A clinical trial to study the effect of andexanet alfa compared to the usual care with regards to stopping severe/life threatening bleeding in patients with bleeding inside the skull.
- Conditions
- Oral FXa inhibitor-treated patients with acute intracranial bleeding.MedDRA version: 20.0Level: LLTClassification code 10075279Term: Anticoagulant reversal therapySystem Organ Class: 100000004865Therapeutic area: Not possible to specify
- Registration Number
- EUCTR2018-002620-17-HU
- Lead Sponsor
- Alexion Pharmaceuticals, Inc
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 1200
1. Written informed consent. Either the patient or his or her legally acceptable representative (LAR) 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 (or LAR) will be obtained as soon as realistically possible after inclusion in Study 18-513 and in accordance with the Declaration of Helsinki, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP), the Data Protection Directive (Directive 95/46/EC) and national and local regulations.
2. Age = 18 years old at the time of consent.
3. An acute intracranial bleeding episode, defined as an estimated blood volume of =0.5 mL 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 intracranial
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], edoxaban [last dose 30 mg or greater] or enoxaparin [last dose 1 mg/kg or greater]):
o =15 hours prior to randomization.
o > 15 hours prior to randomization or unknown time of last dose, only if 1) the local anti -fXa activity > 100 ng/mL (for direct fXa inhibitors (apixaban, rivaroxaban or edoxaban) or > 0.5 IU/mL for enoxaparin, and 2) the local anti-fXa activity level is obtained 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 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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 190
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 1010
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 haematoma 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. Purposefully left blank to align with the programmed database.
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 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,
pulmonary embolism[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 (see Appendix H 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:
a. Vitamin K Antagonist (VKA) (e.g., warfarin).
b. Dabigatran.
c. Prothrombin Complex Concentrate products (PCC, e.g., Kcentra®) or
recombinant factor VIIa (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 & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: • To evaluate the effect of andexanet versus usual care on the rate of effective hemostasis.;Secondary Objective: • To evaluate the effect of andexanet versus usual care on anti-fXa activity.;Primary end point(s): • Effective hemostasis 12 hours post-randomisation as determined by the blinded EAC, based on prespecified criteria documented in the Adjudication Charter (see Appendix B).<br><br>Effective hemostasis is defined as:<br>1 = for patients with hemostatic efficacy rated by the EAC as excellent or good, and<br>0 = for patients with hemostatic efficacy rated by the EAC as poor/none.;Timepoint(s) of evaluation of this end point: 12 Hours post randomizarion
- Secondary Outcome Measures
Name Time Method Secondary end point(s): • Percent change from baseline to nadir in anti-fXa activity during the first 2 hours post-randomization.<br>;Timepoint(s) of evaluation of this end point: 30 days and up to 120 days for patients with positive anti-andexanet antibody response.