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

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ClinicalTrials.gov Identifier: NCT03661528
Recruitment Status : Recruiting
First Posted : September 7, 2018
Last Update Posted : May 17, 2023
Information provided by (Responsible Party):

Brief 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

Condition or disease Intervention/treatment Phase
Acute Intracranial Hemorrhage Drug: andexanet alfa Drug: Usual Care Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Masking Description: ANNEXA-I is a randomized, open-label study with blinded adjudication on primary efficacy and safety outcomes, including death and thrombotic events.
Primary Purpose: Treatment
Official Title: A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor
Actual Study Start Date : June 6, 2019
Estimated Primary Completion Date : May 31, 2024
Estimated Study Completion Date : July 30, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bleeding

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

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.

Primary Outcome Measures :
  1. To evaluate the effect of andexanet alfa (andexanet) versus usual care on the rate of effective hemostasis. [ Time Frame: 12 hours ]
    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.

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

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03661528

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Contact: Alexion Pharmaceuticals, Inc. 1-855-752-2356 clinicaltrials@alexion.com

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Sponsors and Collaborators
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Responsible Party: Alexion
ClinicalTrials.gov Identifier: NCT03661528    
Other Study ID Numbers: 18-513
First Posted: September 7, 2018    Key Record Dates
Last Update Posted: May 17, 2023
Last Verified: May 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alexion:
acute intracranial hemorrhage
andexanet alfa
Additional relevant MeSH terms:
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Intracranial Hemorrhages
Pathologic Processes
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases