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

Acute Intracranial Hemorrhage Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03661528
• Other study ID #: 18-513
• Secondary ID: 2018-002620-17
• Status: Completed
• Phase: Phase 4
• Start date: June 6, 2019
• Est. completion date: August 9, 2023

Study information

• Verified date: April 2024
• Source: Alexion Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 545
• Est. completion date: August 9, 2023
• Est. primary completion date: May 27, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Intracranial Hemorrhage
• Hemorrhage
• Intracranial Hemorrhages

Intervention

Drug:
• andexanet alfa
Andexanet alfa is a recombinant version of human FXa
• 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.

Locations

Country	Name	City	State
Austria	Research Site	Innsbruck
Austria	Research Site	Klagenfurt am Wörthersee
Austria	Research Site	Linz
Austria	Research Site	Salzburg
Austria	Research Site	Sankt Pölten
Austria	Research Site	Vienna
Belgium	Research Site	Belgium
Belgium	Research Site	Genk
Belgium	Research Site	Ghent
Belgium	Research Site	Kortrijk
Belgium	Research Site	Leuven
Belgium	Research Site	Ottignies
Canada	Research Site	Calgary	Alberta
Canada	Research Site	Edmonton	Alberta
Canada	Research Site	Hamilton	Ontario
Canada	Research Site	London	Ontario
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Montreal	Quebec
Canada	Research Site	New Westminster	British Columbia
Canada	Research Site	Québec	Quebec
Canada	Research Site	Vancouver	British Columbia
Czechia	Research Site	Brno
Czechia	Research Site	Ostrava
Czechia	Research Site	Praha 5
Denmark	Research Site	Aalborg
Denmark	Research Site	Århus N
Denmark	Research Site	Copenhagen
Denmark	Research Site	Copenhagen Ø
Denmark	Research Site	Odense C
Finland	Research Site	Helsinki
Finland	Research Site	Turku
France	Research Site	Angers
France	Research Site	Bordeaux Cedex
France	Research Site	Bourg en Bresse
France	Research Site	Clermont Ferrand
France	Research Site	Lyon
France	Research Site	Montpellier cedex 5
France	Research Site	Nancy
France	Research Site	Paris
France	Research Site	Paris
France	Research Site	Suresnes Cedex
France	Research Site	Toulouse
Germany	Research Site	Altenburg
Germany	Research Site	Augsburg
Germany	Research Site	Bad Neustadt
Germany	Research Site	Bochum
Germany	Research Site	Bonn
Germany	Research Site	Bremen
Germany	Research Site	Chemnitz
Germany	Research Site	Dortmund
Germany	Research Site	Dresden
Germany	Research Site	Dresden
Germany	Research Site	Erlangen
Germany	Research Site	Essen
Germany	Research Site	Frankfurt
Germany	Research Site	Frankfurt am Main
Germany	Research Site	Giessen
Germany	Research Site	Goettingen
Germany	Research Site	Hamburg
Germany	Research Site	Hamburg
Germany	Research Site	Hannover
Germany	Research Site	Heidelberg
Germany	Research Site	Konstanz
Germany	Research Site	Lübeck
Germany	Research Site	Lünen
Germany	Research Site	Mannheim
Germany	Research Site	München
Germany	Research Site	Münster
Germany	Research Site	Osnabrück
Germany	Research Site	Sande
Germany	Research Site	Stuttgart
Germany	Research Site	Tübingen
Germany	Research Site	Ulm
Greece	Research Site	Alexandroupolis
Greece	Research Site	Athens
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Debrecen
Hungary	Research Site	Pécs
Israel	Research Site	Ashdod
Israel	Research Site	Beersheba
Israel	Research Site	Haifa
Israel	Research Site	Jerusalem
Israel	Research Site	Jerusalem
Israel	Research Site	Petach-Tikva
Israel	Research Site	Tel Aviv
Italy	Research Site	Bologna
Italy	Research Site	Genova
Italy	Research Site	Milano
Italy	Research Site	Perugia
Italy	Research Site	Roma
Italy	Research Site	Roma
Italy	Research Site	Rome
Italy	Research Site	Rome
Latvia	Research Site	Riga
Lithuania	Research Site	Vilnius
Lithuania	Research Site	Vilnius
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Enschede
Netherlands	Research Site	Leiden
Netherlands	Research Site	Zwolle
Norway	Research Site	Oslo
Poland	Research Site	Krakow
Poland	Research Site	Kraków
Poland	Research Site	Lublin
Poland	Research Site	Wejherowo
Portugal	Research Site	Coimbra
Portugal	Research Site	Vila Nova de Gaia
Russian Federation	Research Site	Arkhangelsk
Russian Federation	Research Site	Novosibirsk
Spain	Research Site	Albacete
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	L'Hospitalet de Llobregat
Spain	Research Site	Lérida
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Sevilla
Spain	Research Site	Sevilla
Spain	Research Site	Valencia
Sweden	Research Site	Lund
Sweden	Research Site	Uppsala
Switzerland	Research Site	Bern
United Kingdom	Research Site	Cambridge
United Kingdom	Research Site	Harrow
United Kingdom	Research Site	Leeds
United Kingdom	Research Site	Leicester
United Kingdom	Research Site	London
United Kingdom	Research Site	Newcastle-upon-Tyne
United States	Research Site	Albany	New York
United States	Research Site	Allentown	Pennsylvania
United States	Research Site	Augusta	Georgia
United States	Research Site	Austin	Texas
United States	Research Site	Austin	Texas
United States	Research Site	Columbus	Ohio
United States	Research Site	Fort Lauderdale	Florida
United States	Research Site	Nashville	Tennessee
United States	Research Site	Royal Oak	Michigan
United States	Research Site	Troy	Michigan
United States	Research Site	Tulsa	Oklahoma

Sponsors (1)

Lead Sponsor	Collaborator
Alexion Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Canada,  Czechia,  Denmark,  Finland,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Latvia,  Lithuania,  Netherlands,  Norway,  Poland,  Portugal,  Russian Federation,  Spain,  Sweden,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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

External Links

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