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)

January 25, 2022 updated by: Alexion Pharmaceuticals

Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding (ANNEXA-4)

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

479

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Belgium
      • Bruxelles, Belgium
        • Clinical Study Site
      • Genk, Belgium
        • Clinical Study Site
      • Leuven, Belgium
        • Clinical Study Site
  • Canada
    • Ontario
      • Hamilton, Ontario, Canada
        • Clinical Study Site
    • Quebec
      • Montreal, Quebec, Canada
        • Clinical Study Site
  • France
      • Clermont-Ferrand, France
        • Clinical Study Site
      • Grenoble, France
        • Clinical Study Site
      • Limoges, France
        • Clinical Study Site
      • Lyon, France
        • Clinical Study Site
      • Poitiers, France
        • Clinical Study Site
  • Germany
      • Altenburg, Germany
        • Clinical Study Site
      • Augsburg, Germany
        • Clinical Study Site
      • Berlin, Germany
        • Clinical Study Site
      • Bremen, Germany
        • Clinical Study Site
      • Celle, Germany
        • Clinical Study Site
      • Chemnitz, Germany
        • Clinical Study Site
      • Coburg, Germany
        • Clinical Study Site
      • Detmold, Germany
        • Clinical Study Site
      • Dresden, Germany
        • Clinical Study Site
      • Essen, Germany
        • Clinical Study Site
      • Greifswald, Germany
        • Clinical Study Site
      • Göttingen, Germany
        • Clinical Study Site
      • Halle, Germany
        • Clinical Study Site
      • Hamburg, Germany
        • Clinical Study Site
      • Hannover, Germany
        • Clinical Study Site
      • Heidelberg, Germany
        • Clinical Study Site
      • Hessen, Germany
        • Clinical Study Site
      • Jena, Germany
        • Clinical Study Site
      • Konstanz, Germany
        • Clinical Study Site
      • Leipzig, Germany
        • Clinical Study Site
      • Lubeck, Germany
        • Clinical Study Site
      • Ludwigshafen, Germany
        • Clinical Study Site
      • Mainz, Germany
        • Clinical Study Site
      • Minden, Germany
        • Clinical Study Site
      • Munich, Germany
        • Clinical Study Site
      • Münster, Germany
        • Clinical Study Site
      • Osnabrück, Germany
        • Clinical Study Site
      • Regensburg, Germany
        • Clinical Study Site
      • Sande, Germany
        • Clinical Study Site
      • Trier, Germany
        • Clinical Study Site
      • Tübingen, Germany
        • Clinical Study Site
      • Ulm, Germany
        • Clinical Study Site
      • Würzburg, Germany
        • Clinical Study Site
  • Japan
      • Fukuoka, Japan
        • Clinical Study Site
      • Gunma, Japan
        • Clinical Study Site
      • Hiroshima, Japan
        • Clinical Study Site
      • Ibaraki, Japan
        • Clinical Study Site
      • Izumisano, Japan
        • Clinical Study Site
      • Kobe, Japan
        • Clinical Study Site
      • Kumamoto, Japan
        • Clinical Study Site
      • Nagoya, Japan
        • Clinical Study Site
      • Sendai, Japan
        • Clinical Study Site
      • Shiwa-gun, Japan
        • Clinical Study Site
      • Suita, Japan
        • Clinical Study Site
      • Tokyo, Japan
        • Clinical Study Site
      • Yamaguchi, Japan
        • Clinical Study Site
      • Yokosuka, Japan
        • Clinical Study Site
  • Netherlands
      • Amsterdam, Netherlands
        • Clinical Study Site
  • Spain
      • Barcelona, Spain
        • Clinical Study Site
      • Caceres, Spain
        • Clinical Study Site
      • Madrid, Spain
        • Clinical Study Site
  • United Kingdom
      • Cardiff, United Kingdom
        • Clinical Study Site
      • London, United Kingdom
        • Clinical Study Site
      • Stoke on Trent, United Kingdom
        • Clinical Study Site
  • United States
    • California
      • Long Beach, California, United States
        • Clinical Study Site
      • Los Angeles, California, United States
        • Clinical Study Site
      • Orange, California, United States
        • Clinical Study Site
    • Florida
      • Fort Lauderdale, Florida, United States
        • Clinical Study Site
      • Jacksonville, Florida, United States
        • Clinical Study Site
      • Sarasota, Florida, United States
        • Clinical Study Site
      • Tampa, Florida, United States
        • Clinical Study Site
    • Maryland
      • Annapolis, Maryland, United States
        • Clinical Study Site
    • Massachusetts
      • Boston, Massachusetts, United States
        • Clinical Study Site
    • Michigan
      • Detroit, Michigan, United States
        • Clinical Study Site
      • Royal Oak, Michigan, United States
        • Clinical Study Site
      • Troy, Michigan, United States
        • Clinical Study Site
    • Missouri
      • Saint Louis, Missouri, United States
        • Clinical Study Site
    • New York
      • Rochester, New York, United States
        • Clinical Study Site
    • North Carolina
      • Asheville, North Carolina, United States
        • Clinical Study Site
      • Chapel Hill, North Carolina, United States
        • Clinical Study Site
      • Raleigh, North Carolina, United States
        • Clinical Study Site
    • Ohio
      • Cincinnati, Ohio, United States
        • Clinical Study Site
      • Cleveland, Ohio, United States
        • Clinical Study Site
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States
        • Clinical Study Site
    • Texas
      • Austin, Texas, United States
        • Clinical Study Site
      • Fort Worth, Texas, United States
        • Clinical Study Site
    • West Virginia
      • Huntington, West Virginia, United States
        • Clinical Study Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Baseline, 12 Hours (post infusion)
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.
12 Hours (post infusion)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Baseline, 12 Hours (post infusion)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Alexion Pharmaceuticals

Collaborators

Population Health Research Institute
Portola Pharmaceuticals, LLC (a wholly owned subsidiary of Alexion Pharmaceuticals)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 10, 2015

Primary Completion (Actual)

September 24, 2020

Study Completion (Actual)

September 24, 2020

Study Registration Dates

First Submitted

December 18, 2014

First Submitted That Met QC Criteria

December 30, 2014

First Posted (Estimate)

December 31, 2014

Study Record Updates

Last Update Posted (Actual)

February 16, 2022

Last Update Submitted That Met QC Criteria

January 25, 2022

Last Verified

January 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 14-505

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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