BleedingPhase 3NCT02329327

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)

A Phase 3 study testing Andexanet in people with Bleeding, run by Alexion Pharmaceuticals, Inc. at 87 sites in 9 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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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. Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Bleeding
What is being tested?: Andexanet
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 479 participants
Where: 87 sitesin 9 countries
Study dates: 10 Apr 2015to 24 Sep 2020
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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.

Who cannot join

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.

Show all 16Show fewer

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.
Planned administration of PCC, fresh frozen plasma or rfVIIa from Screening until within 12 hours after the end of the andexanet infusion.

Trial locations and contacts

87 sites in 9 countries.

Country

City, postcode or hospital

87 sites in 9 countries

Germany33 sites

Clinical Study Site
Altenburg
Clinical Study Site
Augsburg
Clinical Study Site
Berlin
Clinical Study Site
Bremen
Clinical Study Site
Celle
Clinical Study Site
Chemnitz
Clinical Study Site
Coburg
Clinical Study Site
Detmold
Clinical Study Site
Dresden
Clinical Study Site
Essen
Clinical Study Site
Göttingen
Clinical Study Site
Greifswald
Clinical Study Site
Halle
Clinical Study Site
Hamburg
Clinical Study Site
Hanover
Clinical Study Site
Heidelberg
Clinical Study Site
Hessen
Clinical Study Site
Jena
Clinical Study Site
Konstanz
Clinical Study Site
Leipzig
Clinical Study Site
Lübeck
Clinical Study Site
Ludwigshafen
Clinical Study Site
Mainz
Clinical Study Site
Minden
Clinical Study Site
Munich
Clinical Study Site
Münster
Clinical Study Site
Osnabrück
Clinical Study Site
Regensburg
Clinical Study Site
Sande
Clinical Study Site
Trier
Clinical Study Site
Tübingen
Clinical Study Site
Ulm
Clinical Study Site
Würzburg

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United States23 sites

Clinical Study Site
Annapolis, Maryland
Clinical Study Site
Asheville, North Carolina
Clinical Study Site
Austin, Texas
Clinical Study Site
Boston, Massachusetts
Clinical Study Site
Chapel Hill, North Carolina
Clinical Study Site
Cincinnati, Ohio
Clinical Study Site
Cleveland, Ohio
Clinical Study Site
Detroit, Michigan
Clinical Study Site
Fort Lauderdale, Florida
Clinical Study Site
Fort Worth, Texas
Clinical Study Site
Huntington, West Virginia
Clinical Study Site
Jacksonville, Florida
Clinical Study Site
Long Beach, California
Clinical Study Site
Los Angeles, California
Clinical Study Site
Orange, California
Clinical Study Site
Pittsburgh, Pennsylvania
Clinical Study Site
Raleigh, North Carolina
Clinical Study Site
Rochester, New York
Clinical Study Site
Royal Oak, Michigan
Clinical Study Site
Sarasota, Florida
Clinical Study Site
St Louis, Missouri
Clinical Study Site
Tampa, Florida
Clinical Study Site
Troy, Michigan

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Japan14 sites

Clinical Study Site
Fukuoka
Clinical Study Site
Gunma
Clinical Study Site
Hiroshima
Clinical Study Site
Ibaraki
Clinical Study Site
Izumisano
Clinical Study Site
Kobe
Clinical Study Site
Kumamoto
Clinical Study Site
Nagoya
Clinical Study Site
Sendai
Clinical Study Site
Shiwa-gun
Clinical Study Site
Suita
Clinical Study Site
Tokyo
Clinical Study Site
Yamaguchi
Clinical Study Site
Yokosuka

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France5 sites

Clinical Study Site
Clermont-Ferrand
Clinical Study Site
Grenoble
Clinical Study Site
Limoges
Clinical Study Site
Lyon
Clinical Study Site
Poitiers

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Belgium3 sites

Clinical Study Site
Brussels
Clinical Study Site
Genk
Clinical Study Site
Leuven

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Spain3 sites

Clinical Study Site
Barcelona
Clinical Study Site
Cáceres
Clinical Study Site
Madrid

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United Kingdom3 sites

Clinical Study Site
Cardiff
Clinical Study Site
London
Clinical Study Site
Stoke-on-Trent

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Canada2 sites

Clinical Study Site
Hamilton, Ontario
Clinical Study Site
Montreal, Quebec

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Netherlands1 site

Clinical Study Site
Amsterdam

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About this study

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

Conditions: Bleeding
Being tested: Andexanet
Keywords: Factor Xa Inhibitors, Major, Bleeding, Anticoagulant, Major Bleeding, Andexanet Alfa, Reversal Agent
Medical subject headings: Hemorrhage

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

AndexanetBiological
Also called ALXN2070, Andexanet Alfa, PRT064445, Andexxa
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.

Study groups in NCT02329327
Study group	Role	What they receive
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. Receives: Biological: Andexanet

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: 12 Hours (post infusion)

Secondary outcomes (1)

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.
Measured: Baseline, 12 Hours (post infusion)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

10 Apr 201524 Sep 2020

First posted31 Dec 2014 (estimated)
Study start10 Apr 2015
Primary completion24 Sep 2020
Study completion24 Sep 2020

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (8)Papers the sponsor has linked to this study.
Other trials for BleedingStudies of the same condition, open and under way.
More trials run by Alexion Pharmaceuticals, Inc.The sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Other
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrolment: 479 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02329327
Sponsor's protocol ID: 14-505
Status last verified: Jan 2022
First submitted: 18 Dec 2014
Last updated: 16 Feb 2022
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes

Publications

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.
PubMed 27573206
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.
PubMed 28009495
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.
PubMed 30730782
Siepen BM, Polymeris A, Shoamanesh A, Connolly S, Steiner T, Poli S, Lemmens R, Goeldlin MB, Muller M, Branca M, Rauch J, Meinel T, Kaesmacher J, Z'Graggen W, Arnold M, Fischer U, Peters N, Engelter ST, Lyrer P, Seiffge D. Andexanet alfa versus non-specific treatments for intracerebral hemorrhage in patients taking factor Xa inhibitors - Individual patient data analysis of ANNEXA-4 and TICH-NOAC. Int J Stroke. 2024 Jun;19(5):506-514. doi: 10.1177/17474930241230209. Epub 2024 Mar 8.
PubMed 38264861
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.
PubMed 36802876
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.
PubMed 35710578
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.
PubMed 34645283
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.
PubMed 33966491

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 16 Feb 2022. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding (ANNEXA-4)
ClinicalTrials.gov ID: NCT02329327
Acronym / sponsor ID: 14-505
Conditions: Bleeding
Keywords: Factor Xa Inhibitors, Major, Bleeding, Anticoagulant, Major Bleeding, Andexanet Alfa, Reversal Agent
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 479 participants (actual)
Lead sponsor: Alexion Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
Collaborators: Portola Pharmaceuticals, LLC (a wholly owned subsidiary of Alexion Pharmaceuticals), Population Health Research Institute
Study start: 10 Apr 2015 (actual)
Primary completion: 24 Sep 2020 (actual)
Study completion: 24 Sep 2020 (actual)
First posted: 31 Dec 2014 (estimated)
Results: Posted 16 Feb 2022

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Other
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Number of arms: 1

Arm	Type	Receives
Andexanet	Experimental	Biological: AndexanetParticipants received andexanet as an intravenous bolus administered over ~15 to 30 minutes, followed immediately by a continuous infusion administered over ~120 minutes.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (8 listed)

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

Key exclusion criteria (16 listed)

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:
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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
AndexanetAlso: ALXN2070, Andexanet Alfa, PRT064445, AndexxaThere 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.	Biological	Andexanet

Primary outcome

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.
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.

