Atenativ in restoring and maintaining heparin responsiveness in adult patients undergoing cardiac surgery with cardiopulmonary bypass, compared to a placebo. The study is conducted in a double-blind, placebo-controlled, multicentre setting to ensure the reliability and validity of the results.

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary efficacy endpoint is the percentage of patients in each group who do not require further therapy containing **antithrombin** to restore and maintain heparin responsiveness during cardiopulmonary bypass (CPB) after administration of Atenativ or placebo. Secondary endpoints include comparisons of the amounts of additional antithrombin therapy needed, changes in activated clotting time (ACT) values, changes in antithrombin plasma levels, and heparin usage following the infusion of Atenativ or placebo. Additional secondary endpoints involve the comparison of transfusion requirements for fresh plasma (FP) and other allogeneic blood products, administration of coagulation factor concentrates, and other haemostatic-relevant therapies both intraoperatively and postoperatively. The trial will also evaluate postoperative chest tube drainage volume, the need for reoperation due to bleeding, cell saver volume, incidence of adverse events (AEs), standard haematological parameters, survival status, and length of ICU stay.