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A Study in Participants With Acute Major Bleeding to Evaluate the Ability of Andexanet Alfa to Reverse the Anticoagulation Effect of Direct and Indirect Oral Anticoagulants (Extension Study)

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ClinicalTrials.gov Identifier: NCT02329327
Recruitment Status : Completed
First Posted : December 31, 2014
Results First Posted : February 16, 2022
Last Update Posted : February 16, 2022
Sponsor:
Collaborators:
Portola Pharmaceuticals, LLC (a wholly owned subsidiary of Alexion Pharmaceuticals)
Population Health Research Institute
Information provided by (Responsible Party):
Alexion

Study Description
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Brief Summary:
The purpose of this study was to evaluate the hemostatic efficacy of andexanet alfa (andexanet) in participants receiving a factor Xa (FXa) inhibitor (apixaban, rivaroxaban, edoxaban, enoxaparin) who were experiencing an acute major bleed. The safety of andexanet was also studied.

Condition or disease Intervention/treatment Phase
Bleeding Biological: Andexanet Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 479 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding (ANNEXA-4)
Actual Study Start Date : April 10, 2015
Actual Primary Completion Date : September 24, 2020
Actual Study Completion Date : September 24, 2020

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Andexanet
Participants received andexanet as an intravenous bolus administered over ~15 to 30 minutes, followed immediately by a continuous infusion administered over ~120 minutes.
 Biological: Andexanet
There were 2 possible dosing regimens: Low dose = 400 milligram (mg) bolus plus 4 mg/minute continuous infusion for 120 minutes; High dose = 800 mg bolus plus 8 mg/minute continuous infusion for 120 minutes.
Other Names:
  • ALXN2070
  • Andexanet Alfa
  • PRT064445
  • Andexxa


Outcome Measures
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Primary Outcome Measures :
  1. Percent Change From Baseline In Anti-fXa Activity By FXa Inhibitor [ Time Frame: Baseline, 12 Hours (post infusion) ]
    Anti-fXa activity was measured to assess the ability of andexanet to reverse the anticoagulant effect of FXa inhibitors. Baseline was defined as the last value obtained prior to the start of the andexanet bolus. The change from baseline was calculated as the reduction in anti-fXa activity from baseline to the on-treatment nadir (that is, the minimum value between end of bolus and end of infusion). Percent reduction was calculated as the ratio between the maximum change from baseline and the baseline value, multiplied by 100.

  2. Participants Achieving Hemostatic Efficacy [ Time Frame: 12 Hours (post infusion) ]
    Hemostatic efficacy was achieved when the body had time to produce thrombin and a subsequent clot and was rated by the EAC as: excellent; good; poor/none; not evaluable due to non-administrative reasons; not evaluable due to administrative reasons. These ratings were based on pre-specified criteria that were included in the EAC Charter. The EAC was blinded to anti-fXa activity levels. Participant results were classified as either success or failure based on the hemostatic efficacy rating (success = excellent/good, failure = poor/none). Participants rated by the EAC as non-evaluable due to administrative reasons were excluded from the analysis of hemostatic efficacy.


Secondary Outcome Measures :
  1. Percent Change From Baseline In Anti-fXa Activity By Hemostatic Efficacy [ Time Frame: Baseline, 12 Hours (post infusion) ]
    This outcome measure assessed the relationship between hemostatic efficacy and anti-fXa activity in participants receiving an FXa inhibitor who had acute major bleeding. Anti-fXa activity was measured to assess the ability of andexanet to reverse the anticoagulant effect of FXa inhibitors. Baseline was defined as the last value obtained prior to the start of the andexanet bolus. Hemostatic efficacy was achieved when the body had time to produce thrombin and a subsequent clot and was rated by the EAC as: excellent; good; poor/none; not evaluable due to non-administrative reasons; not evaluable due to administrative reasons.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  1. Acute major bleeding episode that required urgent reversal of anticoagulation; defined by at least one of the following:

    • Acute bleeding that was potentially life-threatening, or
    • Acute bleeding associated with a fall in hemoglobin level by ≥2 grams/deciliter (g/dL), or
    • Acute bleeding associated with a hemoglobin level of ≤8 g/dL if no baseline hemoglobin was available, or
    • Acute bleeding in a critical area or organ such as intraspinal, pericardial, or intracranial.
  2. If bleeding was intracranial or intraspinal, the participant must have undergone a head computed tomography (CT) or magnetic resonance imaging (MRI) scan demonstrating the bleeding.
  3. Participant received or was believed to have received one of the following within 18 hours prior to andexanet administration: apixaban, rivaroxaban, edoxaban, or enoxaparin.
  4. For participants with intracranial bleeding, there must be a reasonable expectation that andexanet treatment will commence within 2 hours of the baseline imaging evaluation.

Key Exclusion Criteria:

  1. The participant was scheduled to undergo surgery in less than 12 hours, with the exception of minimally invasive surgery/procedures.

  2. Participant with an intracerebral hemorrhage that had any of the following:

    • Glasgow coma score <7, or
    • Intracerebral hematoma >60 cubic centimeters as assessed by CT or MRI
  3. Participants with visible, musculoskeletal or intra-articular bleeding as their qualifying bleed.
  4. Expected survival of less than 1 month.
  5. Recent history (within 2 weeks) of a diagnosed thrombotic event as follows: venous thromboembolism, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris hospitalization or severe peripheral vascular disease within 2 weeks prior to Screening.
  6. Severe sepsis or septic shock at the time of Screening.
  7. Pregnant or a lactating female.

  8. Participant received any of the following drugs or blood products within 7 days of Screening:

    • Vitamin K antagonist
    • Dabigatran
    • Prothrombin Complex Concentrate (PCC) products or recombinant factor VIIa (rfVIIa)
    • Whole blood, plasma fractions
  9. Treated with an investigational drug <30 days prior to Screening.
  10. Planned administration of PCC, fresh frozen plasma or rfVIIa from Screening until within 12 hours after the end of the andexanet infusion.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02329327


Locations
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Sponsors and Collaborators
Alexion
Portola Pharmaceuticals, LLC (a wholly owned subsidiary of Alexion Pharmaceuticals)
Population Health Research Institute
  Study Documents (Full-Text)

Documents provided by Alexion:
Study Protocol  [PDF] November 30, 2018
Statistical Analysis Plan  [PDF] June 30, 2020

More Information
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Additional Information:

Publications of Results:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Alexion
ClinicalTrials.gov Identifier: NCT02329327    
Other Study ID Numbers: 14-505
First Posted: December 31, 2014    Key Record Dates
Results First Posted: February 16, 2022
Last Update Posted: February 16, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alexion:
Factor Xa Inhibitors
Major
Bleeding
Anticoagulant
 Major Bleeding
Andexanet Alfa
Reversal Agent
Additional relevant MeSH terms:
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Hemorrhage
Pathologic Processes