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Trial of Andexanet in ICH Patients Receiving an Oral FXa Inhibitor

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03661528
Recruitment Status : Recruiting
First Posted : September 7, 2018
Last Update Posted : July 28, 2020
Population Health Research Institute
Information provided by (Responsible Party):
Portola Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE August 30, 2018
First Posted Date  ICMJE September 7, 2018
Last Update Posted Date July 28, 2020
Actual Study Start Date  ICMJE January 18, 2019
Estimated Primary Completion Date March 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 6, 2018)
Proportion of patients with good or excellent hemostatic efficacy as rated by an independent adjudication committee [ Time Frame: 12 hours ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 25, 2020)
  • Change from baseline in anti-fXa activity [ Time Frame: 1-3 hours ]
  • Change from baseline in NIHSS [ Time Frame: 24 hours ]
  • Change from baseline in GCS [ Time Frame: 24 hours ]
  • Proportion of neurological deterioration, as defined by NIHSS increase > 4 or GCS decrease > 2 [ Time Frame: 24 hours ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 6, 2018)
Change from baseline in anti-fXa activity [ Time Frame: 1-3 hours ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Trial of Andexanet in ICH Patients Receiving an Oral FXa Inhibitor
Official Title  ICMJE A Randomized Clinical Trial of Andexanet Alfa [Andexanet Alfa for Injection] in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor
Brief Summary Randomized, controlled clinical trial evaluating the efficacy and safety of andexanet versus usual standard of care in patients with intracranial hemorrhage anticoagulated with a direct oral anticoagulant
Detailed Description This is a randomized, multicenter clinical trial designed to determine the efficacy and safety of andexanet compared to usual care in patients presenting with acute intracranial hemorrhage within 6 hours of symptom onset 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. Approximately 900 patients are planned to be enrolled in the study.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Intracranial Hemorrhage
Intervention  ICMJE Drug: andexanet alfa
Andexanet is a recombinant version of human FXa
Study Arms  ICMJE Not Provided
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 25, 2020)
Original Estimated Enrollment  ICMJE
 (submitted: September 6, 2018)
Estimated Study Completion Date  ICMJE November 1, 2023
Estimated Primary Completion Date March 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 GCP, the Data Protection Directive (Directive 95/46/EC) and national and local regulations.
  2. Age 18 to <90 years old at the time of consent.
  3. An acute intracerebral bleeding episode, defined as an estimated blood volume > 0 to ≤ 60 mL acutely observed radiographically within the cerebrum. Patients may have extracerebral (e.g., subdural, subarachnoid) 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 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 (or over the equivalent IU/mL threshold on a LMWH assay; see Laboratory Manual) within 2 hours prior to consent. 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 second baseline imaging scan.)
  7. Willingness to use medically acceptable methods of contraception through 30 days following study drug dose (for female and male subjects who are fertile).
  8. Have a negative pregnancy test documented prior to enrollment (for women of childbearing potential).

Exclusion Criteria:

  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- Section 7.3 and Appendix F).
  2. Glasgow Coma Scale (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. Any bleeding into the epidural space.
  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:

    o Venous Thromboembolism (VTE: e.g., deep venous thrombosis, pulmonary embolism, cerebral venous thrombosis), myocardial infarction, Disseminated Intravascular Coagulation (DIC), cerebral vascular accident, transient ischemic attack, acute coronary syndrome, or arterial systemic embolism (see Appendix G for DIC scoring algorithm).

  7. Acute decompensated heart failure or cardiogenic shock at the time of randomization (see Appendix H for cardiogenic shock definition).
  8. Severe sepsis or septic shock at the time of randomization (see Appendix H for sepsis definition).
  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. Vitamin K Antagonist (VKA) (e.g., warfarin).
    2. Dabigatran.
    3. Prothrombin Complex Concentrate products (PCC, e.g., KCentra®) or recombinant factor VIIa (rfVIIa) (e.g., NovoSeven®), or anti-inhibitor coagulant complex (e.g., FEIBA®).
  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.
  15. National Institutes of Health Stroke Scale (NIHSS) score >35 at the time of consent.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 89 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Study Clinical Trial Contact 650-246-7000
Listed Location Countries  ICMJE Austria,   Belgium,   Canada,   France,   Germany,   Israel,   Italy,   Netherlands,   Spain,   United Kingdom,   United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03661528
Other Study ID Numbers  ICMJE 18-513
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Portola Pharmaceuticals
Study Sponsor  ICMJE Portola Pharmaceuticals
Collaborators  ICMJE Population Health Research Institute
Investigators  ICMJE Not Provided
PRS Account Portola Pharmaceuticals
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP