In oral FXa inhibitor-treated patients with acute intracranial bleeding, the objectives of this study are as follows:Primary Efficacy Objective:• To evaluate the effect of andexanet versus usual care on the rate of effective hemostasis.Secondary…
ID
Source
Brief title
Condition
- Central nervous system vascular disorders
- Vascular haemorrhagic disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Endpoint
• 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
Secondary outcome
Secondary Efficacy Endpoints
• Maximum reduction in anti-fXa activity.
• Minimum value of anti-fXa activity post randomization.
Background summary
Andexxa® (andexanet) has been approved for use in the United States as a
reversal agent for patients who have taken the blood thinning drugs,
rivaroxaban or apixaban and who are experiencing a serious or life-threatening
bleeding episode. Andexanet is only conditionally (or provisionally) approved,
which means it has not been fully demonstrated that andexanet actually helps to
stop bleeding. This study is intended to determine whether andexanet is more
effective than usual care to stop bleeding in this setting.
Andexanet is not approved in other regions, such as the European Union or
Canada, but is available for use in clinical research studies. In all regions,
andexanet is considered an experimental drug for patients who are taking the
blood thinner edoxaban (also known as Savaysa® or Lixiana®) and who are
experiencing a serious or life-threatening bleeding episode.
Andexanet was specifically made for Factor Xa inhibitors. Andexanet is a
recombinant, modified human protein and inactive form of factor Xa, a protein
in the blood that plays a key role in normal blood clotting. Andexanet works by
binding to the blood thinner drug so the blood thinner drug is no longer able
to interfere with the blood clotting process.
Andexanet has been studied in animals, in approximately 416 healthy volunteers,
most of whom have been treated with andexanet after receiving a blood thinner
drug, and in 185 patients who have experienced a serious or life-threatening
bleed while taking a Factor Xa blood thinner drug.
Study objective
In oral FXa inhibitor-treated patients with acute intracranial bleeding, the
objectives of this study are as follows:
Primary Efficacy Objective:
• To evaluate the effect of andexanet versus usual care on the rate of
effective hemostasis.
Secondary Efficacy Objective:
• To evaluate the effect of andexanet versus usual care on anti fXa activity.
Additional Efficacy Objectives:
• To evaluate the effect of andexanet versus usual care on thrombin generation.
• To evaluate the effect of andexanet versus usual care on clinical and
functional neurologic status.
• To assess the relationship between anti-fXa activity and the achievement of
hemostatic efficacy.
Safety Objectives:
• To evaluate the occurrence of thrombotic events at 30 days.
• To evaluate in-hospital and 30-day mortality (all-cause, cardiovascular, and
bleeding).
• To evaluate the length of initial hospitalization for primary bleeding event.
• To evaluate the rate of re-hospitalization.
• To evaluate adverse events and vital signs.
• To evaluate the immunogenicity of andexanet.
Study design
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 12 hours of symptom onset (from the
baseline scan) and within 15 hours of taking an oral factor Xa inhibitor (from
randomization). The study will use a prospective, randomized, open label
design, as it is unfeasible to blind the Investigator to the treatment
assignment given the many potential therapeutic options available under usual
care treatment. The primary efficacy outcome will be adjudicated by a blinded
Endpoint Adjudication Committee (EAC). To support the adjudication of
hemostatic efficacy, a blinded Imaging Core Laboratory will review all
available scans. Approximately 440 patients are planned to be enrolled in the
study.
Once the Informed Consent Form (ICF) is signed and eligibility is confirmed,
patients will be randomized to receive either andexanet or usual care.
Randomization must occur within 15 hours following the last dose of the FXa
inhibitor. If the time from last dose of FXa inhibitor is unknown, the patient
is not eligible. If a local anti-fXa activity level obtained within 2 hours
prior to consent is > 100 ng/mL, the patient may be enrolled, irrespective of
the time of the last dose (as long as it is known). The prespecified time
periods and/or anti-fXa activity levels are designed to ensure patients have
therapeutic anti-fXa activity levels. Usual care will consist of any
treatment(s) (including no treatment) other than andexanet that the
Investigator and/or other treating physicians consider to be appropriate. For
andexanet treatment, patients will receive one of two dosing regimens of
andexanet based on which FXa inhibitor they received and the amount and timing
of the most recent dose. Andexanet will be given via an intravenous (IV) bolus
administered over ~15-30 minutes followed immediately by a continuous infusion
administered over ~120 minutes. There will be no cross-over between treatment
groups.
It is intended that all patients initiate treatment as soon as possible after
the treatment allocation is known (this will necessitate preparation of
andexanet for all patients prior to randomization, with wastage of andexanet
product for those randomized to usual care). For: 1) anti-fXa activity; and
2) diagnostic evaluations to support hemostatic efficacy (i.e., imaging tests),
baseline is defined as the most recent assessment within 15 minutes and 120
minutes prior to randomization, respectively. For post-baseline efficacy
assessments, time 0 is defined as randomization.
Adverse Events (AEs), including SAEs and survival will be followed through the
Day 30 post-treatment visit for all patients. The study Schedule of Activities
can be found in Appendix A.
The primary efficacy endpoint will be adjudicated based on data collected
through 12 hours post randomization. The following data are planned to be
captured: imaging and clinical modalities: brain Magnetic Resonance Imaging
(MRI) or Computed Tomography (CT), and assessment using the National Institutes
of Health Stroke Score (NIHSS) performed by a person blinded to treatment
allocation (Appendix E).
The blinded, independent EAC will adjudicate hemostatic efficacy, as well as
all deaths and potential thrombotic events. All source documents will be
redacted to maintain the blinding of the EAC. The independent EAC will be
blinded to all anti-fXa levels and treatment assignments. An independent Data
Safety Monitoring Board (DSMB) will periodically review all safety data in
aggregate. In addition, an interim efficacy analysis will be conducted when
50% of the patient population has been adjudicated. Based on the above, DSMB
will be empowered to recommend alterations or stoppage of the study if
warranted.
Intervention
Andexanet will be administered as an IV bolus, immediately followed by a
continuous infusion. There are two possible dosing regimens:
Dose Initial IV Bolus
* Follow-on IV Infusion *
Low 400 mg at a target rate of 30 mg/min for ~15
minutes 480 mg at a target rate of 4 mg/min for 120 minutes
High 800 mg at a target rate of 30 mg/min for up to ~30 minutes 960
mg at a target rate of 8 mg/min for 120 minutes
Study burden and risks
Not applicable
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Listed location countries
Age
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.
In the Netherlands, deferred consent procedure is allowed. 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 for 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,
ICH-GCP, the
Data Protection Directive (Directive 95/46/EC) and national and local
regulations.
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.
Exclusion criteria
If a patient meets any of the following criteria, he/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 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-002620-17-NL |
| ClinicalTrials.gov | NCT03661528 |
| CCMO | NL69515.018.19 |