Surgery
Conditions
Keywords
Urgent Surgery, Thrombosis, Anticoagulant, Surgery, Surgical, Abdominal, Thoracic, Orthopedic, Gynecological, Laparoscopic, Neurosurgery, Gastrointestinal
Brief summary
Prospective, open-label clinical trial to evaluate the efficacy and safety of andexanet alfa patients who require urgent surgery that have been anticoagulated with the FXa (activated factor X) inhibitors.
Detailed description
This is a multicenter, prospective, open-label study to determine the efficacy and safety of andexanet in patients who require urgent surgery who have received 1 of the following FXa inhibitors: apixaban, rivaroxaban, edoxaban, or enoxaparin. The start of surgery must be within 15 hours following the last dose of FXa inhibitor. The primary efficacy outcome will be adjudicated by an independent Endpoint Adjudication Committee.
Interventions
DRUGandexanet alfa
Andexanet is a recombinant version of human FXa
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 84 Years
Healthy volunteers
No
Inclusion criteria
All of the following criteria must be met for the patient to be eligible: * Either the patient or their medical proxy (or legal designee) has given written informed consent. * Age ≥ 18 and \< 85 years old. * Requires urgent surgical intervention that must occur within 12 hours of consent, for which reversal of anti-fXa activity is judged necessary. * Treatment with an oral FXa inhibitor (apixaban \[last dose 2.5 mg or greater\], rivaroxaban \[last dose 10 mg or greater\], edoxaban \[last dose 30 mg or greater\] or enoxaparin \[≥ 1 mg/kg/d\]): * ≤ 15 hours prior to start of surgery. * \> 15 hours prior to start of surgery or unknown time from the last dose, if documented anti fXa activity is \> 100 ng/mL (\> 0.5 IU/mL for enoxaparin, or over the equivalent IU/mL threshold on a low molecular weight heparin assay; see Laboratory Manual) within 2 hours prior to consent. Note: Patients enrolled in this manner should receive a high-andexanet dosing regimen. * Have a negative pregnancy test documented prior to enrollment (for women of childbearing potential). * Willingness to use highly effective methods of contraception through 30 days following study drug dose (for female and male patients who are fertile).
Exclusion criteria
If a patient meets any of the following criteria, he or she is not eligible: * Surgery for which the risk of clinically meaningful uncontrolled or unmanageable bleeding is low. * Acute life-threatening bleeding (ISTH criteria) at the time of Screening: 1. The patient has acute-overt bleeding that is potentially life-threatening, e.g., with signs or symptoms of hemodynamic compromise, such as severe hypotension, poor skin perfusion, mental confusion, low urine output that cannot be otherwise explained. 2. The patient has overt bleeding associated with a fall in hemoglobin level by ≥2g/dL, OR, a hemoglobin ≤8 g/dL if no baseline hemoglobin is available. 3. The patient has acute bleeding in a critical area or organ, such as pericardial, intracranial, or intraspinal. * Any surgical procedure that involves the intraoperative use of systemic, intravascular, unfractionated heparin. * Primary procedure for efficacy assessment is a non-surgical interventional procedure (e.g, lumbar puncture, skin biopsy, cardiac catheterization, endoscopic retrograde cholangio-pancreatography). * Expected survival of \< 1 month due to comorbidity. * Known Do Not Resuscitate order or similar advanced directive. * The patient has a recent history (within 30 days prior to screening) of a diagnosed TE as follows: venous thromboembolism (including deep vein thrombosis, pulmonary embolism, intracardiac thrombus), myocardial infarction (including asymptomatic troponin elevations), disseminated intravascular coagulation, acute traumatic coagulopathy, cerebrovascular accident, transient ischemic attack, unstable angina pectoris hospitalization, or severe peripheral vascular disease. * Acute decompensated heart failure or cardiogenic shock at the time of screening. * The patient has sepsis or septic or severe hemorrhagic shock at the time of Screening. * The patient has heparin-induced thrombocytopenia (with or without thrombosis). * Inherited coagulopathy (e.g., anti-phospholipid antibody syndrome, protein C/S deficiency, Factor V Leiden) at time of Screening. * Platelet count \< 80,000/µL at the time of Screening. * Last dose of apixaban \< 2.5 mg, rivaroxaban \< 10 mg, edoxaban \< 30 mg, or enoxaparin 40 mg. * The patient is pregnant or a lactating female. * The patient has received any of the following drugs or blood products within 7 days of enrollment: * Vitamin K antagonists (e.g., warfarin). * Dabigatran. * Prothrombin complex concentrate products (e.g., Kcentra®) or recombinant factor VIIa (e.g., NovoSeven®). * Whole blood, plasma fractions. Note: Administration of tranexamic acid, platelets or packed red blood cells is not an exclusion criterion. * The patient was treated with an investigational drug \< 30 days prior to Screening. * Prior treatment with andexanet. * Known hypersensitivity to any component of andexanet. * Known allergic reaction to hamster proteins. * Known or suspected (i.e., presumed positive) COVID-19-related illness at the time of Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving Effective Hemostasis | Hemostasis will be assessed from the start of surgery to the end of the procedure | Effective hemostasis is defined as excellent or good as assessed by the Investigator; Ineffective hemostasis is defined as moderate or poor as assessed by the Investigator. All data were prespecified to be collected as a single Arm/Group for any participant who received at least 1 dose of the study drug, regardless of their dose level. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline In Anti-fXa Activity To Treatment Nadir | Baseline, Treatment nadir (not to exceed a total of 6.5 hours of andexanet dosing) | Baseline is defined as the last non-missing value on or before first study drug administration. On treatment nadir is the minimum value of anti-fXa activity during the period of time from the end of the andexanet bolus to the end of the andexanet infusion. All data were prespecified to be collected as a single Arm/Group for any participant who received at least 1 dose of the study drug, regardless of their dose level. |
Countries
Austria, France, Germany, Israel, Japan, United States
Participant flow
Recruitment details
Participants who required urgent surgery and received factor Xa (fXa) inhibitors (apixaban, rivaroxaban, edoxaban, or enoxaparin) before surgery were enrolled in the study.
Pre-assignment details
This study is a single-arm study and all participants received 1 of 2 doses of andexanet based on the specific anticoagulant taken. All data were prespecified to be collected as a single Arm/Group for any participant who received at least 1 dose of the study drug, regardless of their dose level.
Participants by arm
| Arm | Count |
|---|---|
| Andexanet Alfa Participants received a dose of andexanet alfa based on the specific FXa inhibitor, dose, and time since the last dose (\<8 hours, ≥8 hours, or unknown). | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 5 |
Baseline characteristics
| Characteristic | Andexanet Alfa |
|---|---|
| Age, Continuous | 79.8 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 5 / 10 |
| other Total, other adverse events | 2 / 10 |
| serious Total, serious adverse events | 7 / 10 |
Outcome results
Primary
Number of Participants Achieving Effective Hemostasis
Effective hemostasis is defined as excellent or good as assessed by the Investigator; Ineffective hemostasis is defined as moderate or poor as assessed by the Investigator. All data were prespecified to be collected as a single Arm/Group for any participant who received at least 1 dose of the study drug, regardless of their dose level.
Time frame: Hemostasis will be assessed from the start of surgery to the end of the procedure
Population: Efficacy Set: Participants who underwent surgery and had a baseline anti-fXa activity of at least 75 nanograms (ng)/milliliter (mL) for participants receiving apixaban or rivaroxaban, 40 ng/mL for participants receiving edoxaban, and 0.25 international units (IU)/mL for participants on enoxaparin. All data were prespecified to be collected as a single Arm/Group for any participant who received at least 1 dose of the study drug, regardless of their dose level.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Andexanet Alfa | Number of Participants Achieving Effective Hemostasis | 6 Participants |
Secondary
Percent Change From Baseline In Anti-fXa Activity To Treatment Nadir
Baseline is defined as the last non-missing value on or before first study drug administration. On treatment nadir is the minimum value of anti-fXa activity during the period of time from the end of the andexanet bolus to the end of the andexanet infusion. All data were prespecified to be collected as a single Arm/Group for any participant who received at least 1 dose of the study drug, regardless of their dose level.
Time frame: Baseline, Treatment nadir (not to exceed a total of 6.5 hours of andexanet dosing)
Population: Efficacy Set: Participants who underwent surgery and had a baseline anti-fXa activity of at least 75 ng/mL for participants receiving apixaban or rivaroxaban, 40 ng/mL for participants receiving edoxaban, and 0.25 IU/mL for participants on enoxaparin. All data were prespecified to be collected as a single Arm/Group for any participant who received at least 1 dose of the study drug, regardless of their dose level.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Andexanet Alfa | Percent Change From Baseline In Anti-fXa Activity To Treatment Nadir | -96.13 Percent Change |