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)

Bleeding Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02329327
• Other study ID #: 14-505
• Status: Completed
• Phase: Phase 3
• Start date: April 10, 2015
• Est. completion date: September 24, 2020

Study information

• Verified date: January 2022
• Source: Alexion Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 479
• Est. completion date: September 24, 2020
• Est. primary completion date: September 24, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Bleeding
• Hemorrhage

Intervention

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.

Locations

Country	Name	City	State
Belgium	Clinical Study Site	Bruxelles
Belgium	Clinical Study Site	Genk
Belgium	Clinical Study Site	Leuven
Canada	Clinical Study Site	Hamilton	Ontario
Canada	Clinical Study Site	Montreal	Quebec
France	Clinical Study Site	Clermont-Ferrand
France	Clinical Study Site	Grenoble
France	Clinical Study Site	Limoges
France	Clinical Study Site	Lyon
France	Clinical Study Site	Poitiers
Germany	Clinical Study Site	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	Göttingen
Germany	Clinical Study Site	Greifswald
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
Japan	Clinical Study Site	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
Netherlands	Clinical Study Site	Amsterdam
Spain	Clinical Study Site	Barcelona
Spain	Clinical Study Site	Caceres
Spain	Clinical Study Site	Madrid
United Kingdom	Clinical Study Site	Cardiff
United Kingdom	Clinical Study Site	London
United Kingdom	Clinical Study Site	Stoke on Trent
United States	Clinical Study Site	Annapolis	Maryland
United States	Clinical Study Site	Asheville	North Carolina
United States	Clinical Study Site	Austin	Texas
United States	Clinical Study Site	Boston	Massachusetts
United States	Clinical Study Site	Chapel Hill	North Carolina
United States	Clinical Study Site	Cincinnati	Ohio
United States	Clinical Study Site	Cleveland	Ohio
United States	Clinical Study Site	Detroit	Michigan
United States	Clinical Study Site	Fort Lauderdale	Florida
United States	Clinical Study Site	Fort Worth	Texas
United States	Clinical Study Site	Huntington	West Virginia
United States	Clinical Study Site	Jacksonville	Florida
United States	Clinical Study Site	Long Beach	California
United States	Clinical Study Site	Los Angeles	California
United States	Clinical Study Site	Orange	California
United States	Clinical Study Site	Pittsburgh	Pennsylvania
United States	Clinical Study Site	Raleigh	North Carolina
United States	Clinical Study Site	Rochester	New York
United States	Clinical Study Site	Royal Oak	Michigan
United States	Clinical Study Site	Saint Louis	Missouri
United States	Clinical Study Site	Sarasota	Florida
United States	Clinical Study Site	Tampa	Florida
United States	Clinical Study Site	Troy	Michigan

Sponsors (3)

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

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  France,  Germany,  Japan,  Netherlands,  Spain,  United Kingdom, 

References & Publications (3)

Birocchi S, Fiorelli EM, Podda GM. Andexanet Alfa for Factor Xa Inhibitor Reversal. N Engl J Med. 2016 Dec 22;375(25):2498-9. — View 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, Le — View 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, Meek — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	Percent Change From Baseline In Anti-fXa Activity By Hemostatic Efficacy	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)

External Links

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