Primary Efficacy Objectives:* To demonstrate the decrease in anti-fXa activity following andexanet treatment.* To evaluate the hemostatic efficacy following andexanet treatment.Secondary Efficacy Objective:* To assess the relationship between…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Acute Major Bleeding
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The first primary efficacy endpoint * i.e., percent change in anti-fXa activity
from baseline (last measurement before administration of andexanet) to nadir
(the lowest level measured between 5 minutes prior to the start of andexanet
administration and 10 minutes after the end of the andexanet administration) *
will be calculated for each patient as change = 100 %×(post-baseline)/baseline.
Percent change from baseline in anti-fXa activity will be assessed with
two-sided 95% CIs. A nonparametric CI for the median will be reported. If the
nonparametric CI for the median excludes 0, the first primary objective will be
considered to have been met.
The second primary efficacy endpoint * the proportion of patients who are
adjudicated to have effective hemostasis (excellent or good) by the independent
EAC * will be summarized as a point estimate with an asymptotic 95% confidence
interval.
The primary endpoints, including the specific comparators and the specific
analysis sets for the second primary endpoint, will be ordered in a fixed
sequence multiple comparisons (i.e., hierarchical) fashion.
The assessment of the relationship between effective hemostasis and percent
decrease in anti-fXa activity will use the following validation procedures. An
analysis of Receiver Operator Characteristics (ROC) will be the primary tool
used to assess the relationship. A test of change in anti-fXa activity (percent
change from baseline) in patients who do and do not achieve effective
hemostasis will be used to support the ROC graph.
Secondary outcome
Two other analyses will also be presented:
1) Analysis of *Responders* (patients with a large percent decrease in anti-fXa
activity) anchored to Hemostatic Efficacy.
2) Cumulative Distribution Function (CDF) Analysis.
Counts data will be summarized by observed rates and exact 95% CIs.
In addition, other analyses will be performed, allowing for adjustment of
potentially confounding variables. Variables that may confound evaluation of a
correlation between reversal of anti-fXa activity with effective hemostasis
include anatomical location of bleeding, mechanism of injury (e.g., blunt vs.
penetrating trauma; traumatic vs. spontaneous), severity of injury, severity of
bleeding, presence and timing of interventions to stop bleeding (e.g.,
endoscopic cautery of bleeding ulcers, surgical ligation of bleeding vessel),
and use of coagulation or hemostatic factors.
Further details on the analysis methods for the efficacy endpoints will be
provided in the Statistical Analysis Plan (SAP).
Background summary
FXa inhibitors, represent a new class of anticoagulants that are rapidly
increasing in use. Despite their clinical benefit, however, fXa inhibitors are
associated with bleeding events, some of which are life-threatening or fatal.
Despite the urgent need for such an effective antidote, no such agent currently
exists. Andexanet is being developed as a specific antidote for fXa
inhibitors. Andexanet is a modified fXa protein that has been truncated and
inactivated so that it lacks physiologic blood coagulation factor activity.
Reversal of anticoagulation is achieved because andexanet retains the ability
to bind fXa inhibitor drugs with high affinity, thus preventing them from
binding to and inhibiting native fXa.
Study objective
Primary Efficacy Objectives:
* To demonstrate the decrease in anti-fXa activity following andexanet
treatment.
* To evaluate the hemostatic efficacy following andexanet treatment.
Secondary Efficacy Objective:
* To assess the relationship between decrease in anti-fXa activity and
achievement of hemostatic efficacy in patients receiving a fXa inhibitor who
have acute major bleeding and reduced fXa activity.
Study design
This is a multicenter, prospective, open-label study of andexanet alfa in
patients presenting with acute major bleeding who have recently received one of
the following fXa inhibitors: apixaban, rivaroxaban, edoxaban, or enoxaparin.
Intervention
All patients receive a 15-30 minutes bolus infusion immediately followed by an
infusion during 2 hours. The dosing of both type of infusion is dependent on
the type of anticoagulant they used and the time elapsed between last intake of
anticoagulant and occurrence the bleeding.
Study burden and risks
Of the side effects that have been reported, those most common, which are
thought to be related or possibly related to andexanet, include:
* Infusion reactions
* Abnormal taste during the infusion
* Leg twitching
* Sensation of the heart beating rapidly
* Generalized itching
* Fatigue
Another possible risk that may occur with any drug that reverses blood thinning
is the formation of blood clots. Blood clots can cause strokes, heart attacks,
leg swelling, and difficulty breathing. Several test tube experiments showed
that there is a possibility that andexanet interacts with blood proteins which
then makes the blood easier to clot. No animals or people that have received
andexanet in past studies have developed blood clots.
Andexanet is a protein drug and as such, may cause allergic reactions that
could be mild or severe (anaphylaxis). Anaphylaxis (severe allergy) has not
been seen in any of the 211 subjects that have been treated with andexanet.
Symptoms of allergic reactions might include hives, swelling of the face or
throat, and low blood pressure. Allergic reactions might need medical
treatment with drugs, fluids, or if breathing problems develop, with a plastic
tube to protect your windpipe.
Because andexanet is similar to one of your natural clotting factors, it is
possible that an antibody against andexanet could also recognize your natural
clotting factor and perhaps interfere with normal blood clotting for an unknown
period of time. No people receiving andexanet have developed antibodies
against clotting factors.
East Grand Avenue 270
South San Francisco, CA 94080
US
East Grand Avenue 270
South San Francisco, CA 94080
US
Listed location countries
Age
Inclusion criteria
1) 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) The patient must be at least 18 years old at the time of Screening;
3) The patient must have an acute overt major bleeding episode requiring urgent reversal of
anticoagulation; Acute major bleeding requiring urgent reversal of anticoagulation is defined by at
least ONE of the following:
- Acute overt bleeding that is potentially life-threatening, e.g., with signs or symptoms of
haemodynamic compromise, such as severe
hypotension, poor skin perfusion, mental confusion, low urine output that cannot be otherwise
explained;
- Acute overt bleeding associated with a fall in haemoglobin level by * 2 g/dL, OR a Hgb * 8 g/dL
if no baseline Hgb is available;
- Acute bleeding in a critical area or organ, such as, intra-spinal, pericardial or intracranial.
4) The patient, for whom the bleeding is intracranial or intraspinal must have undergone a CT or
MRI scan demonstrating the bleeding.
5) The patient received or is believed to have received one of the following within 18 hours prior
to andexanet administration: apixaban, rivaroxaban, edoxaban or enoxaparin (dose of enoxaparin
*1mg/kg/d).
6) For patients with ICH, there must be a reasonable expectation that andexanet treatment will
commence within 2 hours of the baseline
imaging evaluation.
Exclusion criteria
1) The patient is scheduled to undergo surgery in less than 12 hours
with the exception of minimally invasive surgery/procedures (e.g.,
endoscopy, bronchoscopy, central lines, Burr holes);
2) A patient with ICH has any of the following:
* Glasgow coma score < 7
* Estimated intracerebral haematoma volume >60 cc as assessed by the
CT or MRI.
3) Patients with visible, musculoskeletal, or intra-articular bleeding as
the qualifying bleed.
4) The patient has an expected survival of less than 1 month;
5) The patient has a recent history (within 2 weeks) of a diagnosed
thrombotic event (TE) as follows: 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,
unstable angina pectoris hospitalization, or severe peripheral vascular
disease within 2 weeks prior to Screening;
6) The patient has severe sepsis or septic shock at the time of Screening;
7) The patient is pregnant or a lactating female;
8) The patient has received any of the following drugs or blood products
within 7 days or Screening:
* Vitamin K antagonist (VKA) (e.g., warfarin);
* Dabigatran;
* Prothrombin Complex Concentrate products (PCC, e.g., Kcentra®) or
recombinant factor VIIa (rfVIIa) (e.g., NovoSeven®);
* Whole blood, plasma fractions
Note: Administration of platelets or packed red blood cells (PRBCs) is not
an exclusion criterion;
9) The patient was treated with an investigational drug <30 days prior
to Screening.
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 | EUCTR2015-001785-26-NL |
| ClinicalTrials.gov | NCT02329327 |
| CCMO | NL53914.018.15 |