Acute Intracranial Hemorrhage
Conditions
Keywords
thrombosis, anticoagulant, acute intracranial hemorrhage, andexanet alfa
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
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.
Interventions
DRUGandexanet alfa
Andexanet alfa is a recombinant version of human FXa
DRUGUsual 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.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved Effective Hemostasis | Baseline up to 12 hours | Effective hemostasis was defined as a change from baseline in National Institutes of Health Stroke Scale (NIHSS) of + 6 or less at the 12 hour timepoint and ≤35% increase in haematoma volume compared to baseline on a repeat computed tomography (CT) or magnetic resonance imaging (MRI) scan at 12 hours and no rescue therapies administered between 3 hours and 12 hours after randomization (defined as excellent or good hemostasis). The NIHSS is a validated quantitative assessment tool to measure stroke-related neurological deficits and ranges from 0 (no neurological deficits) to a maximum of 42, indicative of a very severe level of impairment. Data presented is for the number of participants who achieved effective hemostasis (excellent or good hemostasis), as adjudicated by the independent Endpoint Adjudication Committee (IEAC). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline to Nadir in Anti-FXa Activity | Baseline up to 2 hours | Anti-FXa activity was measured from plasma samples to assess the anticoagulant status of FXa inhibitors using a modified chromogenic assay performed at a Central Laboratory. Nadir was defined as the minimum anti-FXa activity post-randomization. |
Countries
Austria, Belgium, Canada, Czechia, Denmark, Finland, France, Germany, Greece, Hungary, Israel, Italy, Latvia, Lithuania, Netherlands, Norway, Poland, Portugal, Russia, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
Data collected for the Andexanet Alfa arm were prespecified to be collected as a single Arm/Group regardless of the dose level the participant received.
Participants by arm
| Arm | Count |
|---|---|
| Andexanet Alfa Participants received a regimen of andexanet alfa administered as an intravenous (IV) bolus, immediately followed by a continuous infusion.
Dosing regimen was based on which FXa inhibitor the participants received and the amount and timing of the most recent dose of treatment. | 263 |
| Usual Care Participants received usual care. Usual care consisted 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 considered to be appropriate. | 267 |
| Total | 530 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 61 | 55 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Disease Progression | 8 | 13 |
| Overall Study | Other than Specified | 5 | 2 |
| Overall Study | Physician Decision | 3 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 3 |
Baseline characteristics
| Characteristic | Usual Care | Total | Andexanet Alfa |
|---|---|---|---|
| Age, Continuous | 78.7 years STANDARD_DEVIATION 8.61 | 79.0 years STANDARD_DEVIATION 8.56 | 79.4 years STANDARD_DEVIATION 8.51 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 28 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 237 Participants | 464 Participants | 227 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 17 Participants | 38 Participants | 21 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 9 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 12 Participants | 28 Participants | 16 Participants |
| Race (NIH/OMB) White | 247 Participants | 486 Participants | 239 Participants |
| Sex: Female, Male Female | 128 Participants | 245 Participants | 117 Participants |
| Sex: Female, Male Male | 139 Participants | 285 Participants | 146 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 75 / 263 | 70 / 267 |
| other Total, other adverse events | 198 / 262 | 200 / 265 |
| serious Total, serious adverse events | 120 / 262 | 96 / 265 |
Outcome results
Primary
Number of Participants Who Achieved Effective Hemostasis
Effective hemostasis was defined as a change from baseline in National Institutes of Health Stroke Scale (NIHSS) of + 6 or less at the 12 hour timepoint and ≤35% increase in haematoma volume compared to baseline on a repeat computed tomography (CT) or magnetic resonance imaging (MRI) scan at 12 hours and no rescue therapies administered between 3 hours and 12 hours after randomization (defined as excellent or good hemostasis). The NIHSS is a validated quantitative assessment tool to measure stroke-related neurological deficits and ranges from 0 (no neurological deficits) to a maximum of 42, indicative of a very severe level of impairment. Data presented is for the number of participants who achieved effective hemostasis (excellent or good hemostasis), as adjudicated by the independent Endpoint Adjudication Committee (IEAC).
Time frame: Baseline up to 12 hours
Population: Measured in the ITT set, primary efficacy population, which included all participants randomized to study intervention based on the first data cut-off. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Andexanet Alfa | Number of Participants Who Achieved Effective Hemostasis | 150 Participants |
| Usual Care | Number of Participants Who Achieved Effective Hemostasis | 121 Participants |
p-value: 0.003295% CI: [4.6, 22.2]Cochran-Mantel-Haenszel
Secondary
Percentage Change From Baseline to Nadir in Anti-FXa Activity
Anti-FXa activity was measured from plasma samples to assess the anticoagulant status of FXa inhibitors using a modified chromogenic assay performed at a Central Laboratory. Nadir was defined as the minimum anti-FXa activity post-randomization.
Time frame: Baseline up to 2 hours
Population: Measured in the ITT set, primary efficacy population, which included all participants randomized to study intervention based on the first data cut-off. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Andexanet Alfa | Percentage Change From Baseline to Nadir in Anti-FXa Activity | -94.41 Percent change |
| Usual Care | Percentage Change From Baseline to Nadir in Anti-FXa Activity | -27.46 Percent change |
p-value: <0.000195% CI: [-199.93, -172.05]ANCOVA