1 secondary outcome

Percent Change From Baseline In Anti-fXa Activity By Hemostatic Efficacy
Time frame: Baseline, 12 Hours (post infusion)

Results and safety

Results posted to the registry on 16 Feb 2022, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Andexanet	477	392
Andexanet - Additional Participants	2	2

Primary outcome: Percent Change From Baseline In Anti-fXa Activity By FXa Inhibitor

Time frame: Baseline, 12 Hours (post infusion). Median (95% Confidence Interval). Unit: Percent Change

Measure	FXa Inhibitor: Apixaban n = 169	FXa Inhibitor: Rivaroxaban n = 130	FXa Inhibitor: Edoxaban n = 28	FXa Inhibitor: Enoxaparin n = 17	FXa Inhibitor: Rivaroxaban - Additional Participants n = 2
Value	-93.3 (-94.2 to -92.5)	-94.1 (-95.1 to -93.0)	-71.3 (-82.3 to -65.2)	-75.41 (-79.17 to -66.67)	-96.3 (-98.3 to -94.3)

Population analysed: Efficacy Population: all participants who received any amount of andexanet, met clinical bleeding criteria, and had an anti-fXa level of ≥75 nanograms/milliliter (ng/mL) for apixaban and rivaroxaban, ≥40 ng/mL for edoxaban, and ≥0.25 international units (IU)/mL for enoxaparin.

Primary outcome: Participants Achieving Hemostatic Efficacy

Time frame: 12 Hours (post infusion). Count of participants. Unit: Participants

Measure	FXa Inhibitor: Apixaban n = 169	FXa Inhibitor: Rivaroxaban n = 127	FXa Inhibitor: Edoxaban n = 28	FXa Inhibitor: Enoxaparin n = 16	Bleed Type: Gastrointestinal n = 74	Bleed Type: Intracranial Hemorrhage n = 244	Bleed Type: Other n = 22	Andexanet: Low Dose n = 269	Andexanet: High Dose n = 71	Overall n = 340	FXa Inhibitor: Rivaroxaban - Additional Participants n = 2	Bleed Type: Intracranial Hemorrhage - Additional Participants n = 2	Andexanet: Low Dose - Additional Participant n = 1	Andexanet: High Dose - Additional Participant n = 1
Excellent/Good	134	102	22	14	61	193	18	218	54	272	2	2	1	1
Poor/None	35	25	6	2	13	51	4	51	17	68	0	0	0	0

Population analysed: Efficacy Population: all participants who received any amount of andexanet, met clinical bleeding criteria, and had an anti-fXa level of ≥75 ng/mL for apixaban and rivaroxaban, ≥40 ng/mL for edoxaban, and ≥0.25 IU/mL for enoxaparin.

1 secondary outcome is reported in the full results.

Adverse events

Time frame: Day 1 through Day 37.. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Andexanet: Low Dose	157 of 382 (41.1%)	40 of 382 (10.5%)	66 of 382
Andexanet: High Dose	43 of 97 (44.3%)	8 of 97 (8.2%)	15 of 97

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 16 Feb 2022.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Results publication: PubMed 27573206Connolly 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.
Results publication: PubMed 28009495Birocchi 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.
Results publication: PubMed 30730782Connolly 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.
Derived from this study: PubMed 38264861Siepen BM, Polymeris A, Shoamanesh A, Connolly S, Steiner T, Poli S, Lemmens R, Goeldlin MB, Muller M, Branca M, Rauch J, Meinel T, Kaesmacher J, Z'Graggen W, Arnold M, Fischer U, Peters N, Engelter ST, Lyrer P, Seiffge D. Andexanet alfa versus non-specific treatments for intracerebral hemorrhage in patients taking factor Xa inhibitors - Individual patient data analysis of ANNEXA-4 and TICH-NOAC. Int J Stroke. 2024 Jun;19(5):506-514. doi: 10.1177/17474930241230209. Epub 2024 Mar 8.
Derived from this study: PubMed 36802876Milling 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.
Derived from this study: PubMed 35710578Costa 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.
Derived from this study: PubMed 34645283Huttner 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.
Derived from this study: PubMed 33966491Demchuk 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.
Neurocrit Care. 2019;31:S37Link provided by the sponsor.
Neurocrit Care. 2019;31:S222Link provided by the sponsor.
Individual participant dataSharing planned: Yes

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

The record lists no contact. Use the official record to reach the sponsor.

87 sites in 9 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Andexanet in people with Bleeding, run by Alexion Pharmaceuticals, Inc. at 87 sites in 9 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 16 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 87 sites in Germany, United States, Japan, France, Belgium and 4 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 Feb 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percent Change From Baseline In Anti-fXa Activity By FXa Inhibitor (time frame: Baseline, 12 Hours (post infusion)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02329327, which also lists 8 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Feb 2022.