A Randomized Study of Andexanet Alfa Compared to Usual Care in Patients Receiving a Factor Xa Inhibitor who Require Urgent Surgery or Procedure (ANNEXA-RS)

The primary objective of this study is to evaluate the efficacy of **andexanet alfa** in achieving effective intraoperative hemostasis compared to usual care in patients who are on a Factor Xa inhibitor and require urgent surgery or procedure. This is clinically relevant as it addresses the critical need for rapid reversal of anticoagulation in situations where patients are at a major risk of bleeding, thereby potentially reducing surgical complications and improving patient outcomes.

Secondary objectives include:

• Assessing the ability of andexanet to rapidly reverse the anticoagulation effect of FXa inhibitors by reducing anti-FXa activity at the start of surgery or procedure compared to usual care.
• Evaluating the ability of andexanet to sustainably reverse the anticoagulation effect of FXa inhibitors by reducing anti-FXa activity at 2 hours post the start of surgery or procedure compared to usual care.

The clinical trial involves a total of **554 participants** who are undergoing a study to assess the ability of andexanet to achieve effective intraoperative hemostasis in comparison to usual care. The study population includes both **male and female subjects** and spans an **age range** that corresponds to categories 3 and 4, which typically include adults and older adults. Participants are selected based on their requirement for urgent surgery or procedure due to the reversal of anticoagulation effects from FXa inhibitors such as apixaban, rivaroxaban, or edoxaban, with a major risk of bleeding. The trial includes individuals who have taken an oral FXa inhibitor within 15 hours prior to the start of surgery or procedure. The study population is characterized by a **vulnerable population** selection, indicating that participants may have specific health considerations or risks. Female participants of childbearing potential are required to have a negative pregnancy test at screening and must agree to use highly effective methods of contraception. The trial does not specify particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants are those who require urgent medical intervention with a high risk of bleeding, thereby focusing on a specific and clinically relevant group.

The clinical trial is designed to evaluate the efficacy of **andexanet alfa** in achieving effective intraoperative hemostasis compared to usual care in patients who are on a **Factor Xa inhibitor** and require urgent surgery or procedures. This is a randomized, double-blind, controlled trial, which is expected to run from December 2023 to November 2026. The trial will involve multiple study visits, starting with an inclusion visit where participants will be screened based on specific criteria, including the need for urgent surgery within 12 hours and recent intake of a **Factor Xa inhibitor** such as **apixaban**, **rivaroxaban**, or **edoxaban**. Female participants of childbearing potential must have a negative pregnancy test at screening and agree to use effective contraception.

Participants will be randomly assigned to receive either **andexanet alfa** or usual care. The primary endpoint is effective intraoperative hemostasis, while secondary endpoints include changes in anti-FXa activity from baseline to the start of surgery and two hours post-surgery. Follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse events. The end-of-study visit will conclude the trial, assessing the overall outcomes and safety of the intervention.

The expected length of participant involvement is approximately one year, with the possibility of early termination if the participant experiences significant adverse effects, withdraws consent, or if the investigator deems it necessary for the participant's safety. The trial aims to provide valuable insights into the management of bleeding risks in patients requiring urgent surgical interventions while on **Factor Xa inhibitors**.

The clinical trial involves the administration of **Andexanet Alfa**, marketed as Ondexxya, which is a powder for solution for infusion. The active substance, **andexanet alfa**, is a protein used to reverse the anticoagulant effects of Factor Xa inhibitors. The pharmaceutical form is a solution for infusion, and it is administered via **intravenous infusion**. The dosing schedule and participant compliance are monitored according to the study protocol, with a maximum treatment period of one day.

**Rivaroxaban** is included as a comparator treatment in the study. It is a chemical substance used as an oral anticoagulant, classified under Factor Xa inhibitors. The pharmaceutical form is denoted as PHF00082MIG, and it is administered orally. The maximum daily dose is 30 mg, with a total dose not exceeding 30 mg per day, over a treatment period of one day.

**Apixaban** is another Factor Xa inhibitor used in the study. It is administered orally in a pharmaceutical form identified as PHF00009MIG. The maximum daily and total dose is 20 mg, with a treatment period of one day. Participant compliance is monitored to ensure adherence to the dosing schedule.

**Edoxaban** is also utilized in the trial as a Factor Xa inhibitor. It is administered orally, with a pharmaceutical form of PHF00082MIG. The maximum daily and total dose is 60 mg, with a treatment period of one day. Compliance monitoring is conducted to ensure proper administration.

**Human Fibrinogen** is included in the study, with a pharmaceutical form of PHF00231MIG. The route of administration is unspecified, and the dosing schedule is determined by the study protocol. The maximum treatment period is one day.

**Etamsylate** is used in the trial, with a pharmaceutical form of PHF00231MIG. The route of administration is unspecified, and the dosing schedule is determined by the study protocol. The maximum treatment period is one day.

**Tranexamic Acid** is included in the study, with a pharmaceutical form of PHF00231MIG. The route of administration is unspecified, and the dosing schedule is determined by the study protocol. The maximum treatment period is one day.

**Protamine Hydrochloride** is used in the trial, with a pharmaceutical form of PHF00231MIG. The route of administration is unspecified, and the dosing schedule is determined by the study protocol. The maximum treatment period is one day.

**Aminocaproic Acid** is included in the study, with a pharmaceutical form of PHF00230MIG. The route of administration is unspecified, and the dosing schedule is determined by the study protocol. The maximum treatment period is one day.

**Aminomethylbenzoic Acid** is used in the trial, with a pharmaceutical form of PHF00245MIG. The route of administration is unspecified, and the dosing schedule is determined by the study protocol. The maximum treatment period is one day.

**Potassium Chloride** is included in the study, with a pharmaceutical form of PHF00230MIG. The route of administration is unspecified, and the dosing schedule is determined by the study protocol. The maximum treatment period is one day.

**Blood and Related Products** are utilized in the trial, with no specified pharmaceutical form or route of administration. The dosing schedule is determined by the study protocol, with a maximum treatment period of one day.

**Other Blood Products** are included in the study, with no specified pharmaceutical form or route of administration. The dosing schedule is determined by the study protocol, with a maximum treatment period of one day.

**Solvents and Diluting Agents, Including Irrigating Solutions** are used in the trial, with a pharmaceutical form of PHF00017MIG. The route of administration is unspecified, and the dosing schedule is determined by the study protocol. The maximum treatment period is one day.

**Blood Coagulation Factors** are included in the study, with a pharmaceutical form of PHF00190MIG. The route of administration is unspecified, and the dosing schedule is determined by the study protocol. The maximum treatment period is one day.

The efficacy of the clinical trial will be assessed by evaluating the ability of **andexanet alfa** to achieve effective intraoperative hemostasis compared to usual care. The primary endpoint for efficacy is the achievement of effective intraoperative hemostasis. Secondary endpoints include the change in anti-FXa activity from baseline to the start of surgery or procedure, and the change in anti-FXa activity from baseline to 2 hours post the start of surgery or procedure. These efficacy parameters will be measured and collected at specified timepoints, including baseline, the start of surgery or procedure, and 2 hours post the start of surgery or procedure. The analysis will focus on comparing the efficacy of andexanet alfa with usual care in patients who require urgent surgery or procedures and have been receiving a Factor Xa inhibitor.