In oral FXa inhibitor-treated patients with acute intracerebral 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
• Effective hemostasis 12 hours post-randomization as determined by the blinded
EAC, based on prespecified criteria documented in the Adjudication Charter (see
Appendix B).
Effective hemostasis is defined as:
1 = for patients with hemostatic efficacy rated by the EAC as excellent or
good, and
0 = for patients with hemostatic efficacy rated by the EAC as poor/none.
Secondary outcome
• Percent change from baseline to nadir in anti-fXa activity during the first 2
hours post-randomization.
• Change from baseline in NIHSS at 24 hours post-randomization.
• Change from baseline in GCS score at 24 hours post-randomization.
• Proportion of neurologic deterioration, as defined by NIHSS increase >=4 or
GCS score decrease >= 2 at 24 hours post-randomization versus
baseline
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 intracerebral 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.
To evaluate the effect of andexanet versus usual care on neurologic function.
Additional Efficacy Objectives:
To evaluate the effect of andexanet versus usual care on thrombin generation.
To assess the relationship between anti-fXa activity and the achievement of
hemostatic efficacy.
To evaluate the occurrence and outcome of extracranial bleeding.
To evaluate the effect of andexanet versus usual care on health-related quality
of life.
Safety Objectives:
To evaluate the occurrence of thrombotic events (TEs) at 30 days.
To evaluate in-hospital and 30-day mortality (all-cause, cardiovascular, and
bleeding).
To evaluate the occurrence of invasive intracranial procedures
post-randomization.
To evaluate the length of initial hospitalization for primary bleeding event.
To evaluate the rate of re-hospitalization.
To evaluate adverse events (AEs) 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 intracerebral hemorrhage within 6 hours of
symptom onset (from the baseline scan) and within 15
hours of taking an oral FXa 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 900
patients are planned to be enrolled in the study.
Once the eligibility criteria are confirmed, and baseline assessments are
performed, patients will be randomized 1:1 to receive either
andexanet or usual care stratified by the site*s intended-usual-care-agent
response and also the time from symptomonset to
baseline scan. Randomization must occur within 15 hours following the last dose
of the FXa inhibitor. If a local anti-fXa activity level
obtained within 2 hours prior to consent is > 100 ng/mL (or over the equivalent
IU/mL threshold on a Low-Molecular-Weight Heparin
(LMWH) assay; see Laboratory Manual), the patient may be enrolled, irrespective
of the time of the last dose, and the patient
should receive the high andexanet dosing regimen. The prespecified time periods
and/or anti-fXa activity levels are designed to
ensure patients have sufficiently high anti-fXa activity. Usual care will
consist of any treatment(s) (including no treatment) other than
andexanet administered within 3 hours after randomization 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 to 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. 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, including serious AEs (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 elements: brain Magnetic
Resonance Imaging (MRI) or Computed Tomography
(CT), assessment using the National Institutes of Health Stroke Score (NIHSS)
performed by a person blinded to treatment
allocation (Appendix E), and concomitant medication entry and hospital records
for rescue therapy.
The blinded, independent EAC will oversee the adjudication of hemostatic
efficacy, as well as all deaths and potential TEs. All
source documents will be redacted to maintain the blinding of the EAC. The
independent EAC will be blinded to all anti-fXa activities
and treatment assignments. An independent Data Safety Monitoring Board (DSMB)
will periodically review all safety data in
aggregate, and also conduct an interim analysis after 50% of the anticipated
sample size has been adjudicated. The DSMB will be
empowered to make recommendations regarding study modification or to suggest
stopping the study early for reasons related to
balance of risk and benefit. The DSMB Charter outlines all activities of this
Committee.
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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Age
Inclusion criteria
1. Written informed consent. Either the patient or his or her legally
authorized 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 the study 18-513 and in
accordance with
the Declaration of Helsinki, International Council for Harmonization of
Technical Requirements for Pharmaceuticals for Human Use (ICH), 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 intracranial bleeding episode, defined as an estimated blood
volume >=0.5 mL to <=60 mL acutely observed radiographically within the
cranium. Patients may have extracerebral (e.g., subdural, subarachnoid,
epidural) or extracranial bleeding (e.g., gastrointestinal, intraspinal)
additionally, but the intracebral hemorrhage must be considered the
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
1) the local anti-fXa activity > 100 ng/mL (for direct fXa inhibitors
(apixaban, rivaroxaban or edoxaban); and
2) the local anti-fXa activity level is obtained within 2 hours prior to
consent, performed as per standard 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 repeated 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
women of childbearing potential).
9. NIHSS score <= 35 at the time of consent.
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 haematoma volume are allowed (e.g.,
Burr holes for intracranial pressure monitoring, endoscopy,
ronchoscopy, central lines*see Section 7.2 and 7.3 and Appendix G).
2. Glasgow Coma score (GCS) < 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
nonneurologic
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 A for cardiogenic shock definition).
8. Severe sepsis or septic shock at the time of randomization (see
Appendix A 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.
Design
Recruitment
Medical products/devices used
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
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 | NL75568.018.20 |