Clinical trial NCT02329327: 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)
Official title: Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding (ANNEXA-4)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Bleeding
Keywords: Factor Xa Inhibitors
Major
Bleeding
Anticoagulant
Major Bleeding
Andexanet Alfa
Reversal Agent
Lead sponsor: Alexion Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Portola Pharmaceuticals, LLC (a wholly owned subsidiary of Alexion Pharmaceuticals)
name: Population Health Research Institute
First posted: 2014-12-31
Enrollment: 479
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.


Eligibility 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.

Primary outcomes:
measure: Percent Change From Baseline In Anti-fXa Activity By FXa Inhibitor
timeFrame: Baseline, 12 Hours (post infusion)
measure: Participants Achieving Hemostatic Efficacy
timeFrame: 12 Hours (post infusion)
Secondary outcomes:
measure: Percent Change From Baseline In Anti-fXa Activity By Hemostatic Efficacy
timeFrame: Baseline, 12 Hours (post infusion)
Other outcomes:
Locations:
city: Long Beach
country: United States
facility: Clinical Study Site
state: California
city: Los Angeles
country: United States
facility: Clinical Study Site
state: California
city: Orange
country: United States
facility: Clinical Study Site
state: California
city: Fort Lauderdale
country: United States
facility: Clinical Study Site
state: Florida
city: Jacksonville
country: United States
facility: Clinical Study Site
state: Florida
city: Sarasota
country: United States
facility: Clinical Study Site
state: Florida
city: Tampa
country: United States
facility: Clinical Study Site
state: Florida
city: Annapolis
country: United States
facility: Clinical Study Site
state: Maryland
city: Boston
country: United States
facility: Clinical Study Site
state: Massachusetts
city: Detroit
country: United States
facility: Clinical Study Site
state: Michigan
city: Royal Oak
country: United States
facility: Clinical Study Site
state: Michigan
city: Troy
country: United States
facility: Clinical Study Site
state: Michigan
city: Saint Louis
country: United States
facility: Clinical Study Site
state: Missouri
city: Rochester
country: United States
facility: Clinical Study Site
state: New York
city: Asheville
country: United States
facility: Clinical Study Site
state: North Carolina
city: Chapel Hill
country: United States
facility: Clinical Study Site
state: North Carolina
city: Raleigh
country: United States
facility: Clinical Study Site
state: North Carolina
city: Cincinnati
country: United States
facility: Clinical Study Site
state: Ohio
city: Cleveland
country: United States
facility: Clinical Study Site
state: Ohio
city: Pittsburgh
country: United States
facility: Clinical Study Site
state: Pennsylvania
city: Austin
country: United States
facility: Clinical Study Site
state: Texas
city: Fort Worth
country: United States
facility: Clinical Study Site
state: Texas
city: Huntington
country: United States
facility: Clinical Study Site
state: West Virginia
city: Bruxelles
country: Belgium
facility: Clinical Study Site
city: Genk
country: Belgium
facility: Clinical Study Site
city: Leuven
country: Belgium
facility: Clinical Study Site
city: Hamilton
country: Canada
facility: Clinical Study Site
state: Ontario
city: Montreal
country: Canada
facility: Clinical Study Site
state: Quebec
city: Clermont-Ferrand
country: France
facility: Clinical Study Site
city: Grenoble
country: France
facility: Clinical Study Site
city: Limoges
country: France
facility: Clinical Study Site
city: Lyon
country: France
facility: Clinical Study Site
city: Poitiers
country: France
facility: Clinical Study Site
city: Altenburg
country: Germany
facility: Clinical Study Site
city: Augsburg
country: Germany
facility: Clinical Study Site
city: Berlin
country: Germany
facility: Clinical Study Site
city: Bremen
country: Germany
facility: Clinical Study Site
city: Celle
country: Germany
facility: Clinical Study Site
city: Chemnitz
country: Germany
facility: Clinical Study Site
city: Coburg
country: Germany
facility: Clinical Study Site
city: Detmold
country: Germany
facility: Clinical Study Site
city: Dresden
country: Germany
facility: Clinical Study Site
city: Essen
country: Germany
facility: Clinical Study Site
city: Greifswald
country: Germany
facility: Clinical Study Site
city: Göttingen
country: Germany
facility: Clinical Study Site
city: Halle
country: Germany
facility: Clinical Study Site
city: Hamburg
country: Germany
facility: Clinical Study Site
city: Hannover
country: Germany
facility: Clinical Study Site
city: Heidelberg
country: Germany
facility: Clinical Study Site
city: Hessen
country: Germany
facility: Clinical Study Site
city: Jena
country: Germany
facility: Clinical Study Site
city: Konstanz
country: Germany
facility: Clinical Study Site
city: Leipzig
country: Germany
facility: Clinical Study Site
city: Lubeck
country: Germany
facility: Clinical Study Site
city: Ludwigshafen
country: Germany
facility: Clinical Study Site
city: Mainz
country: Germany
facility: Clinical Study Site
city: Minden
country: Germany
facility: Clinical Study Site
city: Munich
country: Germany
facility: Clinical Study Site
city: Münster
country: Germany
facility: Clinical Study Site
city: Osnabrück
country: Germany
facility: Clinical Study Site
city: Regensburg
country: Germany
facility: Clinical Study Site
city: Sande
country: Germany
facility: Clinical Study Site
city: Trier
country: Germany
facility: Clinical Study Site
city: Tübingen
country: Germany
facility: Clinical Study Site
city: Ulm
country: Germany
facility: Clinical Study Site
city: Würzburg
country: Germany
facility: Clinical Study Site
city: Fukuoka
country: Japan
facility: Clinical Study Site
city: Gunma
country: Japan
facility: Clinical Study Site
city: Hiroshima
country: Japan
facility: Clinical Study Site
city: Ibaraki
country: Japan
facility: Clinical Study Site
city: Izumisano
country: Japan
facility: Clinical Study Site
city: Kobe
country: Japan
facility: Clinical Study Site
city: Kumamoto
country: Japan
facility: Clinical Study Site
city: Nagoya
country: Japan
facility: Clinical Study Site
city: Sendai
country: Japan
facility: Clinical Study Site
city: Shiwa-gun
country: Japan
facility: Clinical Study Site
city: Suita
country: Japan
facility: Clinical Study Site
city: Tokyo
country: Japan
facility: Clinical Study Site
city: Yamaguchi
country: Japan
facility: Clinical Study Site
city: Yokosuka
country: Japan
facility: Clinical Study Site
city: Amsterdam
country: Netherlands
facility: Clinical Study Site
city: Barcelona
country: Spain
facility: Clinical Study Site
city: Caceres
country: Spain
facility: Clinical Study Site
city: Madrid
country: Spain
facility: Clinical Study Site
city: Cardiff
country: United Kingdom
facility: Clinical Study Site
city: London
country: United Kingdom
facility: Clinical Study Site
city: Stoke on Trent
country: United Kingdom
facility: Clinical Study Site
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.