Trial of Andexanet Alfa in ICrH Patients Receiving an Oral FXa Inhibitor

A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor

Randomized, controlled clinical trial evaluating the efficacy and safety of andexanet alfa versus usual care in patients with intracranial hemorrhage anticoagulated with a direct oral FXa anticoagulant

Study Overview

• Status: Completed
• Conditions: Acute Intracranial Hemorrhage
• Intervention / Treatment: Drug: andexanet alfa; Drug: Usual Care

Detailed Description

This is a randomized, multicenter clinical trial designed to determine the efficacy and safety of andexanet alfa compared to usual care in patients presenting with acute intracranial hemorrhage within 6 hours of symptom onset to baseline scan and within 15 hours of taking an oral factor Xa inhibitor. The study will use a prospective, randomized, open label (PROBE) design. The primary efficacy outcome will be adjudicated by a blinded Endpoint Adjudication Committee. To support the adjudication of hemostatic efficacy, a blinded Imaging Core Laboratory will review all available scans. Between 900 and 1200 patients are planned to be enrolled in the study.

• Study Type: Interventional
• Enrollment (Actual): 545
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Alexion Pharmaceuticals, Inc.; Phone Number: 1-855-752-2356; Email: clinicaltrials@alexion.com

Study Locations

• Austria
  • Innsbruck, Austria, 6020
    • Research Site
  • Klagenfurt am Wörthersee, Austria, 9020
    • Research Site
  • Linz, Austria, 4020
    • Research Site
  • Salzburg, Austria, 5020
    • Research Site
  • Sankt Pölten, Austria, 3100
    • Research Site
  • Vienna, Austria, 1020
    • Research Site
• Belgium
  • Belgium, Belgium, 1200
    • Research Site
  • Genk, Belgium, 3600
    • Research Site
  • Ghent, Belgium, 9000
    • Research Site
  • Kortrijk, Belgium, 8500
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
  • Ottignies, Belgium, 1340
    • Research Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Research Site
    • Edmonton, Alberta, Canada, T6G 2B7
      • Research Site
  • British Columbia
    • New Westminster, British Columbia, Canada, V3L 0E3
      • Research Site
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Research Site
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Research Site
    • London, Ontario, Canada, N6A 5A5
      • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Research Site
    • Montreal, Quebec, Canada, H3A 2B4
      • Research Site
    • Québec, Quebec, Canada, G1J 4Z1
      • Research Site
• Czechia
  • Brno, Czechia, 656 91
    • Research Site
  • Ostrava, Czechia, 703 84
    • Research Site
  • Praha 5, Czechia, 150 06
    • Research Site
• Denmark
  • Aalborg, Denmark, 9100
    • Research Site
  • Copenhagen, Denmark, DK-2400
    • Research Site
  • Copenhagen Ø, Denmark, 2100
    • Research Site
  • Odense C, Denmark, 5000
    • Research Site
  • Århus N, Denmark, 8200
    • Research Site
• Finland
  • Helsinki, Finland, 00029
    • Research Site
  • Turku, Finland, FI-20521
    • Research Site
• France
  • Angers, France, 49933
    • Research Site
  • Bordeaux Cedex, France, 33076
    • Research Site
  • Bourg en Bresse, France, 01012
    • Research Site
  • Clermont Ferrand, France, 63003
    • Research Site
  • Lyon, France, 69437
    • Research Site
  • Montpellier cedex 5, France, 34295
    • Research Site
  • Nancy, France, 54035
    • Research Site
  • Paris, France, 75014
    • Research Site
  • Paris, France, 75019
    • Research Site
  • Suresnes Cedex, France, 92151
    • Research Site
  • Toulouse, France, 31300
    • Research Site
• Germany
  • Altenburg, Germany, 4600
    • Research Site
  • Augsburg, Germany, 86156
    • Research Site
  • Bad Neustadt, Germany, 97616
    • Research Site
  • Bochum, Germany, 44892
    • Research Site
  • Bonn, Germany, 53127
    • Research Site
  • Bremen, Germany, 28755
    • Research Site
  • Chemnitz, Germany, 9116
    • Research Site
  • Dortmund, Germany, 44137
    • Research Site
  • Dresden, Germany, 1307
    • Research Site
  • Dresden, Germany, 1067
    • Research Site
  • Erlangen, Germany, 91054
    • Research Site
  • Essen, Germany, 45131
    • Research Site
  • Frankfurt, Germany, 65929
    • Research Site
  • Frankfurt am Main, Germany, 60528
    • Research Site
  • Giessen, Germany, 35392
    • Research Site
  • Goettingen, Germany, 37075
    • Research Site
  • Hamburg, Germany, 20246
    • Research Site
  • Hamburg, Germany, 22291
    • Research Site
  • Hannover, Germany, 30625
    • Research Site
  • Heidelberg, Germany, 69120
    • Research Site
  • Konstanz, Germany, 78464
    • Research Site
  • Lübeck, Germany, 23538
    • Research Site
  • Lünen, Germany, 44534
    • Research Site
  • Mannheim, Germany, 68135
    • Research Site
  • München, Germany, 81377
    • Research Site
  • Münster, Germany, 48149
    • Research Site
  • Osnabrück, Germany, 49076
    • Research Site
  • Sande, Germany, 26452
    • Research Site
  • Stuttgart, Germany, 70174
    • Research Site
  • Tübingen, Germany, 72076
    • Research Site
  • Ulm, Germany, 89081
    • Research Site
• Greece
  • Alexandroupolis, Greece, 68100
    • Research Site
  • Athens, Greece, 12462
    • Research Site
• Hungary
  • Budapest, Hungary, 1083
    • Research Site
  • Budapest, Hungary, 1134
    • Research Site
  • Budapest, Hungary, 1106
    • Research Site
  • Debrecen, Hungary, 4032
    • Research Site
  • Pécs, Hungary, 7623
    • Research Site
• Israel
  • Ashdod, Israel, 7747629
    • Research Site
  • Beersheba, Israel, 84101
    • Research Site
  • Haifa, Israel, 3109601
    • Research Site
  • Jerusalem, Israel, 91120
    • Research Site
  • Jerusalem, Israel, 9372212
    • Research Site
  • Petach-Tikva, Israel, 4941492
    • Research Site
  • Tel Aviv, Israel, 6423906
    • Research Site
• Italy
  • Bologna, Italy, 40133
    • Research Site
  • Genova, Italy, 16132
    • Research Site
  • Milano, Italy, 20132
    • Research Site
  • Perugia, Italy, 06156
    • Research Site
  • Roma, Italy, 00168
    • Research Site
  • Roma, Italy, 00133
    • Research Site
  • Rome, Italy, 161
    • Research Site
  • Rome, Italy, 152
    • Research Site
• Latvia
  • Riga, Latvia, LV-1002
    • Research Site
• Lithuania
  • Vilnius, Lithuania, LT-08661
    • Research Site
  • Vilnius, Lithuania, 4130
    • Research Site
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Research Site
  • Amsterdam, Netherlands, 1061 AE
    • Research Site
  • Enschede, Netherlands, 7512 KZ
    • Research Site
  • Leiden, Netherlands, 2333 ZA
    • Research Site
  • Zwolle, Netherlands, 8025 AB
    • Research Site
• Norway
  • Oslo, Norway, 450
    • Research Site
• Poland
  • Krakow, Poland, 30-688
    • Research Site
  • Kraków, Poland, 31-913
    • Research Site
  • Lublin, Poland, 20-718
    • Research Site
  • Wejherowo, Poland, 84-200
    • Research Site
• Portugal
  • Coimbra, Portugal, 3000-075
    • Research Site
  • Vila Nova de Gaia, Portugal, 4434-502
    • Research Site
• Russian Federation
  • Arkhangelsk, Russian Federation, 163045
    • Research Site
  • Novosibirsk, Russian Federation, 630003
    • Research Site
• Spain
  • Albacete, Spain, 02006
    • Research Site
  • Barcelona, Spain, 08035
    • Research Site
  • Barcelona, Spain, 08041
    • Research Site
  • L'Hospitalet de Llobregat, Spain, 08907
    • Research Site
  • Lérida, Spain, 25198
    • Research Site
  • Madrid, Spain, 28034
    • Research Site
  • Madrid, Spain, 28041
    • Research Site
  • Sevilla, Spain, 41009
    • Research Site
  • Sevilla, Spain, 41013
    • Research Site
  • Valencia, Spain, 46026
    • Research Site
• Sweden
  • Lund, Sweden, SE-221 85
    • Research Site
  • Uppsala, Sweden, 751 85
    • Research Site
• Switzerland
  • Bern, Switzerland, 3010
    • Research Site
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Research Site
  • Harrow, United Kingdom, HA1 3UJ
    • Research Site
  • Leeds, United Kingdom, LS1 3EX
    • Research Site
  • Leicester, United Kingdom, LE1 5WW
    • Research Site
  • London, United Kingdom, SW17 0QT
    • Research Site
  • Newcastle-upon-Tyne, United Kingdom, NE1 4LP
    • Research Site
• United States
  • Florida
    • Fort Lauderdale, Florida, United States, 33308
      • Research Site
  • Georgia
    • Augusta, Georgia, United States, 30905
      • Research Site
  • Michigan
    • Royal Oak, Michigan, United States, 48073
      • Research Site
    • Troy, Michigan, United States, 48085
      • Research Site
  • New York
    • Albany, New York, United States, 12208
      • Research Site
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Research Site
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74104
      • Research Site
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Research Site
  • Texas
    • Austin, Texas, United States, 78705
      • Research Site
    • Austin, Texas, United States, 78712
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Written informed consent. Either the patient or his or her medical proxy (or legally authorized representative if permissible by local or regional laws and regulations) has been adequately informed of the nature and risks of the study and has given written informed consent prior to Screening.

   • Deferred consent procedure is allowed where approved by local ethics committees. In cases of deferred consent, the time of the study physician's documented decision to include the patient into the study will serve as "time of consent" with respect to protocol-specific procedures.
   • In all cases where the patient does not sign informed consent prior to study entry, informed consent from the patient will be obtained as soon as realistically possible after inclusion in the trial and in accordance with the Declaration of Helsinki, International Conference on Harmonization-Good Clinical Practice (GCP), the EU General Data Protection Regulation (GDPR) and national and local regulations.
2. Age ≥ 18 years old at the time of consent.
3. An acute intracerebral bleeding episode, defined as an estimated blood volume ≥ 0.5 to ≤ 60 mL acutely observed radiographically within the cerebrum. Patients may have extracerebral (e.g., subdural, subarachnoid, epidural) or extracranial (e.g., gastrointestinal, intraspinal) bleeding additionally, but the intracerebral hemorrhage must be considered the most clinically significant bleed at the time of enrollment.
4. Performance of a head CT or MRI scan demonstrating the intracerebral bleeding within 2 hours prior to randomization (the baseline scan may be repeated only once to meet this criterion).

5. Treatment with an oral FXa inhibitor (apixaban [last dose 2.5 mg or greater], rivaroxaban [last dose 10 mg or greater], or edoxaban [last dose 30 mg or greater]):

   • ≤ 15 hours prior to randomization.
   • > 15 hours prior to randomization or unknown time of last dose, if documented anti fXa activity is > 100 ng/mL for direct fXa inhibitors (apixaban, rivaroxaban or edoxaban) may be enrolled, irrespective of the time of the last dose, and the local anti-fXa activity level is obtained within 2 hours prior to consent, performed as per standard of care. Note: Patients enrolled in this manner should receive a high andexanet dosing regimen.
6. Time from bleeding symptom onset < 6 hours prior to the baseline imaging scan. Time of trauma (if applicable) or time last seen normal may be used as surrogates for time of symptom onset. (If the baseline scan is repeated to meet Inclusion Criterion #4, the time from bleeding symptom onset must be < 6 hours prior to the repeat baseline imaging scan.)
7. Female patients of childbearing potential and male patients with female partners of childbearing potential must follow protocol-specified guidance for avoiding pregnancy for 30 days after the last dose of study drug.
8. Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential).
9. NIHSS score ≤ 35 at the time of consent.

Exclusion Criteria

If a patient meets any of the following criteria, he or she is not eligible to participate in this trial:

1. Planned surgery, including Burr holes for hematoma drainage, within 12 hours after randomization. Minimally invasive surgery/procedures not directly related to the treatment of intracranial bleeding and that are not expected to significantly affect hematoma volume are allowed (e.g., Burr holes for intracranial pressure monitoring, endoscopy, bronchoscopy, central lines.
2. GCS score < 7 at the time of consent. If a patient is intubated and/or sedated at the time of consent, they may be enrolled if it can be documented that they were intubated/sedated for non-neurologic reasons within 2 hours prior to consent.
3. Purposefully left blank.
4. Anticipation that the baseline and follow up brain scans will not be able to use the same imaging modalities (i.e., patients with a baseline CT scan should have a CT scan in follow up; similarly, for MRI).
5. Expected survival of less than 1 month (not related to the intracranial bleed).

6. Recent history (within 2 weeks) of a diagnosed TE or clinically relevant symptoms of the following:

   ○ Venous Thromboembolism (VTE: e.g., deep venous thrombosis, PE, cerebral venous thrombosis), myocardial infarction (MI), Disseminated Intravascular Coagulation (DIC), cerebral vascular accident, transient ischemic attack (TIA), acute coronary syndrome, or arterial systemic embolism.

7. Acute decompensated heart failure or cardiogenic shock at the time of randomization.
8. Severe sepsis or septic shock at the time of randomization.
9. The patient is a pregnant or lactating female.

10. Receipt of any of the following drugs or blood products within 7 days prior to consent:

    1. VKA (e.g., warfarin).
    2. Dabigatran.
    3. PCC (e.g., KCentra®) or rfVIIa (e.g., NovoSeven®), or anti-inhibitor coagulant complex (e.g., FEIBA®), FFP, and whole blood.
11. Past use of andexanet (or planned use of commercial andexanet).
12. Treatment with an investigational drug < 30 days prior to consent.
13. Any tumor-related bleeding.
14. Known hypersensitivity to any component of andexanet.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: andexanet alfa; Patients will receive one of two dosing regimens of andexanet alfa based on which FXa inhibitor they received and the amount and timing of the most recent dose.	Drug: andexanet alfa; Andexanet alfa is a recombinant version of human FXa
Other: Usual Care; Usual care will consist of any treatment(s) (including no treatment) other than andexanet alfa administered within 3 hours post-randomization that the Investigator and/or other treating physicians consider to be appropriate.	Drug: Usual Care; Usual care will consist of any treatment(s) (including no treatment) other than andexanet alfa administered within 3 hours post-randomization that the Investigator and/or other treating physicians consider to be appropriate.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the effect of andexanet alfa (andexanet) versus usual care on the rate of effective hemostasis.	Effective haemostasis is defined as change from baseline NIHSS of +6 or less at the 12 hour timepoint AND ≤35% increase in haematoma volume compared to baseline on a repeat CT or MRI scan at 12hrs AND no rescue therapies administered between 3 hours and 12 hours after randomization.	12 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the effect of andexanet versus usual care on anti-fXa activity.	Percent change from baseline to nadir in anti-fXa activity during the first 2 hours post-randomization	1-2 hours

Collaborators and Investigators

• Sponsor: Alexion Pharmaceuticals, Inc.

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): June 6, 2019
• Primary Completion (Actual): May 27, 2023
• Study Completion (Actual): August 9, 2023

Study Registration Dates

• First Submitted: August 30, 2018
• First Submitted That Met QC Criteria: September 6, 2018
• First Posted (Actual): September 7, 2018

Study Record Updates

• Last Update Posted (Actual): April 16, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: anticoagulant; thrombosis; acute intracranial hemorrhage; andexanet alfa
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hemorrhage; Intracranial Hemorrhages
• Other Study ID Numbers: 18-513; 2018-002620-17 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No