E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Oral FXa inhibitor-treated patients with acute intracranial bleeding. |
|
E.1.1.1 | Medical condition in easily understood language |
Serious bleeding complications inside skull of patients who have taken anticoagulant medicine, known as a factor Xa inhibitor. |
|
E.1.1.2 | Therapeutic area | Not possible to specify |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10075279 |
E.1.2 | Term | Anticoagulant reversal therapy |
E.1.2 | System Organ Class | 100000004865 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To evaluate the effect of andexanet versus usual care on the rate of effective hemostasis. |
|
E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of andexanet versus usual care on anti-fXa activity. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent. Either the patient or his or her medical proxy (or legally acceptable designee) has been adequately informed of the nature and risks of the study and has given written informed consent prior to Screening. 2. Age 18 years old or greater at the time of consent. 3. An acute intracranial bleeding episode, defined as any amount of blood acutely observed radiographically within the cranium. Patients may have extracranial bleeding (e.g., gastrointestinal, intraspinal) additionally, but the intracranial hemorrhage must be considered the primary bleed. 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 to meet this criterion). 5. Treatment with an oral FXa inhibitor (apixaban, rivaroxaban, or edoxaban) within 15 hours prior to randomization. If the time of last dose is unknown, the patient is not eligible for the study. If a patient is documented to have an anti-fXa activity > 100 ng/mL within 2 hours prior to consent, they may be enrolled irrespective of the time since last dose (as long as it is known). 6. Time from bleeding symptom onset < 12 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. |
|
E.4 | Principal 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 are allowed (e.g., Burr holes for intracranial pressure monitoring, endoscopy, bronchoscopy, central lines—see Section 7.3 and Appendix F). 2. Glasgow Coma 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. Estimated intracerebral hematoma volume > 60 mL assessed by the baseline CT or MRI. 4. Any bleeding into the (intracranial) epidural space. 5. 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). 6. Expected survival of less than 1 month. 7. Recent history (within 2 weeks) of a diagnosed Thrombotic Event (TE) or clinically relevant symptoms of the following: 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 within 2 weeks prior to Screening (see Appendix G for DIC scoring algorithm). 8. Acute decompensated heart failure or cardiogenic shock at the time of randomization (see Appendix H for cardiogenic shock definition). 9. Severe sepsis or septic shock at the time of randomization (see Appendix H for sepsis definition). 10. Pregnant or lactating. 11. 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®). 12. Past or planned use of andexanet. 13. Treatment with an investigational drug < 30 days prior to consent. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
• Effective hemostasis as determined by the blinded EAC. Effective hemostasis is defined as no greater than a 35% increase from baseline in hematoma volume/thickness at 12 hours post randomization, AND less than a 7 point increase from baseline NIHSS score at 12 hours post randomization (see Section 11.4.2). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 Hours post randomizarion |
|
E.5.2 | Secondary end point(s) |
• Maximum reduction in anti-fXa activity. • Minimum value of anti-fXa activity post randomization.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
30 days and up to 120 days for patients with positive anti-andexanet antibody response. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 46 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
France |
Germany |
Netherlands |
Spain |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |