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)

NCT02329327 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: 14-505
• Study Type: interventional
• Target: 479
• Locations: 9 countries
• Sites: 87

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.

Conditions

Bleeding

Keywords

Factor Xa Inhibitors; Major; Bleeding; Anticoagulant; Major Bleeding; Andexanet Alfa; Reversal Agent

Outcome Measures

Primary Outcomes (2)

• Percent Change From Baseline In Anti-fXa Activity By FXa Inhibitor

  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

  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 Outcomes (1)

• Percent Change From Baseline In Anti-fXa Activity By Hemostatic Efficacy

  Baseline, 12 Hours (post infusion)

Study Arms (1)

Andexanet

EXPERIMENTAL

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

Interventions

Andexanet BIOLOGICAL

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.

Also known as: ALXN2070, Andexanet Alfa, PRT064445, Andexxa

Andexanet

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.
• Participant received or was believed to have received one of the following within 18 hours prior to andexanet administration: apixaban, rivaroxaban, edoxaban, or enoxaparin.
• For participants with intracranial bleeding, there must be a reasonable expectation that andexanet treatment will commence within 2 hours of the baseline imaging evaluation.

You may not qualify if:

• The participant was scheduled to undergo surgery in less than 12 hours, with the exception of minimally invasive surgery/procedures.
• 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
• Participants with visible, musculoskeletal or intra-articular bleeding as their qualifying bleed.
• Expected survival of less than 1 month.
• 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.
• Severe sepsis or septic shock at the time of Screening.
• Pregnant or a lactating female.
• 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
• Treated with an investigational drug \<30 days prior to Screening.

Sponsors & Collaborators

• Alexion Pharmaceuticals, Inc.: lead
• Portola Pharmaceuticals, LLC (a wholly owned subsidiary of Alexion Pharmaceuticals): collaborator
• Population Health Research Institute: collaborator

Study Sites (87)

Clinical Study Site

Long Beach, California, United States

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Los Angeles, California, United States

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Orange, California, United States

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Fort Lauderdale, Florida, United States

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Jacksonville, Florida, United States

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Sarasota, Florida, United States

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Tampa, Florida, United States

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Annapolis, Maryland, United States

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Boston, Massachusetts, United States

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Detroit, Michigan, United States

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Royal Oak, Michigan, United States

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Troy, Michigan, United States

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St Louis, Missouri, United States

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Rochester, New York, United States

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Asheville, North Carolina, United States

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Chapel Hill, North Carolina, United States

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Raleigh, North Carolina, United States

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Cincinnati, Ohio, United States

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Cleveland, Ohio, United States

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Pittsburgh, Pennsylvania, United States

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Austin, Texas, United States

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Fort Worth, Texas, United States

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Huntington, West Virginia, United States

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Brussels, Belgium

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Genk, Belgium

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Leuven, Belgium

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Hamilton, Ontario, Canada

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Montreal, Quebec, Canada

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Clermont-Ferrand, France

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Grenoble, France

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Limoges, France

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Lyon, France

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Poitiers, France

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Altenburg, Germany

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Augsburg, Germany

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Berlin, Germany

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Bremen, Germany

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Celle, Germany

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Chemnitz, Germany

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Coburg, Germany

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Detmold, Germany

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Dresden, Germany

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Essen, Germany

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Göttingen, Germany

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Greifswald, Germany

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Halle, Germany

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Hamburg, Germany

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Hanover, Germany

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Heidelberg, Germany

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Hessen, Germany

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Jena, Germany

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Konstanz, Germany

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Leipzig, Germany

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Ludwigshafen, Germany

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Lübeck, Germany

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Mainz, Germany

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Minden, Germany

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Munich, Germany

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Münster, Germany

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Osnabrück, Germany

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Regensburg, Germany

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Sande, Germany

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Trier, Germany

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Tübingen, Germany

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Ulm, Germany

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Würzburg, Germany

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Fukuoka, Japan

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Gunma, Japan

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Hiroshima, Japan

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Ibaraki, Japan

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Izumisano, Japan

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Kobe, Japan

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Kumamoto, Japan

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Nagoya, Japan

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Sendai, Japan

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Shiwa-gun, Japan

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Suita, Japan

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Tokyo, Japan

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Yamaguchi, Japan

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Yokosuka, Japan

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Amsterdam, Netherlands

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Barcelona, Spain

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Cáceres, Spain

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Madrid, Spain

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Cardiff, United Kingdom

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London, United Kingdom

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Stoke-on-Trent, United Kingdom

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Related Publications (7)

• Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Goodman S, Leeds J, Wiens BL, Siegal DM, Zotova E, Meeks B, Nakamya J, Lim WT, Crowther M; ANNEXA-4 Investigators. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016 Sep 22;375(12):1131-41. doi: 10.1056/NEJMoa1607887. Epub 2016 Aug 30.

  PMID: 27573206 RESULT

• Birocchi S, Fiorelli EM, Podda GM. Andexanet Alfa for Factor Xa Inhibitor Reversal. N Engl J Med. 2016 Dec 22;375(25):2498-9. doi: 10.1056/NEJMc1613270. No abstract available.

  PMID: 28009495 RESULT

• Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, Yue P, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Demchuk AM, Pallin DJ, Concha M, Goodman S, Leeds J, Souza S, Siegal DM, Zotova E, Meeks B, Ahmad S, Nakamya J, Milling TJ Jr; ANNEXA-4 Investigators. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2019 Apr 4;380(14):1326-1335. doi: 10.1056/NEJMoa1814051. Epub 2019 Feb 7.

  PMID: 30730782 RESULT

• Milling TJ Jr, Middeldorp S, Xu L, Koch B, Demchuk A, Eikelboom JW, Verhamme P, Cohen AT, Beyer-Westendorf J, Gibson CM, Lopez-Sendon J, Crowther M, Shoamanesh A, Coppens M, Schmidt J, Albaladejo P, Connolly SJ; ANNEXA-4 Investigators. Final Study Report of Andexanet Alfa for Major Bleeding With Factor Xa Inhibitors. Circulation. 2023 Mar 28;147(13):1026-1038. doi: 10.1161/CIRCULATIONAHA.121.057844. Epub 2023 Feb 20.

  PMID: 36802876 DERIVED

• Costa OS, Connolly SJ, Sharma M, Beyer-Westendorf J, Christoph MJ, Lovelace B, Coleman CI. Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhage: a propensity score-overlap weighted analysis. Crit Care. 2022 Jun 16;26(1):180. doi: 10.1186/s13054-022-04043-8.

  PMID: 35710578 DERIVED

• Huttner HB, Gerner ST, Kuramatsu JB, Connolly SJ, Beyer-Westendorf J, Demchuk AM, Middeldorp S, Zotova E, Altevers J, Andersohn F, Christoph MJ, Yue P, Stross L, Schwab S. Hematoma Expansion and Clinical Outcomes in Patients With Factor-Xa Inhibitor-Related Atraumatic Intracerebral Hemorrhage Treated Within the ANNEXA-4 Trial Versus Real-World Usual Care. Stroke. 2022 Feb;53(2):532-543. doi: 10.1161/STROKEAHA.121.034572. Epub 2021 Oct 14.

  PMID: 34645283 DERIVED

• Demchuk AM, Yue P, Zotova E, Nakamya J, Xu L, Milling TJ Jr, Ohara T, Goldstein JN, Middeldorp S, Verhamme P, Lopez-Sendon JL, Conley PB, Curnutte JT, Eikelboom JW, Crowther M, Connolly SJ; ANNEXA-4 Investigators. Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage: ANNEXA-4 Substudy. Stroke. 2021 Jun;52(6):2096-2105. doi: 10.1161/STROKEAHA.120.030565. Epub 2021 May 10.

  PMID: 33966491 DERIVED

Related Links

• Neurocrit Care. 2019;31:S37
• Neurocrit Care. 2019;31:S222

MeSH Terms

Conditions

Hemorrhage

Interventions

PRT064445

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Alexion Pharmaceuticals, Inc.
• Organization: Alexion Pharmaceuticals, Inc.

clinicaltrials@alexion.com

+1.855.752.2356

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 18, 2014
• First Posted: December 31, 2014
• Study Start: April 10, 2015
• Primary Completion: September 24, 2020
• Study Completion: September 24, 2020
• Last Updated: February 16, 2022
• Results First Posted: February 16, 2022

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will share

Locations

FR (5); GB (3); CA (2); US (23); JP (14); BE (3); DE (33); ES (3); NL (1)